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Background: Behavioral and psychological symptoms of dementia (BPSD) are common among people with dementia from the early stages and can appear even in mild cognitive impairment (MCI). However, the prognostic impact of BPSD is unclear. This study examined the association between BPSD and mortality among people with cognitive impairment. Methods: This longitudinal study involved 1,065 males and 1,681 females (mean age: 77.1 years for males and 78.6 years for females) with MCI or dementia diagnosis from the National Center for Geriatrics and Gerontology-Life Stories of People with Dementia (NCGG-STORIES), a single-center memory clinic-based cohort study in Japan that registered first-time outpatients from 2010–2018. Information about death was collected through a mail survey returned by participants or their close relatives, with an up to 8-year follow-up. BPSD was assessed using the Dementia Behavior Disturbance Scale (DBD) at baseline. Results: During the follow-up period, 229 (28.1%) male and 254 (15.1%) female deaths occurred. Cox proportional hazards regression analysis showed that higher DBD scores were significantly associated with increased mortality risk among males, but not females (compared with the lowest quartile score group, hazard ratios for the highest quartile score group were 1.59; 95% confidence interval, [CI] 1.11–2.29 for males and 1.06; 95% CI, 0.66–1.70 for females). Among the DBD items, lack of interest in daily living, excessive daytime sleep, and refusal to receive care had a higher mortality risk. Conclusion: The findings suggest a potential association between BPSD and poor prognosis among males with cognitive impairment.

Abstract The type 1 ryanodine receptor (RyR1) is a Ca2+ release channel in the sarcoplasmic reticulum that is essential for skeletal muscle contraction. RyR1 forms a channel with six transmembrane segments, in which S5 is the fifth segment and is thought to contribute to pore formation. However, its role in channel gating remains unclear. Here, we performed a functional analysis of several disease-associated mutations in S5 and interpreted the results with respect to the published RyR1 structures to identify potential interactions associated with the mutant phenotypes. We demonstrate that S5 plays a dual role in channel gating: the cytoplasmic side interacts with S6 to reduce the channel activity, whereas the luminal side forms a rigid structural base necessary for S6 displacement in channel opening. These results deepen our understanding of the molecular mechanisms of RyR1 channel gating and provide insight into the divergent disease phenotypes caused by mutations in S5.

Abstract Aims/Introduction This study aimed to characterize the global cognition and executive functions of older adults with type 1 diabetes mellitus in comparison with type 2 diabetes mellitus. Materials and Methods This study included 37 patients with type 1 diabetes mellitus aged ≥65 years and 37 age‐ and sex‐matched patients with type 2 diabetes mellitus. Patients with dementia scoring

Abstract Previous studies have demonstrated associations between enlarged perivascular spaces (EPVS) and dementias such as Alzheimer’s disease. However, an association between EPVS and dementia with Lewy bodies (DLB) has not yet been clarified. We performed a cross-sectional analysis of our prospective study cohort of 109 participants (16 with DLB). We assessed cognitive function, pulse wave velocity (PWV), and brain magnetic resonance imaging features. The relationships between EPVS and DLB were evaluated using multivariable logistic regression analyses. Compared with the non-dementia group, the DLB group was more likely to have EPVS in the basal ganglia. Compared with participants without EPVS, those with EPVS were older and had cognitive impairment and high PWV. In multivariable analyses, EPVS in the basal ganglia was independently associated with DLB. High PWV was also independently associated with EPVS in both the basal ganglia and centrum semiovale. High PWV may cause cerebrovascular pulsatility, leading to accelerated EPVS in DLB participants.

ABSTRACT Objective The incidence rates of dementia, mild cognitive impairment, and cancer increase with age, posing challenges to affected individuals and their families. However, there are currently no clear cancer screening guidelines for individuals with cognitive impairment. This study analyzed the impact of carer health literacy on screening behaviors in this population. Methods We conducted a postal follow‐up survey, associated with the National Center for Geriatrics and Gerontology—Life STORIES of People with Dementia, that targeted primary carers to assess their reports regarding patient attendance at regular cancer screenings recommended by the Japanese Ministry of Health, Labor and Welfare, over the preceding 2 years. Screening rates were compared between the memory clinic cohort and the national average, and the influence of carer health literacy level on screening was analyzed. Results Among the 826 total individuals analyzed, the memory clinic cohort exhibited lower breast cancer screening rates, at 11% among female patients aged 65–74 years versus the national average of 32%. Higher health literacy among carers was significantly associated with increased screening. For female patients, carers with high levels of communicative health literacy were more likely to ensure that patients attended screenings for gastric (adjusted odds ratio [AOR], 1.77; 95% confidence interval [CI], 1.03–3.04), colorectal (AOR, 1.70, 95% CI 1.08–2.70), and breast cancers (AOR, 3.08; 95% CI, 1.40–6.76). Among the male patients, high communicative health literacy was associated with increased lung cancer screening attendance (AOR, 1.82; 95% CI, 1.11–2.99). Conclusions Our research highlights a notable gap in cancer screening attendance between individuals with cognitive impairment and the general population, potentially arising from the intricate nature of screening procedures and the extensive burden on carers. More informed decisions and increased screening rates can be achieved through patient‐centric communication strategies that accommodate the cognitive abilities of patients, ensuring the comprehensibility and accessibility of health‐related information.

Background: Positron emission tomography, which assesses the binding of translocator protein radiotracers, 11C-DPA-713, may be a sensitive method for determining glial-mediated neuroinflammation levels. This study investigated the relationship between regional 11C-DPA713 binding potential (BPND) and anxiety in patients with Alzheimer's disease (AD) continuum. Methods: Nineteen patients with AD continuum determined to be amyloid-/p-tau 181-positive via cerebrospinal fluid analysis were included in this cross-sectional study (mild cognitive impairment [MCI, n = 5] and AD [n = 14]). Anxiety was evaluated using the State-Trait Anxiety Inventory (STAI). A whole-brain voxel-based analysis was performed to examine the relationship between 11C-DPA-713-BPND values at each voxel and the STAI score. Stepwise multiple regression analysis was performed to determine the predictors of STAI scores using independent variables, including 11C-DPA-713-BPND values within significant clusters. 11C-DPA-713-BPND values were compared between patients with AD continuum with low-to-moderate and high STAI scores. Results: Voxel-based analysis revealed a positive correlation between trait anxiety severity and 11C-DPA713-BPND values in the centromedial amygdala and the left inferior occipital area [P

Objectives: This study aimed to investigate the association between abdominal adiposity and change in cognitive function in community-dwelling older adults. Design, Setting, and Participants: This longitudinal study included older adults aged ≥60 years without cognitive impairment who participated in the National Institute for Longevity Sciences – Longitudinal Study of Aging. Measurements: Cognitive function was evaluated biennially using the Mini-Mental State Examination (MMSE) over 10 years. Waist circumference (WC) was measured at the naval level, and subcutaneous fat area (SFA) and visceral fat area (VFA) were assessed using baseline computed tomography scans. WC, SFA, and VFA areas were stratified into sex-adjusted tertiles. A linear mixed model was applied separately for men and women. Results: This study included 873 older adults. In men, the groups with the highest levels of WC, SFA, and VFA exhibited a greater decline in MMSE score than the groups with the lowest levels (β [95% confidence interval]: WC, –0.12 [–0.23 to –0.01]; SFA, –0.13 [–0.24 to –0.02]; VFA, –0.11 [–0.22 to –0.01]). In women, the group with the highest level of WC and SFA showed a greater decline in MMSE score than the group with the lowest level (WC, –0.12 [–0.25 to –0.01]; SFA, –0.18 [–0.30 to –0.06]), but VFA was not associated with cognitive decline. Conclusion: Higher WC, SFA, and VFA in men and higher WC and SFA in women were identified as risk factors for cognitive decline in later life, suggesting that abdominal adiposity involved in cognitive decline may differ according to sex.

