A first-in-human study of the anti-inflammatory profibrinolytic TMS-007, an SMTP family triprenyl phenol.

AIMS: TMS-007, an SMTP family member, modulates plasminogen conformation and enhances plasminogen-fibrin binding, leading to promotion of endogenous fibrinolysis. Its anti-inflammatory action, mediated by soluble epoxide hydrolase inhibition, may contribute to its efficacy. Evidence suggests that TMS-007 can effectively treat experimental thrombotic and embolic strokes with a wide time window, while reducing haemorrhagic transformation. We aim to evaluate the safety, pharmacokinetics and pharmacodynamics of TMS-007 in healthy volunteers. METHODS: This was a randomized, placebo-controlled, double blind, dose-escalation study, administered as a single intravenous infusion of TMS-007 in cohorts of healthy male Japanese subjects. Six cohorts were planned, but only five were completed. In each cohort (n = 8), individuals were randomized to receive one of five doses of TMS-007 (3, 15, 60, 180 or 360 mg; n = 6) or placebo (n = 2). RESULTS: TMS-007 was generally well tolerated, and no serious adverse events were attributed to the drug. A linear dose-dependency was observed for plasma TMS-007 levels. No symptoms of bleeding were observed on brain MRI analysis, and no bleeding-related responses were found on laboratory testing. The plasma levels of the coagulation factor fibrinogen and the anti-fibrinolysis factor α2 -antiplasmin levels were unchanged after TMS-007 dosing. A slight increase in the plasma level of plasmin-α2 -antiplasmin complex, an index of plasmin formation, was observed in the TMS-007 group in cohort 2. CONCLUSIONS: TMS-007 is generally well tolerated and exhibits favourable pharmacokinetic profiles that warrant further clinical development.

Increased care-need in older long-term care insurance users after the 2018 Japan Floods: a retrospective cohort study based on the Japanese long-term care insurance claims.

BACKGROUND: Level of care-need (LOC) is an indicator of elderly person's disability level and is officially used to determine the care services provided in Japan's long-term care insurance (LTCI) system. The 2018 Japan Floods, which struck western Japan in July 2018, were the country's second largest water disaster. This study determined the extent to which the disaster affected the LOC of victims and compared it with that of non-victims. METHODS: This is a retrospective cohort study, based on the Japanese long-term care insurance claims from two months before (May 2018) to five months after the disaster (December 2018) in Hiroshima, Okayama, and Ehime prefectures, which were the most severely damaged areas in the country. A code indicating victim status, certified by a residential municipality, was used to distinguish between victims and non-victims. Those aged 64 years or younger, those who had the most severe LOC before the disaster, and those whose LOC increased even before the disaster were excluded. The primary endpoint was the augmentation of pre-disaster LOC after the disaster, which was evaluated using the survival time analysis. Age, gender, and type of care service were used as covariates. RESULTS: Of the total 193,723 participants, 1,407 (0.7%) were certified disaster victims. Five months after the disaster, 135 (9.6%) of victims and 14,817 (7.7%) of non-victims experienced the rise of LOC. The victim group was significantly more likely to experience an augmentation of LOC than the non-victim group (adjusted hazard ratio 1.24; 95% confidence interval 1.06-1.45). CONCLUSIONS: Older people who were affected by the disaster needed more care than before and the degree of care-need increase was substantially more than non-victims. The result suggests that natural disasters generate more demand for care services among the older people, and incur more resources and cost for society than before.

Development, reliability, and validity of a self-assessment scale for dementia care management.

BACKGROUND: This study aimed to develop a self-assessment scale for care management of people with dementia and examine its reliability and validity. METHODS: Based on Bloom's Taxonomy, previous research, and experts' opinions on dementia and care management, a scale consisting of 18 items was developed to assess care managers' attitudes, knowledge, and skills in their management of people with dementia. To examine the scale's reliability and validity, data were collected from 638 care managers. Construct validity using exploratory factor analysis, known-group validity, and internal consistency reliability of the scale were evaluated. RESULTS: Exploratory factor analysis supported the construct validity with a four-factor model and explained 59.1% of the total variance. Following were the four factors: Factor I 'Person centred care'; Factor II 'Understanding of disease characteristics, treatment and care'; Factor III 'Understanding of people with dementia and care management according to their characteristics'; and Factor IV 'Utilization of local resources surrounding people with dementia'. Regarding the known-group validity, results showed that the group with a qualified chief care manager scored significantly higher than the group without one on Factors I (P = 0.013) and III (P = 0.026). Cronbach's alpha coefficient for the 18 items was 0.928. CONCLUSIONS: The findings prove that the scale has acceptable reliability and validity, and can help care managers reflect on their practice. Future research is desirable to measure the validation of change in the scale.

