Ethnic disparities in cardiovascular and renal responses to canagliflozin between Asian and White patients with type 2 diabetes mellitus: A post hoc analysis of the CANVAS Program.

AIM: To assess the potential heterogeneity in cardiovascular (CV), renal and safety outcomes of canagliflozin between Whites and Asians, as well as these outcomes in each subgroup. MATERIALS AND METHODS: The CANVAS Program enrolled 10 142 patients with type 2 diabetes, comprising 78.34% Whites and 12.66% Asians. CV, renal and safety outcomes were comprehensively analysed using Cox regression models, while intermediate markers were assessed using time-varying mixed-effects models. Racial heterogeneity was evaluated by adding a treatment-race interacion term. RESULTS: Canagliflozin showed no significant racial disparities in the majority of the CV, renal and safety outcomes. The heterogeneity (p = .04) was observed on all-cause mortality, with reduced risk in Whites (hazard ratio 0.84; 95% confidence interval 0.71-0.99) and a statistically non-significant increased risk in Asians (hazard ratio 1.64; 95% confidence interval 0.94-2.90). There was a significant racial difference in acute kidney injury (p = .04) and a marginally significant racial heterogeneity for the composite of hospitalization for heart failure and CV death (p = .06) and serious renal-related adverse events (p = .07). CONCLUSION: Canagliflozin reduced CV and renal risks similarly in Whites and Asians; however, there was a significant racial discrepancy in all-cause mortality. This distinction may be attributed to the fact that Asian patients exhibited diminished CV protection effects and more renal adverse events with canagliflozin, potentially resulting from the smaller reductions in weight and uric acid. These findings highlight the importance of investigating the impact of race on treatment response to sodium-glucose cotransporter-2 inhibitors and provide more precise treatment strategies.

Sex steroid and cognitive function among community-dwelling older men with or without vascular risk factors: a cross-sectional study.

BACKGROUND: The relationship of testosterone and estradiol concentrations with cognitive function among community-dwelling older men was inconclusive. To examine the association of serum testosterone and estradiol concentrations with cognitive function in older men with or without vascular risk factors (VRFs). METHODS: This cross-sectional study consisted of 224 community-dwelling men aged 65-90 years in the Songjiang District of Shanghai, China. Serum testosterone and estradiol were measured by electrochemiluminescence immunoassay. The following five factors were defined as VRFs in this study: obesity, history of hypertension, diabetes, stroke, and coronary heart disease. Multivariable linear regression was used to examine the association of testosterone and estradiol with the Mini-Mental State Examination (MMSE) in participants with or without VRF. Restricted cubic spline (RCS) regression was performed to account for the nonlinearity of these associations. RESULTS: An inverted "U" shaped non-linear relationship was found between testosterone concentration and MMSE score in men with one VRF (P overall =.003, non-linear P =.002). Estradiol showed an inverted "U" shaped non-linear relationship with MMSE score independent of VRFs (men without VRF, P overall =.049, non-linear P =.015; men with one VRF, overall P =.007, non-linear P =.003; men with two or more VRFs, overall P =.009, non-linear P =.005). CONCLUSION: In older men, an optimal level of sex steroid concentration may be beneficial to cognitive function and the VRFs should be considered when interpreting the relationship between sex steroid and cognitive function.

A cohort study of self-perception of ageing and all-cause mortality among older adults in China: a multiple mediators analysis.

BACKGROUND: Positive self-perception of aging (SPA) is a well-known predictor of longevity, while how and to what extent SPA is linked with all-cause mortality among older adults is still unclear. This study aims to elucidate the relationship between positive SPA and all-cause mortality and its potential mediators among Chinese older adults. METHODS: This is a 20-year dynamic cohort study conducted among 22,957 older adults aged ≥ 65 years old from a nationally representative sample. Positive SPA was measured using a validated 7-item scale. Potential mediators including health behaviors and social participation were collected using a self-reported questionnaire. Cox proportional hazards regression models were conducted to examine the association between positive SPA and all-cause mortality. A mediation analysis was conducted to determine whether health behaviors and social participation mediated the association between SPA and all-cause mortality. RESULTS: Throughout follow-up (median [interquartile range], 46 [21-84] months), all-cause mortality was 87.4%. Compared with older adults with the lowest quartile positive SPA, hazard ratio(HR) of all-cause mortality among older adults with the second, third, and fourth quartile of positive SPA was 0.96(95%CI:0.93-1.00), 0.93(95%CI:0.90-0.99), and 0.92(95%CI:0.87-0.96) respectively after controlling for all potential mediators and covariates. The mediation analysis showed that regular daily vegetable intake, physical activity, and high social participation explained 41.1-48.5% of the variance in the association between positive SPA and all-cause mortality. CONCLUSIONS: In this cohort study, we found that high positive SPA was associated with decreased all-cause mortality directly, and indirectly through healthy lifestyle behaviors and social participation. These findings suggest that interventions targeted at promoting or maintaining positive SPA may contribute to healthy ageing among older adults in China.