The link between changes in astrocyte function and the pathological progression of Alzheimer's disease (AD) has attracted considerable attention. Interestingly, activated astrocytes in AD show abnormalities in their lipid content and metabolism. In particular, the expression of apolipoprotein E (ApoE), a lipid transporter, is decreased. Because ApoE has anti-inflammatory and amyloid β (Aβ)-metabolizing effects, the nuclear receptors, retinoid X receptor (RXR) and LXR, which are involved in ApoE expression, are considered promising therapeutic targets for AD. However, the therapeutic effects of agents targeting these receptors are limited or vary considerably among groups, indicating the involvement of an unknown pathological factor that modifies astrocyte and ApoE function. Here, we focused on the signaling lipid, sphingosine-1-phosphate (S1P), which is mainly produced by sphingosine kinase 2 (SphK2) in the brain. Using astrocyte models, we found that upregulation of SphK2/S1P signaling suppressed ApoE induction by both RXR and LXR agonists. We also found that SphK2 activation reduced RXR binding to the APOE promoter region in the nucleus, suggesting the nuclear function of SphK2/S1P. Intriguingly, suppression of SphK2 activity by RNA knockdown or specific inhibitors upregulated lipidated ApoE induction. Furthermore, the induced ApoE facilitates Aβ uptake in astrocytes. Together with our previous findings that SphK2 activity is upregulated in AD brain and promotes Aβ production in neurons, these results indicate that SphK2/S1P signaling is a promising multifunctional therapeutic target for AD that can modulate astrocyte function by stabilizing the effects of RXR and LXR agonists, and simultaneously regulate neuronal pathogenesis.

Abstract Background Multi-domain interventions effectively prevent dementia in clinical settings; however, their efficacy within local communities is unclear. This study assesses the feasibility of an adapted multi-domain intervention for dementia prevention in community-dwelling older adults. Methods The single-arm trial enrolls 60 participants from two Obu City communities, Japan. Primary outcome: participant retention in the adapted multi-domain intervention; secondary outcomes: health and implementation outcomes. Over 12 months, a team of researchers and public health nurse oversees the study in the first half, gradually shifting the management to public health nurses in the second half. Using the Framework for Reporting Adaptations and Modifications-Enhanced, the clinical programme is adjusted for the local community. It includes a 60-minute exercise and 30-minute group sessions, targeting lifestyle, diet, and social participation. Discussion This pioneer study evaluates the feasibility of an adapted intervention programme for dementia prevention in a community setting. Challenges in disseminating dementia prevention programmes warrant further investigation into effective implementation as well as strategies and methods to appeal to the target population. Upon confirming this programme’s feasibility, future studies can further evaluate its broader effectiveness. Trial registration The protocol is registered with the Clinical Trials Registry (UMIN-CTR) of the University Hospital’s Medical Information Network, under registration number UMIN000050581.

Abstract Aim This study aimed to develop a patient‐centred handbook that integrates information on lifestyle modifications and psychological support strategies for individuals with mild cognitive impairment (MCI). This article provides a comprehensive record of the development process. Methods We adopted a participatory research model for the methodology, which comprised five phases and involved an interdisciplinary team specializing in dementia and health literacy. Data were initially collected via interviews conducted among patients with MCI (n = 5) and their families (n = 5). Given the study's preliminary nature, depth and richness of the qualitative data were the key concerns for determining the sample size, rather than broad generalizability. We ensured the inclusion of diverse experiences and perspectives by facilitating the creation of patient questions (PQs) that merged scientific evidence with patient perspectives. To enhance the handbook's accessibility and utility, we continuously evaluated the same using patient interviews, health literacy tool assessments and team discussions. This comprehensive approach harmonized scientific knowledge and patient experience, leading to the development of a personalized MCI management guide. Results The handbook comprises nine domains, encompassing 38 selected PQs: MCI, lifestyle, lifestyle‐related diseases, exercise, nutrition, social participation, cognitive training, psychological care and family support. The health literacy handbook was evaluated based on Clear Communication Index scores. The results revealed that 73.7% of the PQs were deemed difficult prerevision, whereas only 5.3% remained challenging postrevision. The formative evaluation underscored the need for more detailed explanations prerevision, whereas postrevision comments focused primarily on editorial suggestions. Conclusion The inclusion of patients' perspectives right from the outset ensured that the handbook met their specific needs. The final version, which reflects all stakeholders' inputs, is now slated for imminent publication. Patient or Public Contribution Patients and the public participated extensively throughout the project, from initial interviews to material evaluation and refinement.

Abstract Introduction Histiocytic sarcoma (HS) is a rare hematologic malignancy. HS of the breast is extremely rare, and we present a case of an elderly patient with breast HS. Case presentation An 81-year-old woman with unremarkable past medical and family histories presented to our hospital with a palpable mass in her right upper breast. She had noticed a mass in her right breast 3 months before her first visit. Physical examination revealed a mass measuring approximately 30 mm in the right upper quadrant of the breast; there were no cervical or axillary lymphadenopathies. Mammography revealed a high-concentration mass with unclear margins in the upper and outer breast. Ultrasound and magnetic resonance imaging (MRI) revealed a 31 × 23-mm nodule with a relatively clear margin and necrotic sign on the T2-intensified image. A mastectomy was performed upon the patient’s request, and the surgical specimen revealed a 35-mm hemorrhagic mass. The lesion was estrogen receptor-, progesterone receptor-, and HER2/neu-negative. The Ki-67 labeling index was approximately 30%. The immunohistochemical panel showed immune reactivity for the histiocytic markers CD68, CD163, and CD206 and was immune-negative for B lineage, T lineage, Langerhans cells, and keratins. The diagnosis of HS was based on the morphological and immunophenotypic characteristics of the mass. The patient received no systemic therapy and survived for 50 months without recurrence. Conclusions Here, we report the case of an elderly patient with rare breast HS. Although the prognosis of HS seems poor, the breast HS was not as poor as expected, since it might have been discovered in the local region before it metastasized.

Abstract Given its limited accessibility, the CA2 area has been less investigated compared to other subregions of the hippocampus. While the development of transgenic mice expressing Cre recombinase in the CA2 has revealed unique features of this area, the use of mouse lines has several limitations, such as lack of specificity. Therefore, a specific gene delivery system is required. Here, we confirmed that the AAV-PHP.eB capsid preferably infected CA2 pyramidal cells following retro-orbital injection and demonstrated that the specificity was substantially higher after injection into the lateral ventricle. In addition, a tropism for the CA2 area was observed in organotypic slice cultures. Combined injection into the lateral ventricle and stereotaxic injection into the CA2 area specifically introduced the transgene into CA2 pyramidal cells, enabling us to perform targeted patch-clamp recordings and optogenetic manipulation. These results suggest that AAV-PHP.eB is a versatile tool for specific gene transduction in CA2 pyramidal cells.

The paper studies the soft X-ray data of solar flares and found that the distribution functions of flare fluence are successfully modeled by tapered power law or gamma function distributions whose power exponent is slightly smaller than 2, indicating that the total energy of the flare populations is mostly due to a small number of large flares. The largest possible solar flares in 1000 years are predicted to be around X70 (a peak flux of 70 × 10−4 W m−2) in terms of the GOES (Geostationary Operational Environmental Satellites) flare class. The paper also studies superflares (more energetic than solar flares) from solar-type stars and found that their power exponent in the fitting of the gamma function distribution is around 1.05, which is much flatter than solar flares. The distribution function of stellar flare energy extrapolated downward does not connect to the distribution function of solar flare energy.