Factors Associated with Caregiver Burden and Depressive States among Family Caregivers of Patients Admitted due to Behavioral and Psychological Symptoms of Dementia.

INTRODUCTION: Among those caring for people with dementia (PwD) at home, more than 60% feel a caregiver burden (CB), and one in three are depressed. Reducing feelings of burden and depressive states in caregiving families will improve the living environment for PwD. However, very few studies have focused on effective methods and reducing feelings of burden and depressive states of caregivers. Thus, using data from a previous study, we aimed to determine the factors associated with perceived CB and depressive states experienced by caregivers for PwD with behavioral and psychological symptoms of dementia (BPSD) at home. METHODS: We performed single regression analysis on 285 participants' data to determine the association between each item and the Zarit Caregiver Burden Interview and Center for Epidemiologic Studies-Depression Scale scores. We performed multiple regression analysis with variables considered in the single regression analysis as independent variables. RESULTS: Severity of BPSD, caregivers' subjective health status (SHS), time of caregiving, and depressive states were related to CB, and caregivers' SHS and CB were related to depressive states. CONCLUSIONS: Similar to previous studies, we identified an association between family caregivers' perceived CB and BPSD in PwD. Additionally, we found that caregivers' SHS is commonly associated with both perceived CB and depressive states. This is a new finding. Our results suggest that interventions focusing on family caregivers' health status can help not only to reduce family caregivers' CB and depressive states but also stabilize patients' symptoms and provide home-based care for a longer time.

Efficacy of care manager-led support for family caregivers of people with dementia during the COVID-19 pandemic: a randomized controlled study.

BACKGROUND: A prolonged COVID-19 pandemic could exacerbate the risk of infection and undesirable effects associated with infection control measures of older people with dementia (PWD), and the care burden of families. In this study, we examined the efficacy of care manager-led information provision and practical support for families of older PWD who need care, regarding appropriate infection prevention, prevention of deterioration of cognitive and physical functions, and preparedness in cases of infection spread or infection during the pandemic. METHODS: Fifty-three family members (aged ≥20 years) who were primary caregivers living with older PWD using public long-term care services were enrolled in an one-month randomized controlled trial. This duration was set based on behavior modification theory and with consideration of ethical issue that the most vulnerable people not benefiting from the intervention. The intervention group (IG) received care manager-led information provision and practical support, and the control group (CG) received usual care. Care burden (primary outcome) was measured using the Zarit Caregiver Burden Interview, and secondary outcomes were analyzed using Patient Health Questionnaire-9 (PHQ9), the Fear of COVID-19 Scale, and salivary α-amylase activity. Data were collected at baseline and after 1 month. Multiple regression analysis was conducted to examine the efficacy of the intervention. The participants evaluated the care managers' support. RESULTS: The participants were randomly divided into IG (n = 27) and CG (n = 26) groups. After the intervention, compared with the CG, there was a decrease in PHQ-9 (ß = -.202, p = 0.044) and α-amylase activity in saliva (ß = -.265, p = 0.050) in IG. IG also showed an increased fear of COVID-19 after the intervention (ß = .261, p = 0.003). With the care managers' support, 57.2% of the participants felt secure in their daily lives and 53.1% agreed that they were able to practice infection prevention suitable for older PWD. CONCLUSIONS: Our findings suggest that the care manager-led intervention may be useful for families of older PWD to enhance behavioral changes in preventing COVID-19 infection and improve their psychological outcomes in the COVID-19 era. TRIAL REGISTRATION: This study was registered on April 2, 2021 (No. UMIN000043820).

Discontinuation of long-term care among persons affected by the 2018 Japan Floods: a longitudinal study using the Long-term Care Insurance Comprehensive Database.