Joint effect of testosterone and neurofilament light chain on cognitive decline in men: The Shanghai Aging Study.

INTRODUCTION: The association of testosterone and cognitive decline is inconclusive, and its joint effect with neurofilaments light chain (NfL) remains largely unknown. METHODS: A total of 581 non-demented older men in the Shanghai Aging Study were included. Blood total testosterone (TT), free testosterone (FT), and NfL were measured at baseline. The relationships between TT, FT, TT/FT-NfL, and cognitive decline were explored by Cox regression models. RESULTS: During a median follow-up of 6.7 years, there was an inverse association between TT/FT and cognitive decline (TT, trend p = .004, Q1 vs Q4, hazard ratio [HR] = 4.39, 95% confidence interval [CI] = 1.60 to 12.04; FT, trend p = .002, Q1 vs Q4, HR = 5.29, 95% CI = 1.50 to 16.89). Compared to participants with high TT/FT-low NfL, those with low TT/FT-high NfL had significantly higher risks of cognitive decline (TT, HR = 5.10, 95% CI = 1.11 to 23.40; FT, HR = 6.14, 95% CI = 1.34 to 28.06). DISCUSSION: Our findings suggest that the combination of testosterone and neurodegenerative markers may provide reliable predictive insights into future cognitive decline. HIGHLIGHTS: Testosterone is inversely associated with cognitive decline in older men. There is a joint effect of testosterone and NfL on cognitive decline. Sex hormone and neurodegeneration may synergistically contribute to cognitive deterioration.

Life expectancy among older adults with or without frailty in China: multistate modelling of a national longitudinal cohort study.

BACKGROUND: Little is known about life expectancy (LE) with or without frailty. We aimed to estimate the total LE and duration of the state of frailty in China. METHODS: This study included older adults aged 65 years and older from the Chinese Longitudinal Healthy Longevity Study (CLHLS). Frailty status was classified into robust, pre-frailty and frailty based on a cumulative deficit model. Total and specific frailty state LEs at 65 years of age were estimated and stratified by demographic characteristics, behaviours, and psychosocial factors using continuous-time multistate modelling. RESULTS: The total LE of older adults aged 65 years in China was 14.74 years on average (95% CI: 14.52-14.94), of which 4.18 years (95% CI: 4.05-4.30) were robust, 7.46 years (95% CI: 7.31-7.61) pre-frail and 3.10 years (95% CI: 3.01-3.20) frail. Older adults with higher robust LE included men (4.71 years, 95% CI: 4.56-4.88), married older adults (4.41 years, 95% CI: 4.27-4.56), those engaging in physical activity (4.41 years, 95% CI: 4.23-4.59), those consuming fruits daily (4.48 years, 95% CI: 4.22-4.77) and those with high social participation (4.39 years, 95% CI: 4.26-4.53). Increased educational attainment were gradually associated with increased robust LE. CONCLUSIONS: Frailty may lead to a reduced total LE and robust LE of older adults in China. In addition to finding inequalities in total and robust LEs by socioeconomic status, our findings also highlight that healthy behaviours and social participation may ease frailty-related reductions in total and robust LE. Our findings imply that national life-course strategies aimed at frailty screening and psychosocial and behavioural interventions could be important for health aging in China.

Association between alcohol use and frailty among elder adults in three Chinese cities.