ABSTRACT Aims/Introduction To investigate the changes in the glycated hemoglobin (HbA1c) levels and the relative status of the glycemic control related to the new glycemic targets recommended by the Japan Diabetes Society/Japan Geriatrics Society Joint Committee in 2016 in patients with diabetes mellitus visiting a memory clinic from 2012 to 2020. Materials and Methods This cross‐sectional study included 1,436 patients aged ≥65 years with diabetes. Patients were categorized into three categories as follows: category I, intact cognitive function and activities of daily living (ADL); category II, mild cognitive deficits or impaired instrumental ADL; and category III, moderate to severe cognitive impairment or impaired basic ADL. Trends in HbA1c levels, glycemic control status (optimally/poorly/excessively controlled) and proportion of individuals receiving drugs potentially associated with severe hypoglycemia among all patients and categories (I, II or III) from 2012 to 2020 were examined using linear, logistic and multinominal logistic regression models adjusted for confounding factors. Results Between 2012 and 2020, the HbA1c levels, as well as the proportion of patients with poor glycemic control, increased, whereas the proportion of patients with excessive glycemic control and those receiving drugs potentially associated with severe hypoglycemia decreased. Conclusions Increased levels of HbA1c and decreased proportions of individuals under excessive glycemic control might reflect recent treatment strategies that avoid hypoglycemia in older patients. Given the adverse complications associated with hyperglycemia, more flexible and individualized glycemic targets based on comprehensive assessments, including vascular complications and comorbidities, might be necessary.

IntroductionPsychological resilience is an indicator of mental health, but there has been no research to date on changes in psychological resilience among older adults with mild cognitive impairment (MCI) during the stress of the coronavirus disease 2019 (COVID-19) pandemic including factors related to those changes. To fill the gap, this study examined the factors and the changes in psychological resilience of older adults with MCI during the COVID-19 pandemic.MethodsOne hundred thirty participants completed the 10-item version of the Connor-Davidson Resilience Scale (CD-RISC-10) between December 2020 and June 2021 as a baseline assessment and between December 2021 and February 2022 as a follow-up. Participants also answered questions on sleep quality, depression symptoms, activities in daily living (ADL), instrumental ADL and social participation to explore factors associated with changes.ResultsIn this cohort, the mean CD-RISC-10 scores were significantly higher than the baseline at follow-up (p < 0.05), indicating the improvement of psychological resilience. In multiple regression analyses, sleep quality was significantly correlated with change in CD-RISC-10 score (coefficient = 3.94, 95% confidence interval = 1.11 to 6.78).DiscussionPsychological resilience could improve even during the stress of the COVID-19 pandemic in older adults with MCI who were at risk of developing dementia. The factor associated with improved psychological resilience was good sleep quality.

This observational pilot study aimed to investigate continuous glucose monitoring (CGM) metrics in older Japanese patients with type 2 diabetes mellitus (T2DM) using a CGM system (FreeStyle Libre Pro) during the first tirzepatide administration and compare the glycemic control measures before and after the initial injection. The four patients had a mean age of 79.5 years (standard deviation [SD]: 5.8), a mean body mass index of 24.6 kg/m2 (SD: 4.7), a mean glycated hemoglobin level of 9.1% (SD: 2.1), and a mean measurement period of 10.5 days (SD: 3.5). After the inclusion of tirzepatide treatment, the mean of time in range, time above range, and time below range changed from 53.2% to 78.9% (p = 0.041), 45.8% to 19.7% (p = 0.038), and 1.0% to 1.5% (p = 0.206), respectively. Improved hyperglycemia reduced the oral hypoglycemic medication in two cases and decreased the frequency of insulin injections in two cases. To elucidate the potential benefits of tirzepatide, future studies should investigate the long-term impact on functional prognosis, safety, and tolerability and distinguish between the use of other weekly agonists, especially in nonobese older Asian patients. However, tirzepatide-associated robust glycemic improvement may simplify diabetes treatment regimens in older patients with T2DM.

Ryanodine receptor 2 (RyR2) is a Ca2+ release channel essential for cardiac excitation-contraction coupling. Here, the authors use structural and functional analysis to reveal RyR2 gating mechanism and its alterations by pathogenic mutations.

Alzheimer’s disease (AD) is a progressive neurodegenerative brain disorder and the most common cause of dementia in the elderly. The presence of large numbers of senile plaques, neurofibrillary tangles, and cerebral atrophy is the characteristic feature of AD. Amyloid β peptide (Aβ), derived from the amyloid precursor protein (APP), is the main component of senile plaques. AD has been extensively studied using methods involving cell lines, primary cultures of neural cells, and animal models; however, discrepancies have been observed between these methods. Dissociated cultures lose the brain’s tissue architecture, including neural circuits, glial cells, and extracellular matrix. Experiments with animal models are lengthy and require laborious monitoring of multiple parameters. Therefore, it is necessary to combine these experimental models to understand the pathology of AD. An experimental platform amenable to continuous observation and experimental manipulation is required to analyze long-term neuronal development, plasticity, and progressive neurodegenerative diseases. In the current study, we provide a practical method to slice and cultivate rodent hippocampus to investigate the cleavage of APP and secretion of Aβ in an ex vivo model. Furthermore, we provide basic information on Aβ secretion using slice cultures. Using our optimized method, dozens to hundreds of long-term stable slice cultures can be coordinated simultaneously. Our findings are valuable for analyses of AD mouse models and senile plaque formation culture models.

Abstract Background Gait disturbance and musculoskeletal changes are evident in persons living with Alzheimer's disease (AD). Because complex gait control requires the integration of neural networks, cerebral small vessel disease (SVD), which is highly prevalent in persons with AD, might have an additional impact on gait disturbance. This study investigated whether white matter hyperintensities (WMH) are more predominantly associated with gait disturbance in persons with AD than in individuals with mild cognitive impairment (MCI) and normal cognition (NC) and further identified the regional impact of WMH on specific gait changes. Methods This study included 396 subjects (aged 65 to 86 years, 63.9% female) diagnosed with AD (n = 187), MCI (n = 118), or NC (n = 91). WMH, lacunes, perivascular spaces, and cerebral microbleeds were assessed as markers of SVD. The volume of WMH was quantified in each brain lobe (frontal, temporal, occipital, and parietal) and sublobar regions in the basal ganglia and thalamus. Gait function was assessed using an electronic walkway. We investigated the association between regional WMH and gait disturbance in individuals with AD, MCI, and NC, adjusted for classical and musculoskeletal confounders. Results Among markers of SVD, WMH were most associated with gait disturbance. In AD subjects, periventricular WMH in the frontal and parietal lobes were associated with slow gait speed (rs = −0.21, P = 0.007 and rs = −0.18, P = 0.019, respectively). These lesions were also associated with changes in stride time, double‐leg support time, and walking angle (all rs > 0.20, P

Background: Neuroinflammation is a well-known feature of Alzheimer’s disease (AD), and a blood-based test for estimating the levels of neuroinflammation would be expected. In this study, we examined and validated a model using blood-based biomarkers to predict the level of glial activation due to neuroinflammation, as estimated by 11C-DPA-713 positron emission tomography (PET) imaging. Methods: We included 15 patients with AD and 10 cognitively normal (CN) subjects. Stepwise backward deletion multiple regression analysis was used to determine the predictors of the TSPO-binding potential (BPND) estimated by PET imaging. The independent variables were age, sex, diagnosis, apolipoprotein E4 positivity, body mass index and the serum concentration of blood-based biomarkers, including monocyte chemotactic protein 1 (MCP-1), fractalkine, chitinase 3-like protein-1 (CHI3L1), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and clusterin. Results: Sex, diagnosis, and serum concentrations of MCP1 and sTREM2 were determined as predictors of TSPO-BPND in the Braak1-3 area. The serum concentrations of MCP1 and sTREM2 correlated positively with TSPO-BPND. In a leave one out (LOO) cross-validation (CV) analysis, the model gave a LOO CV R2 of 0.424, which indicated that this model can account for approximately 42.4% of the variance of brain TSPO-BPND. Conclusions: We found that the model including serum MCP-1 and sTREM2 concentration and covariates of sex and diagnosis was the best for predicting brain TSPO-BPND. The detection of neuroinflammation in AD patients by blood-based biomarkers should be a sensitive and useful tool for making an early diagnosis and monitoring disease progression and treatment effectiveness.