BACKGROUND: Most older people with disabilities or illnesses continue to use long-term care (LTC) services for the rest of their lives. However, disasters can cause a discontinuation of LTC services, which usually means tragic outcomes of affected persons. In view of the recent progression of population aging and the increase in natural disasters, this study focuses on the impact of disasters on older people's discontinuation of LTC services, and those more risk of such discontinuation than others. However, current evidence is scarce. METHODS: We conducted a retrospective cohort study with 259,081 subjects, 2,762 of whom had been affected by disaster and 256,319 who had not been affected during the 2018 Japan Floods. The sample in the three most disaster-affected prefectures was drawn from the Long-term Care Insurance Comprehensive Database and included older people certified with care-need level. The observation period was two months before the disaster and five months after it. We calculated the hazard ratio (HR) of municipality-certified subjects affected by the disaster versus those who were not. Subgroup analyses were conducted for categories of individual-, facility- and region-associated factors. RESULTS: Affected persons were twice as likely to discontinue LTC services than those who were not affected (adjusted HR, 2.06 95% CI, 1.91-2.23). 34% of affected persons whose facilities were closed discontinued their LTC services at five months after the disaster. A subgroup analysis showed that the risk of discontinuing LTC services for affected persons compared to those who were not affected in the relatively younger subgroup (age < 80: adjusted HR, 2.55; 95% CI, 2.20-2.96 vs. age ≥ 80 : 1.91; 1.75-2.10), and the subgroup requiring a lower level of care (low: 3.16; 2.74-3.66 vs. high: 1.71; 1.50-1.96) were more likely to discontinue than the older and higher care level subgroups. CONCLUSIONS: A natural disaster has a significant effect on the older people's discontinuation of LTC services. The discontinuations are supposedly caused by affected persons' death, hospitalization, forced relocation of individuals, or the service provider's incapacity. Accordingly, it is important to recognize the risk of disasters and take measures to avoid discontinuation to protect older persons' quality of life.

Person-centered dementia care during COVID-19: a qualitative case study of impact on and collaborations between caregivers.

BACKGROUND: Little is known about the actual impact of COVID-19 on caregivers of older people with dementia and resultant collaborations among them to provide continued person-centered care while undertaking infection control measures. In this study, we explored the impact of providing dementia care during COVID-19 on caregivers involved in dementia care. METHODS: This is an exploratory qualitative case study. The participants were family members living with older people with dementia, care managers, and the medical and long-term care facility staff. Data were collected from 46 caregivers via face-to-face and semi-structured interviews and analyzed using thematic analysis. RESULTS: The interviews identified 22 themes related to the impact of COVID-19 on different positions of the caregivers involved in dementia care and their collaboration, and we categorized them into six categories. The core themes were "re-acknowledgement of care priorities" and "rebuilding of relationships." When caregivers' perceptions were aligned in the decision-making processes regarding care priorities, "reaffirmation of trust" and "strengthening of intimate relationships" emerged as positive changes in their relationships. Furthermore, the differences in the ability of each caregiver to access and select correct and appropriate information about COVID-19, and the extent of infection spread in the region were related to "anxiety during COVID-19 pandemic" and caused a "gap in perception" regarding infection control. CONCLUSIONS: The present study clarified that the process of aligning the perceptions of caregivers to the objectives and priorities of care for older people with dementia during COVID-19 pandemic strengthened the relationships among caregivers. The findings of this study are useful for caregivers involved in person-centered dementia care.

Effects of the 2018 Japan Floods on long-term care insurance costs in Japan: retrospective cohort study.