BACKGROUND: Frailty is often described as a condition of the elderly and alcohol use is associated with frailty. The aim of this study is to examine the associations between alcohol use and frailty in three cities in elder adults. METHODS: A cross-sectional study was conducted in three cities in China from June 2017 to October 2018. In total, 2888 residents aged ≥65 years old were selected by using a multi-level stage sampling procedure. Alcohol use was assessed by Focusing on Cutting down, Annoyance by criticism, Guilty feeling, and Eye-openers (CAGE) four-item questionnaire. Frailty was measured by a validated Chinese version of the Fatigue, Resistance, Ambulation, Illness, and Loss of weight (FRAIL) scale. Multinomial logistic regressions were used to examine the association of alcohol use with pre-frailty and frailty after controlling for varied covariates. RESULTS: In general, the prevalence of pre-frailty and frailty was 38.64 and 20.26%, respectively. After controlling for covariates and interaction of age and problematic drinking, non-problematic drinkers neither had association with pre-frailty (OR: 1.15, 95%CI:0.86-1.52) nor with frailty (OR:0.90, 95%CI:0.60-1.36), and problematic drinkers neither had association with frailty (OR: 1.21, 95%CI:0.83-1.76), while problematic drinkers had high odd ratios of frailty (OR:3.28, 95%CI:2.02-5.33) compared with zero-drinker. CONCLUSIONS: Our study found a positive association between problematic drinking and frailty, no relationship between non-problematic drinking and (pre-)frailty compared with zero-drinking among Chinese elder adults. Based on previous findings and ours, we conclude it is important for the prevention of frailty to advocate no problematic drinking among elder adults.

Development of 10-Hydroxycamptothecin-crizotinib conjugate based on the synergistic effect on lung cancer cells.

The effect of the combination of 10-Hydroxycamptothecin (HCPT) and crizotinib (CRI) on EGFR- and KRAS-mutant lung cancer cells was investigated and the conjugates of the two drugs were synthesised. HCPT combined with CRI synergistically inhibited the cell growth and proliferation of H1975, HCC827, and H460 without aggravating adverse effect on the normal cells. The combination synergistically enhanced the cell apoptosis rate through releasing Cyto-C by activation of Bcl-2 family-mediated mitochondrial signalling, which was associate with inactivating of EGFR related downstream signalling pathways including AKT, ERK, JNK, and p38 MAPK. Based on this synergy, the conjugates of HCPT and CRI (compounds CH-1 and CH-2) with different chemical bonds were synthesised. Compound CH-1 exhibited stronger cytotoxicity than HCPT and CRI alone or in combination. The combination of HCPT and CRI might be a promising therapeutic regimen and the conjugate CH-1was a potential target drug for the treatment of lung cancer.

Peli1 signaling blockade attenuates congenital zika syndrome.

Zika virus (ZIKV) infects pregnant women and causes devastating congenital zika syndrome (CZS). How the virus is vertically transmitted to the fetus and induces neuronal loss remains unclear. We previously reported that Pellino (Peli)1, an E3 ubiquitin ligase, promotes p38MAPK activation in microglia and induction of lethal encephalitis by facilitating the replication of West Nile virus (WNV), a closely related flavivirus. Here, we found that Peli1 expression was induced on ZIKV-infected human monocytic cells, peripheral blood mononuclear cells, human first-trimester placental trophoblasts, and neural stem cell (hNSC)s. Peli1 mediates ZIKV cell attachment, entry and viral translation and its expression is confined to the endoplasmic reticulum. Moreover, Peli1 mediated inflammatory cytokine and chemokine responses and induced cell death in placental trophoblasts and hNSCs. ZIKV-infected pregnant mice lacking Peli1 signaling had reduced placental inflammation and tissue damage, which resulted in attenuated congenital abnormalities. Smaducin-6, a membrane-tethered Smad6-derived peptide, blocked Peli1-mediated NF-κB activation but did not have direct effects on ZIKV infection. Smaducin-6 reduced inflammatory responses and cell death in placental trophoblasts and hNSCs, and diminished placental inflammation and damage, leading to attenuated congenital malformations in mice. Collectively, our results reveal a novel role of Peli1 in flavivirus pathogenesis and suggest that Peli1 promotes ZIKV vertical transmission and neuronal loss by mediating inflammatory cytokine responses and induction of cell death. Our results also identify Smaducin-6 as a potential therapeutic candidate for treatment of CZS.

Dimethylarginine dimethylaminohydrolase 1 protects PM2.5 exposure-induced lung injury in mice by repressing inflammation and oxidative stress.