Abstract There are many subtypes of dementia, and identification of diagnostic biomarkers that are minimally-invasive, low-cost, and efficient is desired. Circulating microRNAs (miRNAs) have recently gained attention as easily accessible and non-invasive biomarkers. We conducted a comprehensive miRNA expression analysis of serum samples from 1348 Japanese dementia patients, composed of four subtypes—Alzheimer’s disease (AD), vascular dementia, dementia with Lewy bodies (DLB), and normal pressure hydrocephalus—and 246 control subjects. We used this data to construct dementia subtype prediction models based on penalized regression models with the multiclass classification. We constructed a final prediction model using 46 miRNAs, which classified dementia patients from an independent validation set into four subtypes of dementia. Network analysis of miRNA target genes revealed important hub genes, SRC and CHD3, associated with the AD pathogenesis. Moreover, MCU and CASP3, which are known to be associated with DLB pathogenesis, were identified from our DLB-specific target genes. Our study demonstrates the potential of blood-based biomarkers for use in dementia-subtype prediction models. We believe that further investigation using larger sample sizes will contribute to the accurate classification of subtypes of dementia.

Breast angiosarcoma is an extremely rare malignant tumor with poor prognosis. An older woman who had undergone bilateral breast augmentation approximately 30 years ago visited our outpatient clinic complaining of a right breast mass. A soft, elastic mass with good mobility was observed in the right breast. A surgical resection was performed following a core needle biopsy that revealed pathological features of angiosarcoma. The patient had a good postoperative course and has remained recurrence-free for 4 years. However, since very few reports on the association between implants and breast angiosarcoma are available, further studies assessing this relationship are warranted.

Hybrid rockets are safe and inexpensive; however, boundary-layer combustion poses a problem in achieving a fuel regression rate equivalent to that of solid propellants. The fundamental combustion conditions, such as the fuel regression rate of LT421, a paraffin-based low-melting-point thermoplastic fuel, were investigated using a swirling-flow combustion method. Firing tests were conducted using the oxygen mass flow rate and burn time parameters. The LT fuel exhibited an ignition delay compared to polypropylene, and the pressure increased slowly relative to the thrust. The combustion pressure increased or remained constant with time, suggesting that the fuel regression rate was more dependent on the oxygen mass flow rate than the oxidizer mass flux. The shear force generated in the grain owing to the swirling flow caused fuel-grain separation when the oxygen mass flow rate exceeded 100 g/s. Fuel-grain separation was prevented by modifying the case geometry. The maximum fuel regression rate obtained in the tests was 4.88 mm/s at an oxygen mass flow rate of 190 g/s and mass flux of 72.4 kg/(m2s), which was four times higher than that of polypropylene at the same oxidizer mass flux. The fuel regression rate correlation was obtained using the oxygen mass-flow-rate-based parameter, although further modification was necessary to apply this correlation when the burning time was varied.

Abstract Although solar activity may significantly impact the global environment and socioeconomic systems, the mechanisms for solar eruptions and the subsequent processes have not yet been fully understood. Thus, modern society supported by advanced information systems is at risk from severe space weather disturbances. Project for solar–terrestrial environment prediction (PSTEP) was launched to improve this situation through synergy between basic science research and operational forecast. The PSTEP is a nationwide research collaboration in Japan and was conducted from April 2015 to March 2020, supported by a Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology of Japan. By this project, we sought to answer the fundamental questions concerning the solar–terrestrial environment and aimed to build a next-generation space weather forecast system to prepare for severe space weather disasters. The PSTEP consists of four research groups and proposal-based research units. It has made a significant progress in space weather research and operational forecasts, publishing over 500 refereed journal papers and organizing four international symposiums, various workshops and seminars, and summer school for graduate students at Rikubetsu in 2017. This paper is a summary report of the PSTEP and describes the major research achievements it produced.

Mutations in ryanodine receptor 1 (RyR1), a Ca2+ release channel in skeletal muscle, cause malignant hyperthermia (MH) and are involved in heat stroke. Here, the authors show that an oxolinic acid-derivative RyR1 inhibitor effectively prevents and treats MH and heat stroke in various MH mouse models.

Background The AT(N) classification was proposed for categorising individuals according to biomarkers. However, AT(N) profiles may vary depending on the markers chosen and the target population.Methods We stratified 177 individuals who participated in the Japanese Alzheimer’s Disease Neuroimaging Initiative by AT(N) classification according to cerebrospinal fluid (CSF) biomarkers. We compared the frequency of AT(N) profiles between the classification using total tau and neurofilament light chain (NfL) as N markers (AT(N)tau and AT(N)NfL). Baseline characteristics, and longitudinal biological and clinical changes were examined between AT(N) profiles.Results We found that 9% of cognitively unimpaired subjects, 49% of subjects with mild cognitive impairment, and 61% of patients with Alzheimer’s disease (AD) dementia had the biological AD profile (ie, A+T+) in the cohort. The frequency of AT(N) profiles substantially differed between the AT(N)tau and AT(N)NfL classifications. When we used t-tau as the N marker (AT(N)tau), those who had T− were more frequently assigned to (N)−, whereas those who had T+were more frequently assigned to (N)+ than when we used NfL as the N marker (AT(N)NfL). During a follow-up, the AD continuum group progressed clinically and biologically compared with the normal biomarker group in both the AT(N)tau and AT(N)NfL classifications. More frequent conversion to dementia was observed in the non-AD pathological change group in the AT(N)tau classification, but not in the AT(N)NfL classification.Conclusions AT(N)tau and AT(N)NfL in CSF may capture different aspects of neurodegeneration and provide a different prognostic value. The AT(N) classification aids in understanding the AD continuum biology in various populations.

Psychological resilience refers to the ability to cope with adversities, and deficits in resilience might lead to mental illness. The COVID-19 pandemic has had impact on psychological resilience for older adults, but there are as yet no data on its impacts on the mental health of older adults who were living with mild cognitive impairment (MCI). Therefore, the aim of this study was to investigate the impact of the COVID-19 pandemic on psychological resilience in older adults with MCI and to explore associated physical and psychosocial factors. In this cross-sectional study of 268 older adults aged 65–85, we defined MCI as age- and education-adjusted cognitive decline with a standard deviation of 1.0 or more from the reference threshold. During December 2020 to April 2021, we carried out to all participants the 10-item version of the Connor-Davidson Resilience Scale (CD-RISC-10) to measure psychological resilience. We also conducted a comprehensive geriatric assessment including sleep quality and depressive symptoms (Pittsburgh Sleep Quality Index and 15-item Geriatric Depression Scale, respectively). To identify factors associated with CD-RISC-10 scores (mean: 23.3 ± 0.4), multiple regression analysis revealed that older age [coefficient = 0.23, 95% confidence interval (CI) = 0.06–0.39] was significantly correlated with higher scores, whereas poor sleep quality (coefficient = −2.06, 95% CI = −3.93 to −0.19) and depressive symptoms (coefficient = −2.95, 95% CI = −5.70 to −0.21) were significantly correlated with lower scores. In this study, older adults with MCI showed low psychological resilience during the COVID-19 pandemic, and people with low psychological resilience indicated poor sleep quality and depressive symptoms. Our findings suggest directions for devising interventions to maintain mental health and psychological resilience among the vulnerable population of older adults with MCI living under the socially isolated conditions of COVID-19 pandemic restrictions. Our recommendation includes continuous assessment of this population and appropriate care for poor sleep quality and depressive symptoms.