BACKGROUND: Climate change has increased the frequency and severity of torrential rains and floods around the world. Estimating the costs of these disasters is one of the five global research priorities identified by WHO. The 2018 Japan Floods hit western Japan causing extensive destruction and many deaths, especially among vulnerable elderly. Such affected elderly would need long-term care due to the various health problems caused by the disaster. A Long-Term Care Insurance (LTCI) system provides care services in Japan. The aim of this study was to evaluate the effect of the 2018 Japan Floods on LTCI costs and service utilization. METHODS: The participants of this retrospective cohort study were all verified persons utilizing LTCI services in Hiroshima, Okayama and Ehime prefectures. The observation period was from 2 months before to 6 months after the disaster. We used Generalized Estimating Equations (GEEs) to examine the association between disaster status (victims or non-victims) and the monthly total costs of LTCI service (with gamma-distribution/log-link) by residential environment (home or facility). Among home residents, we also examined each service utilization (home-based service, short-stay service and facility service), using the GEEs. After the GEEs, we estimated Average Marginal Effects (AME) over all observation periods by months as the attributable disaster effect. RESULTS: The total number of participants was 279,578. There were 3024 flood victims. The disaster was associated with significantly higher total costs. The AME for home residents at 2 months after was $214 (Standard Error (SE): 12, p < 0.001), which was the highest through the observation period. Among facility residents, the AME immediately after the disaster increased by up to $850 (SE: 29, p < 0.001). The service utilization among home residents showed a different trend for each service. The AME of home-based services decreased by up to - 15.2% (SE:1.3, p < 0.001). The AME for short-stay service increased by up to 8.2% (SE: 0.9, p < 0.001) and the AME for facility service increased by up to 7.4% (SE: 0.7, p < 0.001), respectively. CONCLUSIONS: The 2018 Japan Floods caused an increase in LTCI costs and the utilization of short-stay and facility services, and a decrease in utilization of home-based services.

Impact of the 2018 Japan Floods on benzodiazepine use: a longitudinal analysis based on the National Database of Health Insurance Claims.

PURPOSE: Natural disaster has an impact on mental health. The 2018 Japan Floods, which took place in July 2018 were one of the largest water disasters in Japan's recorded history. We aimed to evaluate the change in the number of benzodiazepine prescriptions by physicians before and after the disaster. METHODS: A retrospective cohort study based on the National Database of Health Insurance Claims was conducted in the flood-stricken areas between July 2017 and June 2019. The subjects were divided between victims and non-victims according to certification by local governments. Members of both groups were then categorized into three groups based on their pre-flood use of benzodiazepines: non-user, occasional user, and continuous user. Difference-in-differences (DID) analysis with a logistic regression model was conducted to estimate the effect of the disaster among victims by comparing the occurrence of benzodiazepine prescriptions before and after the disaster. RESULTS: Of 5,000,129 people enrolled, 31,235 were victims. Among all participants, the mean prescription rate for benzodiazepines in victims before the disaster (11.3%) increased to 11.8% after the disaster, while that in non-victims (8.3%) decreased to 7.9%. The DID analysis revealed that benzodiazepine prescription among victims significantly increased immediately after the disaster (adjusted ratio of odds ratios (ROR) 1.07: 95% confidence interval 1.05-1.11), and the effect of the disaster persisted even 1 year after the disaster (adjusted ROR 1.2: 95% confidence interval 1.16-1.24). CONCLUSION: The flood increased the number of benzodiazepines prescriptions among victims, and the effect persisted for at least 1 year.

Steady-state relationship between average glucose, HbA1c and RBC lifespan.

HbA1c is used to estimate average glucose. Previous studies showed linear relationship between average glucose and HbA1c. We made a new theoretical relationship using recently proposed Γ-like function model of erythrocyte lifespan. We showed the relationship between average glucose and HbA1c; we approximated it into a simple hyperbolic function: HbA1c=MRBCkgAG/(1+(2/3)MRBCkgAG), whose inverse function is easily obtained. Apparent linear relationship is an approximation of the curved relationship. Hyperbolic function would provide a more accurate approximation than a linear equation. Physicians should keep in mind the curved relationship and be aware that extremely high HbA1c indicates acceleratingly high glucose level.

Identifying drug substances of screening tool for older persons' appropriate prescriptions for Japanese.

