Adrenergic microenvironment driven by cancer-associated Schwann cells contributes to chemoresistance in patients with lung cancer.

Doublecortin (DCX)-positive neural progenitor-like cells are purported components of the cancer microenvironment. The number of DCX-positive cells in tissues reportedly correlates with cancer progression; however, little is known about the mechanism by which these cells affect cancer progression. Here we demonstrated that DCX-positive cells, which are found in all major histological subtypes of lung cancer, are cancer-associated Schwann cells (CAS) and contribute to the chemoresistance of lung cancer cells by establishing an adrenergic microenvironment. Mechanistically, the activation of the Hippo transducer YAP/TAZ was involved in the acquisition of new traits of CAS and DCX positivity. We further revealed that CAS express catecholamine-synthesizing enzymes and synthesize adrenaline, which potentiates the chemoresistance of lung cancer cells through the activation of YAP/TAZ. Our findings shed light on CAS, which drive the formation of an adrenergic microenvironment by the reciprocal regulation of YAP/TAZ in lung cancer tissues.

Research progress of microfluidics-based food safety detection.

High demands for food safety detection and analysis have been advocated with people's increasing living standards. Even though numerous analytical testing techniques have been proposed, their widespread adoption is still constrained by the high limit of detection, narrow detection ranges, and high implementation costs. Due to their advantages, such as reduced sample and reagent consumption, high sensitivity, automation, low cost, and portability, using microfluidic devices for food safety monitoring has generated significant interest. This review provides a comprehensive overview of the latest microfluidic detection platforms (published in recent 4 years) and their applications in food safety, aiming to provide references for developing efficient research strategies for food contaminant detection and facilitating the transition of these platforms from laboratory research to practical field use.

A portable CRISPR-Cas12a triggered photothermal biosensor for sensitive and visual detection of Staphylococcus aureus and Listeria monocytogenes.

The detection of foodborne pathogens is crucial for ensuring the maintenance of food safety. In the present study, a portable CRISPR-Cas12a triggered photothermal biosensor integrating branch hybrid chain reaction (bHCR) and DNA metallization strategy for sensitive and visual detection of foodborne pathogens was proposed. The sheared probes were utilized to block the locker probes, which enabled preventing the assembly of bHCR in the absence of target bacteria, while target bacteria can activate the cleavage of sheared probes through CRISPR-Cas12a. Therefore, the locker probes functioned as initiating chains, triggering the formation of the branching double-stranded DNA consisting of H1, H2, and H3. The silver particles, which were in situ deposited on the DNA structure, functioned as a signal factor for conducting photothermal detection. Staphylococcus aureus and Listeria monocytogenes were selected as the foodborne pathogens to verify the analytical performance of this CRISPR-Cas12a triggered photothermal sensor platform. The sensor exhibited a sensitive detection with a low detection limit of 1 CFU/mL, while the concentration ranged from 100 to 108 CFU/mL. Furthermore, this method could efficiently detect target bacteria in multiple food samples. The findings demonstrate that this strategy can serve as a valuable reference for the development of a portable platform enabling quantitative analysis, visualization, and highly sensitive detection of foodborne bacteria.

Tenecteplase versus alteplase in treatment of acute ST-segment elevation myocardial infarction: A randomized non-inferiority trial.

BACKGROUND: A phase II trial on recombinant human tenecteplase tissue-type plasminogen activator (rhTNK-tPA) has previously shown its preliminary efficacy in ST elevation myocardial infarction (STEMI) patients. This study was designed as a pivotal postmarketing trial to compare its efficacy and safety with rrecombinant human tissue-type plasminogen activator alteplase (rt-PA) in Chinese patients with STEMI. METHODS: In this multicenter, randomized, open-label, non-inferiority trial, patients with acute STEMI were randomly assigned (1:1) to receive an intravenous bolus of 16 mg rhTNK-tPA or an intravenous bolus of 8 mg rt-PA followed by an infusion of 42 mg in 90 min. The primary endpoint was recanalization defined by thrombolysis in myocardial infarction (TIMI) flow grade 2 or 3. The secondary endpoint was clinically justified recanalization. Other endpoints included 30-day major adverse cardiovascular and cerebrovascular events (MACCEs) and safety endpoints. RESULTS: From July 2016 to September 2019, 767 eligible patients were randomly assigned to receive rhTNK-tPA ( n = 384) or rt-PA ( n = 383). Among them, 369 patients had coronary angiography data on TIMI flow, and 711 patients had data on clinically justified recanalization. Both used a -15% difference as the non-inferiority efficacy margin. In comparison to rt-PA, both the proportion of patients with TIMI grade 2 or 3 flow (78.3% [148/189] vs. 81.7% [147/180]; differences: -3.4%; 95% confidence interval [CI]: -11.5%, 4.8%) and clinically justified recanalization (85.4% [305/357] vs. 85.9% [304/354]; difference: -0.5%; 95% CI: -5.6%, 4.7%) in the rhTNK-tPA group were non-inferior. The occurrence of 30-day MACCEs (10.2% [39/384] vs. 11.0% [42/383]; hazard ratio: 0.96; 95% CI: 0.61, 1.50) did not differ significantly between groups. No safety outcomes significantly differed between groups. CONCLUSION: rhTNK-tPA was non-inferior to rt-PA in the effect of improving recanalization of the infarct-related artery, a validated surrogate of clinical outcomes, among Chinese patients with acute STEMI. TRIAL REGISTRATION: www.ClinicalTrials.gov (No. NCT02835534).