Abstract Background Mild hyponatremia (serum sodium 130–135 mEq/L) is a common electrolyte disorder in the elderly. However, its association with both sarcopenia and cognitive function remains to be clarified. Therefore, here we investigated the association of mild hyponatremia with skeletal muscle mass, physical function, and cognitive function in the elderly. Methods We enrolled 75 participants with mild hyponatremia and 2907 with normonatremia (serum sodium, 136–145 mEq/L) aged ≥70 years who visited the Memory Disorder Outpatient Center of Japan’s National Center for Geriatrics and Gerontology. Skeletal muscle mass index (SMI), grip strength (GS), walking speed (WS), one-leg standing (OLS) test times, and neuropsychological test scores were determined. Results One-way analysis of covariance showed that elderly participants with mild hyponatremia had lower SMI (7.1 ± 0.2, 7.2 ± 0.2 kg/m2, p = 0.04), weaker GS (19.1 ± 1.9 vs 21.4 ± 1.8 kg, p = 0.01), slower WS (0.9 ± 0.1 vs 1.1 ± 0.1 m/s, p = 0.001), and higher GDS- 15 score (6.4 ± 0.9 vs 5.2 ± 0.9, p = 0.002) than those with normonatremia. Multiple logistic regression analysis indicated that mild hyponatremia was independently associated with sarcopenia (odds ratio [OR]: 2.2, p = 0.02), slower WS (OR: 5.3, p = 0.04) and shorter OLS time (OR: 2.5, p = 0.02) as well as with severe depressive mood (OR: 2.6 p = 0.006) but not with SMI (OR: 1.6, p = 0.2) or GS (OR: 1.9, p = 0.09). Conclusions Our results suggest that elderly people with even mild hyponatremia had physical function impairment and depressive mood.

Summary: Endosomal anomalies because of vesicular traffic impairment have been indicated as an early pathology of Alzheimer’| disease (AD). However, the mechanisms and therapeutic targets remain unclear. We previously reported that βCTF, one of the pathogenic metabolites of APP, interacts with TMEM30A. TMEM30A constitutes a lipid flippase with P4-ATPase and regulates vesicular trafficking through the asymmetric distribution of phospholipids. Therefore, the alteration of lipid flippase activity in AD pathology has got attention. Herein, we showed that the interaction between βCTF and TMEM30A suppresses the physiological formation and activity of lipid flippase in AD model cells, A7, and AppNL−G-F/NL−G-F model mice. Furthermore, the T-RAP peptide derived from the βCTF binding site of TMEM30A improved endosomal anomalies, which could be a result of the restored lipid flippase activity. Our results provide insights into the mechanisms of vesicular traffic impairment and suggest a therapeutic target for AD.

ObjectivePreventive measures to limit the spread of COVID-19 are essential, but often cause social isolation, affecting the physical and mental health of older adults. Patients with dementia are likely to have worsening behavioral and psychological symptoms of dementia (BPSD) owing to pandemic restrictions. To examine this, we described BPSD before and during the COVID-19 pandemic.MethodsWe identified patients at a memory clinic in Japan between October 2018 and December 2019 (15 months before the pandemic began, n = 1,384) and between April 2020 and June 2021 (15 months after the State of Emergency was declared; n = 675 patients). A propensity score was used to match 576 patients from each group. The Mini-Mental State Exam was used to classify cognitive function into mild and moderate/severe. Dementia Behavioral Disturbance Scale was used to evaluate BPSD. The association between BPSD before and during the pandemic was evaluated using binomial logistic regression models.ResultsThe levels of frequent night waking were higher in individuals before the pandemic than in those evaluated during the pandemic in both the mild group [adjusted odds ratio (AOR) = 1.82, 95% CI 1.02–3.23] and the moderate/severe group (AOR = 1.96, 95% CI 1.19–3.23). During the pandemic, physical attacks were higher in the mild group (AOR = 4.25, 95% CI 1.12–16.07), while night wandering was higher in the moderate/severe group (AOR = 2.22, 95% CI 1.03–4.81).ConclusionIn patients with cognitive impairment, some BPSD were more prevalent during the pandemic, depending on dementia severity. The findings pertaining to the higher frequency of sleep disturbance and aggressiveness during COVID-19 should be used to guide BPSD screening in patients with dementia and to provide evidence-based interventions.

Abstract Background Mild cognitive impairment (MCI) is a precursor to Alzheimer’s disease (AD), but not all MCI patients develop AD. Biomarkers for early detection of individuals at high risk for MCI-to-AD conversion are urgently required. Methods We used blood-based microRNA expression profiles and genomic data of 197 Japanese MCI patients to construct a prognosis prediction model based on a Cox proportional hazard model. We examined the biological significance of our findings with single nucleotide polymorphism-microRNA pairs (miR-eQTLs) by focusing on the target genes of the miRNAs. We investigated functional modules from the target genes with the occurrence of hub genes though a large-scale protein-protein interaction network analysis. We further examined the expression of the genes in 610 blood samples (271 ADs, 248 MCIs, and 91 cognitively normal elderly subjects [CNs]). Results The final prediction model, composed of 24 miR-eQTLs and three clinical factors (age, sex, and APOE4 alleles), successfully classified MCI patients into low and high risk of MCI-to-AD conversion (log-rank test P = 3.44 × 10−4 and achieved a concordance index of 0.702 on an independent test set. Four important hub genes associated with AD pathogenesis (SHC1, FOXO1, GSK3B, and PTEN) were identified in a network-based meta-analysis of miR-eQTL target genes. RNA-seq data from 610 blood samples showed statistically significant differences in PTEN expression between MCI and AD and in SHC1 expression between CN and AD (PTEN, P = 0.023; SHC1, P = 0.049). Conclusions Our proposed model was demonstrated to be effective in MCI-to-AD conversion prediction. A network-based meta-analysis of miR-eQTL target genes identified important hub genes associated with AD pathogenesis. Accurate prediction of MCI-to-AD conversion would enable earlier intervention for MCI patients at high risk, potentially reducing conversion to AD.