BACKGROUND: In 2015, the Japan Geriatric Society (JGS) updated "the Guidelines for Medical Treatment and its Safety in the elderly," accompanied with the Screening Tool for Older Persons' Appropriate Prescriptions for Japanese (STOPP-J): "drugs to be prescribed with special caution" and "drugs to consider starting." The JGS proposed the STOPP-J to contribute to improving prescribing quality; however, each decision should be carefully based on medical knowledge. The STOPP-J shows examples of commonly prescribed drug substances, but not all relevant drugs. This research aimed to identify substances using such coding, as a standardized classification system would support medication monitoring and pharmacoepidemiologic research using such health-related information. METHODS: A voluntary team of three physicians and two pharmacists identified possible approved medicines based on the STOPP-J, and matched certain drug substances to the Anatomical Therapeutic Chemical Classification (ATC) and the Japanese price list as of 2017 February. Injectables and externally used drugs were excluded, except for self-injecting insulin, since the STOPP-J guidelines are intended to cover medicines used chronically for more than one month. Some vaccines are not available in the Japanese price list since they not reimbursed through the national health insurance. RESULTS: The ATC 5th level was not available for 39 of the 235 identified substances, resulting in their classification at the ATC 4th level. Furthermore, among 26 combinations, 10 products were matched directly to the ATC 5th level of the exact substances, and others were linked to the ATC representing the combination or divided into multiple substances for classification if the combination was not listed in the ATC. CONCLUSION: This initial work demonstrates the challenge of matching ATC codes and the Japan standard commodity classification codes corresponding to STOPP-J substances. Since coding facilitates database analysis, the proposed drug list could be applied to research using large databases to examine prescribing patterns in patients older than 75 years or who are frail. Since ATC is not available for some substances, Japanese medicines need the process to be registered in the ATC for an effective screening tool to be developed for STOPP-J.

Boiling effect in liquid nitrogen directly cooled Yb³âº:YAG laser.

Liquid nitrogen (LN2) behavior on the surface of excited Yb(3+):YAG is investigated using fluorometry. From the time-resolved temperature variations and integrated fluorescence spectra intensity on this directly cooled Yb(3+):YAG surface, we observe a phase transition of LN2 from nucleate boiling to film boiling. As a result of this pool boiling, good beam quality should occur when the temperature and heat flux at an excited surface of Yb(3+):YAG are below 95 K and 15.8 W/cm2, respectively. That is, the LN2 should remain in a steady state of nucleate boiling to produce good beam quality using pool boiling.

Cutoff value of thyroid uptake of (99m)Tc-pertechnetate to discriminate between Graves' disease and painless thyroiditis: a single center retrospective study.

Thyroid uptake of (99m)Tc-pertechnetate is a useful way to determine the cause of thyrotoxicosis. In daily clinical practice, (99m)Tc-pertechnetate uptake is used to discriminate between Graves' disease and painless thyroiditis when clinical information is not enough to make the distinction. However, since the optimal cutoff value of (99m)Tc-pertechnetate uptake has not yet been elucidated, our aim was to determine this value. We recruited patients with thyrotoxicosis in whom (99m)Tc-pertechnetate uptake was measured in clinical settings between 2009 and 2013. Three experienced endocrinologists (who were blinded to the value of (99m)Tc-pertechnetate uptake and initial treatment) diagnosed the cause of thyrotoxicosis based on thyrotropin, free triiodothyronine, free thyroxine, and thyrotropin receptor antibody levels, and by ultrasound findings and using images of thyroid uptake of (99m)Tc-pertechnetate without the actual values. Ninety-four patients diagnosed as having Graves' disease or painless thyroiditis were finally included. According to the diagnosis, the optimal cutoff value of (99m)Tc-pertechnetate uptake was determined by receiver operating characteristics analysis. A cutoff value of 1.0% provided optimal sensitivity and specificity of 96.6% and 97.1%, respectively. Then, its validity was confirmed in 78 patients with confirmed Graves' disease or painless thyroiditis diagnosed at another institute. Applying this cutoff value to the patients with thyrotoxicosis revealed positive and negative predictive values for Graves' disease of 100% and 88.9%, respectively. In conclusion, a cutoff value for (99m)Tc-pertechnetate uptake of 1.0% was useful to discriminate between Graves' disease and painless thyroiditis.

Amplification characteristics of a cryogenic Yb³âº:YAG total-reflection active-mirror laser.