BACKGROUND: Airborne fine particulate matter with aerodynamic diameter ≤ 2.5 µm (PM2.5) pollution is associated with the prevalence of respiratory diseases, including asthma, bronchitis and chronic obstructive pulmonary disease. In patients with those diseases, circulating asymmetric dimethylarginine (ADMA) levels are increased, which contributes to airway nitric oxide deficiency, oxidative stress and inflammation. Overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1), an enzyme degrading ADMA, exerts protective effects in animal models. However, the impact of DDAH1/ADMA on PM2.5-induced lung injury has not been investigated. METHODS: Ddah1-/- and DDAH1-transgenic mice, as well as their respective wild-type (WT) littermates, were exposed to either filtered air or airborne PM2.5 (mean daily concentration ~ 50 µg/m3) for 6 months through a whole-body exposure system. Mice were also acutely exposed to 10 mg/kg PM2.5 and/or exogenous ADMA (2 mg/kg) via intratracheal instillation every other day for 2 weeks. Inflammatory response, oxidative stress and related gene expressions in the lungs were examined. In addition, RAW264.7 cells were exposed to PM2.5 and/or ADMA and the changes in intracellular oxidative stress and inflammatory response were determined. RESULTS: Ddah1-/- mice developed more severe lung injury than WT mice after long-term PM2.5 exposure, which was associated with greater induction of pulmonary oxidative stress and inflammation. In the lungs of PM2.5-exposed mice, Ddah1 deficiency increased protein expression of p-p65, iNOS and Bax, and decreased protein expression of Bcl-2, SOD1 and peroxiredoxin 4. Conversely, DDAH1 overexpression significantly alleviated lung injury, attenuated pulmonary oxidative stress and inflammation, and exerted opposite effects on those proteins in PM2.5-exposed mice. In addition, exogenous ADMA administration could mimic the effect of Ddah1 deficiency on PM2.5-induced lung injury, oxidative stress and inflammation. In PM2.5-exposed macrophages, ADMA aggravated the inflammatory response and oxidative stress in an iNOS-dependent manner. CONCLUSION: Our data revealed that DDAH1 has a marked protective effect on long-term PM2.5 exposure-induced lung injury.

Sleep characteristic profiles and the correlation with spectrum of metabolic syndrome among older adult: a cross-sectional study.

BACKGROUND: Metabolic Syndrome (MetS) is a common health problem among older adults. Previous studies have revealed the relationship between sleep duration as well as global sleep status and MetS. OBJECTIVES: This study aims to examine the association between the specific sleep characteristic and MetS as well as MetS components among community-dwelling old adults. METHODS: This cross-sectional study included 1499 community residents aged ≥ 60 years. Sleep characteristics were assessed using the Pittsburgh Sleep Quality Index (PSQI) and bed/rise time of the residents. Logistic regression analysis and multiple linear regression analysis were used to examine the associations between sleep characteristics and MetS as well as MetS components. A generalized additive model was built to assess the smooth relationship between triglyceride (TG) levels and sleep duration. RESULTS: Of the 1499 participants, 449 (30.0%) had MetS, and 443 (29.6%) had poor sleep quality. The rise time was found to be associated with MetS (> 6:00 vs. 5:00 ~ 6:00: adjusted OR (95%) = 1.77 (1.17-2.69), P = 0.007). For the MetS components, a U-shaped relationship was first revealed for sleep duration and TG levels (EDF = 1.85, P < 0.001). Furthermore, significant associations also included the associations of subjective sleep quality and daytime dysfunction with hypertension, the associations of sleep efficiency and rise time with hyperglycemia, the associations of rise time with TG levels, and the association of bedtime with waist circumference. CONCLUSIONS: The different sleep characteristics were associated with different MetS components.

Motor neuron disease-associated loss of nuclear TDP-43 is linked to DNA double-strand break repair defects.