Abstract Background With demographic shifts toward older populations, the number of people with dementia is steadily increasing. Alzheimer’s disease (AD) is the most common cause of dementia, and no curative treatment is available. The current best strategy is to delay disease progression and to practice early intervention to reduce the number of patients that ultimately develop AD. Therefore, promising novel biomarkers for early diagnosis are urgently required. Methods To identify blood-based biomarkers for early diagnosis of AD, we performed RNA sequencing (RNA-seq) analysis of 610 blood samples, representing 271 patients with AD, 91 cognitively normal (CN) adults, and 248 subjects with mild cognitive impairment (MCI). We first estimated cell-type proportions among AD, MCI, and CN samples from the bulk RNA-seq data using CIBERSORT and then examined the differentially expressed genes (DEGs) between AD and CN samples. To gain further insight into the biological functions of the DEGs, we performed gene set enrichment analysis (GSEA) and network-based meta-analysis. Results In the cell-type distribution analysis, we found a significant association between the proportion of neutrophils and AD prognosis at a false discovery rate (FDR)

We investigated the probability distributions of sunspot area and magnetic flux by using data from the Royal Greenwich Observatory and USAF/NOAA. We constructed a sample of 2995 regions with maximum-development areas ≥500 MSH (millionths of solar hemisphere), covering 146.7 yr (1874–2020). The data were fitted by a power-law distribution and four two-parameter distributions (tapered-power-law, gamma, lognormal, and Weibull distributions). The power-law model was unfavorable compared to the four models in terms of AIC, and was not acceptable according to the classical Kolmogorov–Smirnov test. The lognormal and Weibull distributions were excluded because their behavior extended to smaller regions ( S ≪ 500 MSH) do not connect to previously published results. Therefore, our choices were tapered-power-law and gamma distributions. The power-law portion of the tapered-power-law and gamma distributions was found to have a power exponent of 1.35–1.9. Due to the exponential falloff of these distributions, the expected frequencies of large sunspots are low. The largest sunspot group observed had an area of 6132 MSH, and the frequency of sunspots larger than 10 ^4 MSH was estimated to be every 3–8 × 10 ^4 yr. We also estimated the distributions of the Sun-as-a-star total sunspot areas. The largest total area covered by sunspots on record was 1.67% of the visible disk, and can be up to 2.7% by artificially increasing the lifetimes of large sunspots in an area evolution model. These values are still smaller than those found on active Sun-like stars.

A growing body of evidence clearly indicates the beneficial effects of physical activity (PA) on cognition. The importance of PA is now being reevaluated due to the increase in sedentary behavior in older adults during the COVID-19 pandemic. Although many studies in humans have revealed that PA helps to preserve brain health, the underlying mechanisms have not yet been fully elucidated. In this review, which mainly focuses on studies in humans, we comprehensively summarize the mechanisms underlying the beneficial effects of PA or exercise on brain health, particularly cognition. The most intensively studied mechanisms of the beneficial effects of PA involve an increase in brain-derived neurotrophic factor (BDNF) and preservation of brain volume, especially that of the hippocampus. Nonetheless, the mutual associations between these two factors remain unclear. For example, although BDNF presumably affects brain volume by inhibiting neuronal death and/or increasing neurogenesis, human data on this issue are scarce. It also remains to be determined whether PA modulates amyloid and tau metabolism. However, recent advances in blood-based biomarkers are expected to help elucidate the beneficial effects of PA on the brain. Clinical data suggest that PA functionally modulates cognition independently of neurodegeneration, and the mechanisms involved include modulation of functional connectivity, neuronal compensation, neuronal resource allocation, and neuronal efficiency. However, these mechanisms are as yet not fully understood. A clear understanding of the mechanisms involved could help motivate inactive persons to change their behavior. More accumulation of evidence in this field is awaited.

Background: The misuse of opioids has led to an epidemic in recent times. The endothelin A receptor (ETAR) has recently attracted attention as a novel therapeutic target to enhance opioid analgesia. We hypothesized that endothelin A receptors may affect pain mechanisms by heterodimerization with μ opioid receptors. We examined the mechanisms of ETAR-mediated pain and the potential therapeutic effects of an ETAR antagonist, Compound-E, as an agent for analgesia. Methods: Real-time in vitro effect of Compound-E on morphine response was assessed in HEK293 cells expressing both endothelin A and μ opioid receptors through CellKey™ and cADDis cAMP assays. Endothelin A/μ opioid receptor dimerization was assessed by immunoprecipitation and live cell imaging. The in vivo effect of Compound-E was evaluated using a morphine analgesia mouse model that observed escape response behavior, body temperature, and locomotor activity. Results: In CellKey™ and cAMP assays, pretreatment of cells with endothelin-1 attenuated morphine-induced responses. These responses were improved by Compound-E, but not by BQ-123 nor by bosentan, an ETAR and endothelin B receptor antagonist. Dimerization of ETARs and μ opioid receptors was confirmed by Western blot and total internal reflection fluorescence microscopy in live cells. In vivo, Compound-E potentiated and prolonged the analgesic effects of morphine, enhanced hypothermia, and increased locomotor activity compared to morphine alone. Conclusion: The results suggest that attenuation by endothelin-1 of morphine analgesia may be caused by dimerization of Endothelin A/μ opioid receptors. The novel ETAR antagonist Compound-E could be an effective adjunct to reduce opioid use.

Type 2 DM is a risk factor for dementia, including Alzheimer’s disease (AD), and is associated with brain atrophy. Amyloid β protein (Aβ) deposition in the brain parenchyma is implicated in the neurodegeneration that occurs in AD. Platelets, known as abundant storage of Aβ, are recognized to play important roles in the onset and progression of AD. We recently showed that Aβ negatively regulates platelet activation induced by thrombin receptor-activating protein (TRAP) in healthy people. In the present study, we investigated the effects of Aβ on the TRAP-stimulated platelet activation in DM patients, and the relationship between the individual responsiveness to Aβ and quantitative findings of MRI, the volume of white matter hyperintensity (WMH)/intracranial volume (IC) and the volume of parenchyma (PAR)/IC. In some DM patients, Aβ reduced platelet aggregation induced by TRAP, while in others it was unchanged or rather enhanced. The TRAP-induced levels of phosphorylated-Akt and phosphorylated-HSP27, the levels of PDGF-AB and the released phosphorylated-HSP27 correlated with the degree of platelet aggregability. The individual levels of not WMH/IC but PAR/IC was correlated with those of TRAP-stimulated PDGF-AB release. Collectively, our results suggest that the reactivity of TRAP-stimulated platelet activation to Aβ differs in DM patients from healthy people. The anti-suppressive feature of platelet activation to Aβ might be protective for brain atrophy in DM patients.

Background: The Japan-Multi-domain Intervention Trial for Prevention of Dementia in Older Adults with Diabetes (J-MIND-Diabetes) is an 18-month, multi-centered, open-labeled, randomized controlled trial designed to identify whether multi-domain intervention targeting modifiable risk factors for dementia could prevent the progression of cognitive decline among older adults with type 2 diabetes mellitus (T2DM). This manuscript describes the study protocol for the J-MIND-Diabetes trial.Materials and Methods: Subjects of this trial will comprise a total of 300 T2DM outpatients aged 70–85 years with mild cognitive impairment. Subjects will be centrally randomized into intervention and control groups at a 1:1 allocation ratio using the stratified permuted-block randomization methods. The intervention group will participate in multi-domain intervention programs aimed at: (1) management of metabolic and vascular risk factors; (2) physical exercise and self-monitoring of physical activity; (3) nutritional guidance; and (4) social participation. The control group will receive usual T2DM care and general instructions on dementia prevention. The primary and secondary outcomes will be assessed at baseline, at 6- and 18-month follow-up. The primary outcome is change from baseline at 18 months in a global composite score combining several neuropsychological domains, including global cognitive function, memory, attention, executive function, processing speed and language. Secondary outcomes include: (1) cognitive changes in neuropsychological tests; (2) changes in geriatrics assessments; (3) metabolic control and diabetic complications; (4) changes in blood and urinary markers.Discussion: This trial will be the first trial to demonstrate the effectiveness of multi-domain intervention in preventing cognitive decline in older adults with T2DM at increased risk of dementia in Japan.Trial Registration: UMIN000035911; Registered on the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) 18 February 2019. (https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000040908).