We have studied the amplification characteristics of a cryogenically cooled Yb³âº:YAG total-reflection active-mirror (TRAM) ceramic laser including wavefront distortion, birefringence loss, small signal gain (SSG), and temperature rise for developing high-performance master oscillator power amplifier (MOPA) systems. A 0.6 mm thick Yb³âº:YAG ceramic sample was used, and maximum pump intensity ~10 kW/cm² was reached. The transmitted wavefront was measured by using a Shack-Hartmann wavefront sensor, and we evaluated the thermal lens focal length and Strehl ratio for different pump conditions. We have also observed a butterfly-like leakage profile of thermally induced birefringence loss at the maximum pump intensity. From SSG measurements, we obtained moderate laser gain of G=3 for one bounce with a near aberration-free wavefront. Gain calculations, which included also temperature dependence of the emission cross section and reabsorption of Yb³âº:YAG, were in good agreement with the experiments. These experimental results will be useful as benchmark data for numerical simulations of temperature distribution in TRAM and for designing multikilowatt-class high-performance MOPA systems.

Prevalence and associated factors of work impairment among geriatricians during the COVID-19 pandemic in Japan.

AIM: This study investigated work impairment and its associated factors among geriatricians during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: This cross-sectional study was carried out using an anonymous online survey questionnaire administered to members of the Japanese Geriatric Society between October and December 2022. The questionnaire included questions regarding psychological distress (Kessler Psychological Distress Scale), fear of COVID-19 (Fear of COVID-19 Scale) and work impairment (Work Functioning Impairment Scale). Multivariate logistic regression analyses were carried out to determine the factors associated with work impairment. Causal mediation analyses were performed to delineate the relationship between work impairment, psychological distress and fear of COVID-19. RESULTS: The analytic sample included 386 geriatricians, and work impairment was observed in 24.8% of them. Work impairment was associated with age, prefecture where the institution was located and fear of COVID-19. Mediation analysis showed that the effect of fear of COVID-19 on work impairment was almost completely mediated by psychological distress. CONCLUSION: During the COVID-19 pandemic, work impairment was commonly observed among geriatricians. We found that fear of COVID-19 might cause work impairment; however, this effect was exerted entirely through psychological distress. This implies that interventions to prevent or reduce work impairment among doctors should mainly target psychological distress; however, the fear of COVID-19, if it causes psychological distress, should also be addressed. Managers of hospitals and long-term care facilities must take steps to protect healthcare workers' mental well-being and maintain work productivity. Therefore, understanding the factors related to work impairment might help them devise effective measures. Geriatr Gerontol Int 2024; 24: 215-220.

Changing trends in health orientation among older adults: A scoping review.

Older people's health condition is not uniform, and the components of their health are interrelated. Concepts regarding the health of older people have emerged and changed over time. However, the transition of concepts and influencing factors are not well examined through research. We have conducted a scoping review of the changes over time in the concept of health for older people and the factors influencing these changes. The public websites of international organizations and academic societies related to older people's health and research paper database were searched, and the extracted data were summarized in a chronological table. Consequently, this study revealed changing trends in health orientation after health had been defined by WHO, namely, successful aging, productive aging, active aging, and healthy aging, and their components, not the concept of health. The emergence and changes of health orientation among older people may have accompanied proposals and measures of international organizations and academic societies developed in response to changes in the demographic structure, and changes in how society perceives and supports older people. With the changing eras that bring about advances in health technology, prolongation of life expectancy, and changes in lifestyles, the needs of older people, society's perceptions of aging and older people, and how to support them will also change. Our findings may provide a valuable basis for understanding aging and older people, reconsidering their health orientation based on the health issues of older people and their significance, and formulating policies for older people in the future. Geriatr Gerontol Int 2024; 24: 5-17.

Engineering CD3/CD137 dual specificity into a DLL3-targeted T-cell engager enhances T-cell infiltration and efficacy against small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive cancer for which immune checkpoint inhibitors (ICIs) have had only limited success. Bispecific T-cell engagers are promising therapeutic alternatives for ICI-resistant tumors, but not all SCLC patients are responsive. Herein, to integrate CD137 costimulatory function into a T-cell engager format and thereby augment therapeutic efficacy, we generated a CD3/CD137 dual-specific Fab and engineered a DLL3-targeted trispecific antibody (DLL3 trispecific). The CD3/CD137 dual-specific Fab was generated to competitively bind to CD3 and CD137 to prevent DLL3-independent cross-linking of CD3 and CD137, which could lead to systemic T-cell activation. We demonstrated that DLL3 trispecific induced better tumor growth control and a marked increase in the number of intratumoral T cells compared to a conventional DLL3-targeted bispecific T-cell engager. These findings suggest that DLL3 trispecific can exert potent efficacy by inducing concurrent CD137 costimulation and provide a promising therapeutic option for SCLC.