Genome damage and their defective repair have been etiologically linked to degenerating neurons in many subtypes of amyotrophic lateral sclerosis (ALS) patients; however, the specific mechanisms remain enigmatic. The majority of sporadic ALS patients feature abnormalities in the transactivation response DNA-binding protein of 43 kDa (TDP-43), whose nucleo-cytoplasmic mislocalization is characteristically observed in spinal motor neurons. While emerging evidence suggests involvement of other RNA/DNA binding proteins, like FUS in DNA damage response (DDR), the role of TDP-43 in DDR has not been investigated. Here, we report that TDP-43 is a critical component of the nonhomologous end joining (NHEJ)-mediated DNA double-strand break (DSB) repair pathway. TDP-43 is rapidly recruited at DSB sites to stably interact with DDR and NHEJ factors, specifically acting as a scaffold for the recruitment of break-sealing XRCC4-DNA ligase 4 complex at DSB sites in induced pluripotent stem cell-derived motor neurons. shRNA or CRISPR/Cas9-mediated conditional depletion of TDP-43 markedly increases accumulation of genomic DSBs by impairing NHEJ repair, and thereby, sensitizing neurons to DSB stress. Finally, TDP-43 pathology strongly correlates with DSB repair defects, and damage accumulation in the neuronal genomes of sporadic ALS patients and in Caenorhabditis elegans mutant with TDP-1 loss-of-function. Our findings thus link TDP-43 pathology to impaired DSB repair and persistent DDR signaling in motor neuron disease, and suggest that DSB repair-targeted therapies may ameliorate TDP-43 toxicity-induced genome instability in motor neuron disease.

Work competence of general practitioners working in the community health services of Shanghai: a cross-sectional study based on self-assessment.

OBJECTIVES: The aim of the study was to investigate the work competence of general practitioners (GPs) in the community health services (CHSs) of Shanghai, China. METHODS: A questionnaire was designed based on a previous capacity evaluation indicator system. We used a stratified and proportional cluster sampling method in this self-assessment and cross-sectional study. We collected data with the questionnaire on GPs' demographic variables and work competence including patient care ability, teaching ability, communication skill and coordination ability. Univariate analyses were performed by Mann-Whitney U test and Kolmogorov-Smirnov test. Multivariate analyses were done with generalized liner model with significant univariate factors. RESULTS: A total of 2954 GPs were sampled from 116 CHSs in Shanghai. The response rate was 99.9%. The median scores of patient care ability, teaching ability, communication skill and coordination ability were 80[70-88.75], 76[60-80] and 80[70-85] on a scale of 100, respectively. GPs who were 30-39 years old, or worked in urban CHSs, or took GP trainer's training or had teaching experience got higher scores in patient care ability. GPs who worked for 5-19 years in CHSs, or worked in CHSs with GP training program or took GP trainer's training had higher scores in teaching ability. For communication skill and coordination ability, GPs who worked in CHSs with GP standardized training program, or took GP trainer's training or had teaching experience in CHSs got higher scores. CONCLUSIONS: The work competence of GPs in CHSs of Shanghai could mainly cover daily work, but still needed more improvement in teaching ability.

Elevated miR-29a Contributes to Axonal Outgrowth and Neurological Recovery After Intracerebral Hemorrhage via Targeting PTEN/PI3K/Akt Pathway.

Spontaneous intracerebral hemorrhage (ICH) is a clinical challenge with high disability and lacks an effective treatment. miR-29a strongly expressed in the brain has been implicated in various neurological disorders. In this study, we investigated the biological roles of miR-29a in axonal outgrowth and neurological outcomes after ICH and relevant molecular mechanism. The rat model of ICH was established by injection of autologous whole blood into the right basal ganglia. First, a significant decrease in miR-29a level was found in perihematomal brain tissues and cerebrospinal fluid (CSF) after ICH in vivo and hemin-treated neurons in vitro. Further study documented that lentivirus-mediated miR-29a overexpression could remarkably attenuate hemorrhagic brain injury, promoted regenerative outgrowth of injured axons and improved neurobehavioral and cognitive impairments after ICH in rats. In addition, we also identified that overexpression of miR-29a obviously alleviated neuronal damage and mitochondrial dysfunctions, and facilitated neurite outgrowth in cultured neurons exposed to hemin in vitro. Furthermore, luciferase reporter assay showed that miR-29a directly targeted the 3'-UTR region of phosphatase and tensin homolog (PTEN) mRNA and negatively regulated its expression. More importantly, pharmacological inhibition of PTEN has similar neuroprotective effects as miR-29a overexpression involving activation of the PI3K/Akt pathway after hemorrhagic stroke. Collectively, these results suggested that elevated miR-29a could contribute to axonal outgrowth and neurological recovery through targeting PTEN/PI3K/Akt pathway after ICH, thereby providing a potential therapeutic target for patients with ICH.

