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 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.

Characterizations of a neutralizing antibody broadly reactive to multiple gluten peptide:HLA-DQ2.5 complexes in the context of celiac disease.

In human celiac disease (CeD) HLA-DQ2.5 presents gluten peptides to antigen-specific CD4+ T cells, thereby instigating immune activation and enteropathy. Targeting HLA-DQ2.5 with neutralizing antibody for treating CeD may be plausible, yet using pan-HLA-DQ antibody risks affecting systemic immunity, while targeting selected gluten peptide:HLA-DQ2.5 complex (pHLA-DQ2.5) may be insufficient. Here we generate a TCR-like, neutralizing antibody (DONQ52) that broadly recognizes more than twenty-five distinct gluten pHLA-DQ2.5 through rabbit immunization with multi-epitope gluten pHLA-DQ2.5 and multidimensional optimization. Structural analyses show that the proline-rich and glutamine-rich motif of gluten epitopes critical for pathogenesis is flexibly recognized by multiple tyrosine residues present in the antibody paratope, implicating the mechanisms for the broad reactivity. In HLA-DQ2.5 transgenic mice, DONQ52 demonstrates favorable pharmacokinetics with high subcutaneous bioavailability, and blocks immunity to gluten while not affecting systemic immunity. Our results thus provide a rationale for clinical testing of DONQ52 in CeD.

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.

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.

How the 2018 Japan Floods Impacted Nursing Home Admissions for Older Persons: A Longitudinal Study Using the Long-Term Care Insurance Comprehensive Database.

OBJECTIVES: As disasters become more frequent because of global warming, countries across the world are seeking ways to protect vulnerable older populations. Although these conditions may increase nursing home admission (NHA) rates for older persons, we know of no studies that have directly tested this hypothesis. DESIGN: This was a retrospective cohort study. SETTING AND PARTICIPANTS: We analyzed data from long-term care insurance (LTCI) users in 3 Japanese prefectures that incurred heavy damage from the 2018 Japan Floods, which is the largest recorded flooding disaster in national history. Specifically, we extracted NHA data from the LTCI comprehensive database, both for disaster-affected and unaffected individuals. METHODS: We employed the Cox proportional hazards model to calculate multivariate-adjusted hazard ratios (HRs) for NHAs within a 6-month period following the 2018 Japan Floods, with adjustments for potential confounding factors. RESULTS: Of the 187,861 individuals who used LTCI services during the investigated period, we identified 2156 (1.1%) as disaster affected. The HR for NHA was significantly higher for disaster-affected (vs unaffected) individuals (adjusted HR 3.23: 95% CI 2.88‒3.64), and also higher than the HRs for older age (90-94 years vs 65-69 years: 2.29, CI 1.93‒2.70), cognitive impairment (severe impairment vs normal: 1.40, CI 1.25‒1.57), and physical function (bedridden vs independent: 2.27, CI 1.83‒2.70). According to our subgroup analyses, the adjusted HR for disaster-affected individuals unable to feed themselves was 6.00 (CI 3.68‒9.79), with a significant interaction between the 2 variables (P = .01). CONCLUSIONS AND IMPLICATIONS: Natural disasters increase the risk of NHA for older persons, especially those who are unable to feed themselves. Health care providers and policymakers should understand and prepare for this emerging risk factor.

Association of disability level with polypharmacy and potentially inappropriate medication in community dwelling older people.

AIMS: To investigate the influence of disability severity level on polypharmacy and the prescription of potentially inappropriate medication (PIM) using health insurance and long-term care (LTC) insurance claim data. METHODS: Data were obtained from a health-care insurance and long-term care insurance claims database of citizens of Kure city, Japan, in April 2017. Data including age, sex, and drug profile were obtained, and the level of LTC needs was used to measure disability level. Factors associated with polypharmacy (≥5 prescribed drugs) and PIM prescription (≥1 PIM) defined by STOPP-J were analyzed statistically. RESULTS: Among 67,169 people aged ≥65 (mean age 77.2 ± 7.9, male 40.7%), the frequency of polypharmacy increased with age until 85-89 (male 58.3%, female 57.6%) in both genders, and polypharmacy was most prevalent in those at the mildest LTC level (support level: male 68.9%, female 73.7%). PIM prescriptions was also frequent in those with LTC needs. On multiple logistic regression analysis, polypharmacy was significantly associated with older age and LTC needs, and PIM prescription was associated with older age and higher LTC level, suggesting that there is a large difference in prescription according to the person's age and disability level. CONCLUSION: Polypharmacy was prevalent especially in older persons which peaked at the age of 85-89 or at mild disability level, and PIM prescription was prevalent in those with older age and higher care levels. When optimizing polypharmacy or PIM prescription in older patients, healthcare providers should focus on not only age but also disability level.

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.

The role of discrimination in the relation between COVID-19 sequelae, psychological distress, and work impairment in COVID-19 survivors.