Engineering CD3/CD137 Dual Specificity into a DLL3-Targeted T-Cell Engager Enhances T-Cell Infiltration and Efficacy against Small-Cell Lung Cancer.

Small-cell lung cancer (SCLC) is an aggressive cancer for which immune checkpoint inhibitors (ICI) have had only limited success. Bispecific T-cell engagers are promising therapeutic alternatives for ICI-resistant tumors, but not all patients with SCLC are responsive. Herein, to integrate CD137 costimulatory function into a T-cell engager format and thereby augment therapeutic efficacy, we generated a CD3/CD137 dual-specific Fab and engineered a DLL3-targeted trispecific antibody (DLL3 trispecific). The CD3/CD137 dual-specific Fab was generated to competitively bind to CD3 and CD137 to prevent DLL3-independent cross-linking of CD3 and CD137, which could lead to systemic T-cell activation. We demonstrated that DLL3 trispecific induced better tumor growth control and a marked increase in the number of intratumoral T cells compared with a conventional DLL3-targeted bispecific T-cell engager. These findings suggest that DLL3 trispecific can exert potent efficacy by inducing concurrent CD137 costimulation and provide a promising therapeutic option for SCLC.

Prevalence of dementia in Japan: a systematic review.

BACKGROUND/AIMS: The actual prevalence of dementia in Japan as well as the changes in the prevalence are not well known. Therefore, we undertook a systematic review to collect evidence regarding the prevalence of dementia in Japan. METHODS: For this systematic review, we searched 2 electronic databases to identify cross-sectional or repeated cross-sectional studies with data regarding the study population, study location, diagnostic criteria, and prevalence of dementia. RESULTS: Twenty-one studies were selected from 782 references. Sixteen studies surveyed individuals living at home; of these, 5 studies also included hospitalized or institutionalized patients. Most of the studies were conducted using a two-phase survey (phase I: screening, phase II: diagnosis of dementia). The clinical diagnosis of dementia was made based on the guidelines of the Diagnostic and Statistical Manual of Mental Disorders (DSM) in a majority of the studies. The prevalence of all types of dementia ranged from 2.9 to 12.5% and has been gradually increasing over the past few years. CONCLUSION: The results of this systematic review suggest that the prevalence of dementia has recently increased. However, further well-designed studies taking into account factors that affect the prevalence of dementia are needed to clarify the actual prevalence.

Impact of COVID-19 on Long-Term Care Service Utilization of Older Home-Dwelling Adults in Japan.

OBJECTIVES: The COVID-19 outbreak severely affected long-term care (LTC) service provision. This study aimed to quantitatively evaluate its impact on the utilization of LTC services by older home-dwelling adults and identify its associated factors. DESIGN: A retrospective repeated cross-sectional study. SETTING AND PARTICIPANTS: Data from a nationwide LTC Insurance Comprehensive Database comprising monthly claims from January 2019 to September 2020. METHODS: Interrupted time series analyses and segmented negative binomial regression were employed to examine changes in use for each of the 15 LTC services. Results of the analyses were synthesized using random effects meta-analysis in 3 service types (home visit, commuting, and short-stay services). RESULTS: LTC service use declined in April 2020 when the state of emergency (SOE) was declared, followed by a gradual recovery in June after the SOE was lifted. There was a significant association between decline in LTC service use and SOE, whereas the association between LTC service use and the status of the infection spread was limited. Service type was associated with changes in service utilization, with a more precipitous decline in commuting and short-stay services than in home visiting services during the SOE. Service use by those with dementia was higher than that by those without dementia, particularly in commuting and short-stay services, partially canceling out the decline in service use that occurred during the SOE. CONCLUSIONS AND IMPLICATIONS: There was a significant decline in LTC service utilization during the SOE. The decline varied depending on service types and the dementia severity of service users. These findings would help LTC professionals identify vulnerable groups and guide future plans geared toward effective infection prevention while alleviating unfavorable impacts by infection prevention measures. Future studies are required to examine the effects of the LTC service decline on older adults.