Cognitive leisure activity and all-cause mortality in older adults: a 4-year community-based cohort.

BACKGROUND: Cognitive leisure activity, such as reading, playing mahjong or cards and computer use, is common among older adults in China. Previous studies suggest a negative correlation between cognitive leisure activity and cognitive impairment. However, the relationship between cognitive leisure activity and all-cause mortality has rarely been reported. OBJECTIVES: This study aims to explore the relationships between cognitive leisure activity and all-cause mortality in a community-based older people cohort in China. METHODS: The current study sample comprised 4003 community residents aged ≥60 y who were enrolled in June 2015, and were followed up every year from 2015 to 2018. Reading, playing mahjong or cards and computer use were measured by questionnaires and summed into a cognitive leisure activity index (CLAI) score. Time-Dependent Cox Regression Model and Kaplan-Meier survival analysis were used to examine the association of cognitive leisure activity with all-cause mortality. RESULTS: During the 4-year follow-up of 4003 participants, 208 (5.2%) deaths were registered. Of all participants, 66.8, 26.7, 6.1 and 0.35% reported CLAI scores of 0, 1, 2 and 3, respectively. A strong association was noted between the CLA score and all-cause mortality (adjusted hazard ratio [HR] = 0.72, 95% confidence intervals [CI]: 0.54-0.97, P = 0.028). Stratified analysis suggested that a higher CLAI score was significantly associated with a decreased risk of all-cause mortality mainly among those who were male, aged ≥80 y, cognitively impaired, and not diagnosed with cancer (P < 0.05). CONCLUSION: Cognitive leisure activity was positively associated with reduced risk of death from all cause among the older people in major city of China, which helped promote a comprehensive understanding of health characteristics at advanced ages.

Generalized anxiety disorder and resilience during the COVID-19 pandemic: evidence from China during the early rapid outbreak.

BACKGROUND: Generalized Anxiety Disorder (GAD) is a common but urgent mental health problem during disease outbreaks. Resilience buffers against the negative impacts of life stressors on common internalizing psychopathology such as GAD. This study assesses the prevalence of GAD and examines the protective or compensatory effect of resilience against worry factors during the COVID-19 outbreak. METHODS: A cross-sectional online survey was conducted among Chinese citizens aged ≥18 years from January 31 to February 2, 2020. A total of 4827 participants across 31 provinces and autonomous regions of the mainland of China participated in this study. The Generalized Anxiety Disorder scale (GAD-7), the Connor-Davidson Resilience Scale (CD-RISC), and a self-designed worry questionnaire were used to asses anxiety disorder prevalence, resilience level, and anxiety risk factors. Multivariable logistic regression was used to identify the associations of resilience and worry factors with GAD prevalence after controlling for other covariates. RESULTS: The prevalence of anxiety disorder was 22.6% across the 31 areas, and the highest prevalence was 35.4% in Hubei province. After controlling for covariates, the results suggested a higher GAD prevalence among participants who were worried about themselves or family members being infected with COVID-19 (adjusted odds ratio, AOR 3.40, 95%CI 2.43-4.75), worried about difficulty obtaining masks (AOR 1.92, 95%CI 1.47-2.50), worried about difficulty of distinguishing true information (AOR 1.65, 95%CI 1.36-2.02), worried about the prognosis of COVID-19 (AOR 2.41, 95%CI 1.75-3.33), worried about delays in working (AOR 1.71, 95%CI 1.27-.31), or worried about decreased income (AOR 1.45, 95%CI 1.14-1.85) compared with those without such worries. Additionally, those with a higher resilience level had a lower prevalence of GAD (AOR 0.59, 95%CI 0.51-0.70). Resilience also showed a mediating effect, with a negative influence on worry factors and thereby a negative association with GAD prevalence. CONCLUSION: It may be beneficial to promote public mental health during the COVID-19 outbreak through enhancing resilience, which may buffer against adverse psychological effects from worry factors.

Health Belief Model Perspective on the Control of COVID-19 Vaccine Hesitancy and the Promotion of Vaccination in China: Web-Based Cross-sectional Study.