Abstract Background Dementia with Lewy bodies (DLB) is the second most common subtype of neurodegenerative dementia in humans following Alzheimer’s disease (AD). Present clinical diagnosis of DLB has high specificity and low sensitivity and finding potential biomarkers of prodromal DLB is still challenging. MicroRNAs (miRNAs) have recently received a lot of attention as a source of novel biomarkers. Methods In this study, using serum miRNA expression of 478 Japanese individuals, we investigated potential miRNA biomarkers and constructed an optimal risk prediction model based on several machine learning methods: penalized regression, random forest, support vector machine, and gradient boosting decision tree. Results The final risk prediction model, constructed via a gradient boosting decision tree using 180 miRNAs and two clinical features, achieved an accuracy of 0.829 on an independent test set. We further predicted candidate target genes from the miRNAs. Gene set enrichment analysis of the miRNA target genes revealed 6 functional genes included in the DHA signaling pathway associated with DLB pathology. Two of them were further supported by gene-based association studies using a large number of single nucleotide polymorphism markers (BCL2L1: P = 0.012, PIK3R2: P = 0.021). Conclusions Our proposed prediction model provides an effective tool for DLB classification. Also, a gene-based association test of rare variants revealed that BCL2L1 and PIK3R2 were statistically significantly associated with DLB.

Cancer cachexia is a systemic wasting syndrome characterized by anorexia and loss of body weight. The xanthine oxidase (XO) inhibitor febuxostat is one of the promising candidates for cancer cachexia treatment. However, cachexic symptoms were not alleviated by oral administration of febuxostat in our cancer cachexia model. Metabolomic analysis with brains of our cachexic model showed that purine metabolism was activated and XO activity was increased, and thus suggested that febuxostat would not reach the brain. Accordingly, targeting XO in the brain, which controls appetite, may be an effective strategy for treatment of cancer cachexia. Keywords: Cancer cachexia, Metabolome, Xanthine oxidase

Abundant secretory immunoglobulin A (SIgA) in the mucus, breast milk, and saliva provides immunity against infection of mucosal surfaces. Pre-pandemic breast milk samples containing SIgA have been reported to cross-react with SARS-CoV-2; however, it remains unknown whether SIgA showing the cross-reaction with SARS-CoV-2 exists in saliva. We aimed to clarify whether SIgA in saliva cross-reacts with SARS-CoV-2 spike 1 subunit in individuals who have not been infected with this virus. The study involved 137 (men, n = 101; women, n = 36; mean age, 38.7; age range, 24-65 years) dentists and doctors from Kanagawa Dental University Hospital. Saliva and blood samples were analyzed by polymerase chain reaction (PCR) and immunochromatography for IgG and IgM, respectively. We then identified patients with saliva samples that were confirmed to be PCR-negative and IgM-negative for SARS-CoV-2. The cross-reactivity of IgA-positive saliva samples with SARS-CoV-2 was determined by enzyme-linked immunosorbent assay using a biotin-labeled spike recombinant protein (S1-mFc) covering the receptor-binding domain of SARS-CoV-2. The proportion of SARS-CoV-2 cross-reactive IgA-positive individuals was 46.7%, which correlated negatively with age (r = -0.218, p = 0.01). The proportion of IgA-positive individuals aged ≥50 years was significantly lower than that of patients aged ≤49 years (p = 0.008). SIgA was purified from the saliva of patients, which could partially suppress the binding of SARS-CoV-2 spike protein to the angiotensin converting enzyme-2 receptor. This study demonstrates the presence of SARS-CoV-2 cross-reactive SIgA in the saliva of individuals who had never been infected with the virus, suggesting that SIgA may help prevent SARS-CoV-2 infection.

Job-hunting activities in Japan are different from those in other countries. The features of this are the simultaneous recruitment of new graduates, joining the company in April, and the use by most students of such resources as employment information websites. In recent years, website job boards for new graduates have provided Japanese students with assistance in finding companies for which they want to work. On these boards, students can bookmark companies that they are interested in before deciding to apply. After bookmarking, a company bookmarked by a user can examine the information again later. However, even if the students rate various companies, many of these bookmarks do not lead to job applications. In other words, this can be regarded as a lost opportunity for gaining job applications from the perspective of the company. It is important for companies to gain as many job applications as possible to be successful in their recruitment activities. Therefore, a method of analyzing the entry behavior of students on job boards using factorization machines is proposed. The model predicts whether a student will submit a job application to a company. The prediction is based on student attributes and activity information, as well as information about the companies that they are interested in, as input variables. The interactions between input variables are also considered in making the prediction. In addition, the method supports student job-hunting activities and company measures for targeting students. To clarify the proposed model, analytical experiments were conducted with actual data from a website job board for new graduates.

Abstract Introduction The coronavirus disease‐19 (COVID‐19) pandemic presents challenges to the conduct of randomized clinical trials of lifestyle interventions. Methods World‐Wide FINGERS is an international network of clinical trials to assess the impact of multidomain lifestyle intervention on cognitive decline in at‐risk adults. Individual trials are tailoring successful approaches from the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) to local cultures and environments. The network convened a forum for researchers to discuss statistical design and analysis issues they faced during the pandemic. We report on experiences of three trials that, at various stages of conduct, altered designs and analysis plans to navigate these issues. We provide recommendations for future trials to consider as they develop and launch behavioral intervention trials. Results The pandemic led researchers to change recruitment plans, interrupt timelines for assessments and intervention delivery, and move to remote intervention and assessment protocols. The necessity of these changes add emphasis to the importance, in study design and analysis, of intention to treat approaches, flexibility, within‐site stratification, interim power projections, and sensitivity analyses. Discussion Robust approaches to study design and analysis are critical to negotiate issues related to the intervention. The world‐wide network of similarly oriented clinical trials will allow us to evaluate the effectiveness of responses to the pandemic across cultures, local environments, and phases of the pandemic.

A lower body mass is associated with the progression of Alzheimer’s disease (AD) and the risk of mortality in patients with AD; however, evidence of genetic determinants of decreased body mass in cognitively impaired older adults is limited. We therefore investigated the genetic effect of APOE-ε4 on body composition in older adults with mild cognitive impairment (MCI) and early-to-moderate-stage AD. A total of 1631 outpatients (aged 65–89 years) with MCI and early-to-moderate-stage AD were evaluated for the association between body composition and APOE-ε4 status. After adjusting for covariates, including cognitive function evaluated with the Mini-Mental State Examination, the presence of the APOE-ε4 was associated with lower weight (β = −1.116 ± 0.468 kg per presence, p = 0.017), fat mass (β = −1.196 ± 0.401 kg per presence, p = 0.003), and percentage of body fat (β = −1.700 ± 0.539% per presence, p = 0.002) in women but not in men. Additionally, the impact of APOE-ε4 on measures of body composition in women was more remarkable in MCI than in AD patients. The presence of the APOE-ε4 allele was associated with lower fat mass, particularly in women with MCI, independent of cognitive decline.

Burning experiments were conducted to better understand the fuel regression behavior in a swirling-injection end-burning hybrid rocket engine using paraffin wax/gaseous oxygen propellant. The oxidizer mass flow rate, grain diameter, and the distance between the oxidizer injector and the grain end-surface were the variable parameters taken as influencing the regression rate. The engine attained an overall axial regression rate as high as approximately 5 mm/s, whereas unstable combustion occurred with increasing burning time owing to low melting temperature of paraffin wax. The fuel grain with a diameter of 90 mm also resulted in unstable combustion caused by the initial shallow crack of the cast grain. The radial distribution of the local regression rate exhibited dependency on the radial position and had two peaks: close to the periphery and the middle of the chamber. From the analogy of the heat transfer at the end surface in a vortex flow chamber, the controlling parameter of the overall axial regression rate was derived. Since this parameter depends on the distance between the oxidizer injector outlet and the fuel grain end-surface, to hold the grain end-surface by using some kind of actuator is necessary to attain constant O/F combustion.