Perceived discrimination and work impairment are commonly observed in COVID-19 survivors, but their relationship has not been well understood. We aimed to evaluate the role of discrimination in the development of psychological distress and work impairment in COVID-19 survivors. From April 2020 to November 2021, 309 patients were recruited at two designated COVID-19 hospitals in Japan. Participants completed a standardized questionnaire including COVID-19 sequelae, psychological distress, impairments in work performance and perceived discrimination. The majority of participants (62.5%) experienced one or more COVID-19 sequelae. Psychological distress was observed in 36.9% and work impairment in 37.9%. In multivariate logistic regression analyses, COVID-19 sequelae and discrimination were associated with both psychological distress and work impairment. Mediation analysis demonstrated that the direct effect of sequelae on work impairment was non-significant after accounting for psychological distress, suggesting that the effect of sequelae on work impairment was mainly mediated through psychological distress. These findings were replicated in a subgroup analysis limited to patients with mild COVID-19. We conclude that discrimination plays an important role in the development of psychological distress and work impairment, and that both discrimination and psychological distress should be targets of intervention in COVID-19 survivors.

Development of a predictive model using the Kihon Checklist for older adults at risk of needing long-term care based on cohort data of 19 months.

AIM: This study developed a risk scoring tool and examined its applicability using data from the Kihon Checklist cohort dataset for 19 months to predict the transition from no certification for long-term care to long-term care level 3 or above. METHODS: Data were collected from 26 357 functionally independent, community-dwelling older adults in a Japanese city who answered the Checklist in 2014 and were followed for 19 months. Individuals certified for long-term care during the follow-up period were classified into three levels depending on their certification status: low, moderate, and high long-term care levels. Relationships between the Kihon Checklist domains and high long-term care levels were examined using the logistic regression model. A score chart predicting incidents of high long-term care levels was created to facilitate its applicability. RESULTS: As of 2016, 971 participants were certified for long-term care (3.7%), of which 168 (0.6%), 357 (1.4%), and 446 (1.7%) were certified as high, moderate, and low long-term care levels, respectively. Variables associated with the certification of high long-term care level included difficulties in activities of daily living, a decline in locomotor and cognitive function in the Kihon Checklist domains, and age. The score chart was created based on these variables and demonstrated excellent discriminatory ability, with an area under curve of 0.817 (95% confidence interval: 0.785-0.849). CONCLUSIONS: The Kihon Checklist can predict the future development of a high degree of dependency. The score chart we developed can be easily implemented to identify older adults at high risk with reasonable accuracy. Geriatr Gerontol Int 2022; 22: 797-802.

Change in long-term care service usage in Japan following the COVID-19 pandemic: A survey using a nationwide statistical summary in 2018-2021.

AIM: Social restrictions due to the coronavirus disease (COVID-19) pandemic forced many long-term care (LTC) service-users to refrain from using services. We aimed to evaluate the degree of change in the use of LTC services. METHODS: We retrospectively analyzed data from the publicly distributed nationwide statistics summarizing the monthly number of public LTC insurance users in Japan between April 2018 and March 2021. The degree of decline was quantified as a ratio, where the ratio of a certain month to the reference month was divided by the ratio in the previous year. RESULTS: The use of LTC services started to decline in March 2020 and reached its largest decline in May 2020. Thereafter, it recovered but insufficiently, even as of late 2020. The degree of decline was particularly large for services provided in facilities for community-dwelling elderly individuals [Ratio to the previous year = 0.717 (95% CI: 0.645-0.796) in short-stay services, and Ratio = 0.876 (95% CI: 0.802-0.957) in outpatient services], but was non-significant in other types of services, including those provided for elderly individuals living in nursing homes. CONCLUSIONS: Community-dwelling elderly individuals who had used outpatient or short-stay services were especially affected by the COVID-19 pandemic in 2020. This underlines the need for further investigation of the medium- or long-term influence of the decline in service usage on the mental and physical health of the LTC service-users and their caregivers. Geriatr Gerontol Int 2022; 22: 803-809.

Long-term impact of the COVID-19 pandemic on facility- and home-dwelling people with dementia: Perspectives from professionals involved in dementia care.

AIM: The present study aimed to investigate the impact of the coronavirus disease 2019 (COVID-19) pandemic on facility- and home-dwelling people with dementia (PWD). METHODS: This observational study included two anonymous online survey questionnaires to explore the impact of the first wave of the COVID-19 pandemic in Japan and the long-term impact during the 2 years from the onset of the pandemic. The participants were medical and long-term care facilities representatives for older people (945 facilities in the first survey, 686 in the second), and care managers (751 in the first survey, 241 in the second). A χ2 -test was carried out between the two surveys. RESULTS: For facility-dwelling PWD, activities that stimulate cognitive and physical functioning increased significantly compared with the first wave of the pandemic (P < 0.05). Also, a decline in cognitive and walking functions and falls increased in the second survey compared with the first (P < 0.01). For home-dwelling PWD, the broader impact of the pandemic on support for activities of daily living, social interaction and provision of medical care did not mitigate. The high prevalence of cognitive and physical functional decline in the first survey was similar in the second. CONCLUSIONS: The prolonged COVID-19 pandemic produced changes in the lives of home- and facility-dwelling PWD, with widespread negative consequences for them. Our findings are useful to consider preventive supports to mitigate or avoid functional decline and symptom exacerbation in PWD due to changes in their living environment and the care they receive in the COVID-19 era. Geriatr Gerontol Int 2022; 22: 832-838.