BACKGROUND: The control of vaccine hesitancy and the promotion of vaccination are key protective measures against COVID-19. OBJECTIVE: This study assesses the prevalence of vaccine hesitancy and the vaccination rate and examines the association between factors of the health belief model (HBM) and vaccination. METHODS: A convenience sample of 2531 valid participants from 31 provinces and autonomous regions of mainland China were enrolled in this online survey study from January 1 to 24, 2021. Multivariable logistic regression was used to identify the associations of the vaccination rate and HBM factors with the prevalence of vaccine hesitancy after other covariates were controlled. RESULTS: The prevalence of vaccine hesitancy was 44.3% (95% CI 42.3%-46.2%), and the vaccination rate was 10.4% (9.2%-11.6%). The factors that directly promoted vaccination behavior were a lack of vaccine hesitancy (odds ratio [OR] 7.75, 95% CI 5.03-11.93), agreement with recommendations from friends or family for vaccination (OR 3.11, 95% CI 1.75-5.52), and absence of perceived barriers to COVID-19 vaccination (OR 0.51, 95% CI 0.35-0.75). The factors that were directly associated with a higher vaccine hesitancy rate were a high level of perceived barriers (OR 1.63, 95% CI 1.36-1.95) and perceived benefits (OR 0.51, 95% CI 0.32-0.79). A mediating effect of self-efficacy, influenced by perceived barriers (standardized structure coefficient [SSC]=-0.71, P<.001), perceived benefits (SSC=0.58, P<.001), agreement with recommendations from authorities (SSC=0.27, P<.001), and agreement with recommendations from friends or family (SSC=0.31, P<.001), was negatively associated with vaccination (SSC=-0.45, P<.001) via vaccine hesitancy (SSC=-0.32, P<.001). CONCLUSIONS: It may be possible to increase the vaccination rate by reducing vaccine hesitancy and perceived barriers to vaccination and by encouraging volunteers to advocate for vaccination to their friends and family members. It is also important to reduce vaccine hesitancy by enhancing self-efficacy for vaccination, due to its crucial mediating function.

Long-term chemogenetic activation of M1 glutamatergic neurons attenuates the behavioral and cognitive deficits caused by intracerebral hemorrhage.

Acute spontaneous intracerebral hemorrhage (ICH) is a life-threatening disease. It is often accompanied by severe neurological sequelae largely caused by the loss of integrity of the neural circuits. However, these neurological sequelae have few strong medical interventions. Designer receptors exclusively activated by designer drugs (DREADDs) are important chemogenetic tools capable of precisely modulating the activity of neural circuits. They have been suggested to have therapeutic effects on multiple neurological diseases. Despite this, no empirical research has explored the effects of DREADDs on functional recovery after ICH. We aimed to explore whether the long-term excitation of glutamatergic neurons in primary motor cortex (M1) by DREADD could promote functional recovery after ICH. We used CaMKII-driven Gq/Gi-DREADDs to activate/inhibit M1 glutamatergic neurons for 21 consecutive days, and examined their effects on behavioral and cognitive deficits caused by ICH in a mouse model of ICH targeting striatum. Long-term chemogenetic activation of the M1 glutamatergic neurons increased the spatial memory and sensorimotor ability of mice suffering from ICH. It also attenuated the mitochondrial dysfunctions of striatal neurons by raising the ATP levels and mitochondrial membrane potential while decreasing the 8-OHdG levels. These results strongly suggest that selective stimulation of the M1 glutamatergic neurons contributes to functional recovery after ICH presumably through alleviation of mitochondrial dysfunctions.

How does ageism influence frailty? A preliminary study using a structural equation model.

BACKGROUND: Based on the Stereotype Embodiment Theory (SET), this study aims to examine the mechanism of ageism on frailty through the proposed framework of "Experiences of Ageism (EA) → Age Stereotypes (AS) → Attitudes to Ageing (AA) → Frailty" using a structural equation model (SEM). METHODS: A community-based study involving 630 participants aged 60 years and older was conducted in Shanghai. EA, AS, AA and frailty status were assessed by validated scales. In particular, EA included three parts in this study, as the first part was the experiences of explicit prejudice or discrimination because of age, another two parts were the experiences of witnessed and encountered implicit negative age-based stereotypes. A SEM was performed to examine whether the proposed paths from EA to frailty were supported. RESULTS: EA had a significant indirect effect (ß' = .360*-.456*-.576 = .095, p < .001) on frailty through the path of "EA → AS → AA → Frailty" after controlling for covariates. AA had a direct effect (ß = -.576, p < .001) on frailty; AS fully mediated the association between EA and AA (indirect effect = .360*-.456 = -.164, p < .001), and AA fully mediated the association between AS and frailty (indirect effect = -.456*-.576 = .263, p < .001). CONCLUSIONS: These findings demonstrated a mechanism from ageism to frailty, and highlighted the potential threat of negative AS on health. Ageism and frailty are both great challenges for the process of healthy ageing.