Abstract Background Eribulin mesylate is currently indicated as a sequential monotherapy to be administered after two chemotherapeutic regimens, including anthracycline and taxane treatments, for treatment of metastatic breast cancer. This open-label, multicenter phase II study was designed to evaluate the efficacy and safety of eribulin as a first- or second-line treatment for patients with metastatic breast cancer. Methods The primary objective was to determine the overall response rate. Secondary objectives were to evaluate progression-free survival and the safety profile. Patients were scheduled to receive eribulin mesylate 1.4 mg/m2 intravenously on days 1 and 8 of a 21-day cycle. Patients received the study treatment unless disease progression, unacceptable toxicity, or a request to discontinue from the patient and/or investigator eventuated. Results Between December 2012 and September 2015, 32 patients with metastatic breast cancer were enrolled at 10 participating clinical institutions in Japan, and toxicity and response rates were evaluated. The overall response rate was 43.8% (95% confidence interval [CI] 26.5–61.0). The clinical benefit and tumor control rates were 56.3% (95% CI 39.0–73.5) and 78.1% (95% CI 63.8–92.5), respectively. Median progression-free survival was 8.3 months (95% CI 7.1–9.4). A subgroup analysis did not identify any factors affecting the efficacy of eribulin. The most common adverse events were neutropenia (71.9%), alopecia (68.7%), and peripheral neuropathy (46.9%). As a first- or second-line therapy, eribulin showed sufficient efficacy for metastatic breast cancer compared with taxane and capecitabine treatment in previous clinical trials. The safety profile of eribulin was acceptable. Conclusions Eribulin may be another option for first-line chemotherapeutic regimens for metastatic breast cancer. Trial registrations This trial was retrospectively registered at the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (ID number: UMIN000010334). Date of trial registration: April 1st, 2013.

Background/Aims: Behavioral and psychological symptoms of dementia (BPSD) are exhibited in most patients with Alzheimer disease (AD). Although white matter hyperintensity (WMH) is often observed with AD, the precise role of WMH in BPSD remains unclear. The current study aimed to identify the impact of regional WMH on specific features of BPSD in persons with mild to moderate AD and amnestic mild cognitive impairment (aMCI). Methods: A sample of 256 female outpatients with AD (n = 217) and aMCI (n = 39) were recruited. We assessed BPSD using the Dementia Behavior Disturbance Scale. WMH and brain atrophy were evaluated using an automatic segmentation program. Regional WMH was evaluated as periventricular hyperintensity (PVH) and deep WMH in frontal, temporal, occipital, and parietal lobes. Results: Whole-brain WMH was associated with verbal aggressiveness. In multivariate analysis, PVH in the frontal lobe was independently associated with verbal aggressiveness after adjustment for brain atrophy and clinical confounders. Conclusion: The current results indicated that PVH in the frontal lobe was independently associated with verbal aggressiveness.

Regulation of intracellular Ca2+ concentration ([Ca2+]i) is vital for eukaryotic organisms. Recently, we identified a Ca2+ channel (TcIP3R) associated with intracellular Ca2+ stores in Trypanosoma cruzi, the parasitic protist that causes Chagas disease. In this study, we measured [Ca2+]i during the parasite life cycle and determined whether TcIP3R is involved in the observed variations. Parasites expressing R‐GECO1, a red fluorescent, genetically encoded Ca2+ indicator for optical imaging that fluoresces when bound to Ca2+, were produced. Using these R‐GECO1‐expressing parasites to measure [Ca2+]i, we found that the [Ca2+]i in epimastigotes was significantly higher than that in trypomastigotes and lower than that in amastigotes, and we observed a positive correlation between TcIP3R mRNA expression and [Ca2+]i during the parasite life cycle both in vitro and in vivo. We also generated R‐GECO1‐expressing parasites with TcIP3R expression levels that were approximately 65% of wild‐type (wt) levels (SKO parasites), and [Ca2+]i in the wt and SKO parasites was compared. The [Ca2+]i in SKO parasites was reduced to approximately 50–65% of that in wt parasites. These results show that TcIP3R is the determinant of [Ca2+]i in T. cruzi. Since Ca2+ signaling is vital for these parasites, TcIP3R is a promising drug target for Chagas disease.

Background: Sarcopenia is frequently seen in patients with mild cognitive impairment (MCI) and early-stage Alzheimer's disease (AD). While appetite loss and physical inactivity, which are also frequently seen in dementia, appear to contribute to sarcopenia, to date, no study has investigated this association.Objective: The aim of this study was to examine factors associated with sarcopenia, including appetite and physical activity, in patients with MCI and early-stage AD.Methods: The study subjects comprised 205 outpatients (MCI, n = 151; early-stage AD, n = 54) who were being treated at the Memory Clinic, National Center for Geriatrics, and Gerontology and had a Mini-Mental State Examination (MMSE) score of 21 or higher. All subjects were assessed for appetite by using the Council on Nutrition Appetite Questionnaire (CNAQ). Confounding variables assessed included physical activity, activities of daily living, mood, body mass index (BMI), nutritional status, and medications. Sarcopenia was defined as low muscle mass and low handgrip strength or slow gait speed. Multivariate logistic regression analyses were performed with adjustment for age, gender, education, and confounding variables to examine the association of sarcopenia with physical activity and appetite. Furthermore, sub-analyses were also conducted to clarify the relationship between CNAQ sub-items and sarcopenia.Results: The prevalence of sarcopenia among the subjects was 14.6% (n = 30). Patients with sarcopenia had lower CNAQ scores (those with sarcopenia, 26.7 ± 3.5; those without, 29.1 ± 2.5). Multivariate analysis showed that BMI (odds ratio [OR], 0.675; 95% confidence interval [CI], 0.534–0.853), polypharmacy (OR, 4.489; 95% CI, 1.315–15.320), and CNAQ (OR, 0.774; 95% CI, 0.630–0.952) were shown to be associated with sarcopenia. Physical activity was not associated with sarcopenia. Of the sub-items of the CNAQ, appetite (OR, 0.353; 95% CI, 0.155–0.805), feeling full (OR, 0.320; 95% CI = 0.135–0.761), and food tastes compared to when younger (OR, 0.299; 95% CI, 0.109–0.818) were shown to be associated with sarcopenia.Conclusions: These results suggest that appetite could be a modifiable risk factor for sarcopenia in patients with MCI and early-stage AD. A comprehensive approach to improving appetite may prove effective in preventing sarcopenia.

Status epilepticus (SE) is a life-threatening emergency that can cause neurodegeneration with debilitating neurological disorders. However, the mechanism by which convulsive SE results in neurodegeneration is not fully understood. It has been shown that epileptic seizures produce markedly increased levels of nitric oxide (NO) in the brain, and that NO induces Ca2+ release from the endoplasmic reticulum via the type 1 ryanodine receptor (RyR1), which occurs through S-nitrosylation of the intracellular Ca2+ release channel. Here, we show that through genetic silencing of NO-induced activation of the RyR1 intracellular Ca2+ release channel, neurons were rescued from seizure-dependent cell death. Furthermore, dantrolene, an inhibitor of RyR1, was protective against neurodegeneration caused by SE. These results demonstrate that NO-induced Ca2+ release via RyR is involved in SE-induced neurodegeneration, and provide a rationale for the use of RyR1 inhibitors for the prevention of brain damage following SE.