Changes in frailty among community-dwelling Chinese older adults and its predictors: evidence from a two-year longitudinal study.

BACKGROUND: It is important to clarify the transitions and related factors of frailty for prevention of frailty. We evaluated the transitions of frailty among community-dwelling older adults and examined the predictors of the transitions. METHODS: A cohort study was conducted among 3988 community residents aged ≥60 years during 2015 and 2017. A multiple deficits approach was used to construct the Frailty Index (FI) according to the methodology of FI construction, and sociodemographic characteristics and lifestyles were also collected in 2015. After 2-year follow-up, the transitions of frailty between baseline and were evaluated. Multinomial logistic regressions were used to examine associations between predictors and the transitions of frailty. RESULTS: The proportion of robust, prefrail, and frail was 79.5, 16.4, and 4.1% among 3988 participants at baseline, which changed to 68.2, 23.0, and 8.8% after 2 years with 127 deaths and 23 dropped out. Twelve kinds of transitions from the three frailty statuses at baseline to four outcomes at follow-up (including death) significantly differed within each of gender and age group, as well between genders and age groups. Among these, 7.8% of prefrail or frail elders improved, 70.0% retained their frailty status, and 22.2% of robust or prefrail elders worsened in frailty status. In multivariable models, age was significantly associated with changes in frailty except for in the frail group; higher educational level and working predicted a lower risk of robust worsening. Of the lifestyle predictors, no shower facilities at home predicted a higher risk of robust worsening; more frequent physical exercise predicted a lower risk of robust worsening and a higher chance of frailty improvement; more frequent neighbor interaction predicted a lower risk of robust worsening and prefrail worsening; and more frequent social participation predicted a higher chance of prefrail improvement. CONCLUSIONS: The status of frailty was reversible among community-dwelling elderly, and sociodemographic and lifestyle factors were related to changes in frailty. These findings help health practitioners to recognize susceptible individuals in a community and provide health promotional planning to target aged populations.

Lipoxin A4 Methyl Ester Reduces Early Brain Injury by Inhibition of the Nuclear Factor Kappa B (NF-κB)-Dependent Matrix Metallopeptidase 9 (MMP-9) Pathway in a Rat Model of Intracerebral Hemorrhage.

BACKGROUND Intracerebral hemorrhage (ICH) is associated with inflammation and disruption of the blood-brain barrier (BBB). Lipoxin A4 methyl ester (LXA4 ME), is a stable synthetic analog of lipoxin with anti-inflammatory properties. This study aimed to investigate the effects of LXA4 ME in a rat model of ICH. MATERIAL AND METHODS Male Sprague-Dawley rats (n=120), between 12-13 weeks of age, were divided into the sham group (sham-operated), the vehicle-treated group (ICH+vehicle), the LXA4 ME-L group (ICH+low-dose LXA4 ME, 10 ng/d), and the LXA4 ME-H group (ICH+high-dose LXA4 ME, 100 ng/d). The ICH model was created by injection of autologous blood into the right basal ganglia. LXA4 ME was injected into the ventricle 10 min after the development of ICH. A modified neurological severity score (mNSS), rotarod latencies, and brain water content were used to evaluate the rats. The TUNEL assay measured neuronal cell death. Western blot was used to measure protein expression of nuclear factor kappa B (NF-kappaB), matrix metalloproteinase-9 (MMP-9), zonula occludens-1 (ZO-1), and claudin-5. RESULTS In the rat model of ICH, treatment with LXA4 ME reduced the levels of proinflammatory cytokines, improved neurologic function, reduced neuronal apoptosis, and reduced cerebral edema associated with damage to the BBB, and reduced the expression levels of NF-kB, MMP-9, ZO-1, and claudin-5. CONCLUSIONS In a rat model of ICH, treatment with LXA4 reduced early brain injury and protected the BBB by inhibiting the NF-kappaB-dependent MMP-9 pathway.