Facile prepared microfluidic chip for multiplexed digital RT-qPCR test.

The chip-based digital polymerase chain reaction (PCR) is an indispensable technique for amplifying and quantifying nucleic acids, which has been widely employed in molecular diagnostics at both fundamental and clinical levels. However, the previous designs have yet to achieve widespread application due to limitations in complex chip fabrication, pretreatment procedures, special surface properties, and low throughput. This study presents a facile digital microfluidic chip driven by centrifugal force for digital PCR analysis. Interestingly, regardless of the hydrophilicity or hydrophobicity of the inner chip surface, an efficient digitization process can be achieved. PCR reagents introduced into the inlet can be allocated to 9600 microchambers and subsequently isolated by the immiscible phase (silicone oil). The centrifugal priming approach offers a facile means to achieve high-throughput analysis. The design was further employed for the quantification of nucleic acids using digital PCR. The calculated result exhibited a strong correlation with the measured value at the concentrations from 1 copy/µL to 1000 copies/µL (R2  = 0.99). Additionally, the chip also allowed digital multiplexed analysis, thereby indicating its potential for multi-target detection applications.

Acupuncture versus sham acupuncture and usual care for Antiandrogen-Induced hot fLashes in prostate cancer (AVAIL): study protocol for a randomized clinical trial.

BACKGROUND: Hot flashes are the common and debilitating symptom among prostate cancer (PCa) patients undergoing androgen deprivation therapy (ADT). Strong evidence from multiple rigorously designed studies indicated that pharmacological option such as venlafaxine provides partial relief, but the tolerability is poor when dose is not tapered. Hence, alternative therapy is needed. Previous studies reported that acupuncture may be helpful in the management of hot flashes. However, the insufficient randomized controlled trial limited the quality of evidence. METHODS: Five hospitals will recruit 120 acupuncture naïve patients with moderate-to-severe hot flashes after prostate cancer received ADT in China from February 2023 to December 2024. Participants will be randomly 2:1:1 allocated to the 18 sessions of verum acupuncture at true acupuncture points plus usual care, 18 sessions of non-penetrating sham acupuncture at non-acupuncture points plus usual care, or usual care alone over 6 weeks. The primary outcome measure is the change of mean weekly hot flashes symptom severity score (HFSSS) at the end of treatment compared with baseline. EXPECTED RESULTS AND CONCLUSION: We will be able to measure the effectiveness of acupuncture for patients with PCa suffering from ADT-induced hot flashes and whether acupuncture is superior to sham acupuncture and usual care. The proposed acupuncture treatment might provide an alternative option for those patients. TRIAL REGISTRATION: Clinicaltrials.gov (NCT05069467).

Periostin secreted by cancer-associated fibroblasts promotes cancer progression and drug resistance in non-small cell lung cancer.

Cancer-associated fibroblasts (CAFs) are important components in the tumor microenvironment, and we sought to identify effective therapeutic targets in CAFs for non-small cell lung cancer (NSCLC). In this study, we established fibroblast cell lines from the cancerous and non-cancerous parts of surgical lung specimens from patients with NSCLC and evaluated the differences in behaviors towards NSCLC cells. RNA sequencing analysis was performed to investigate the differentially expressed genes between normal fibroblasts (NFs) and CAFs, and we identified that the expression of periostin (POSTN), which is known to be overexpressed in various solid tumors and promote cancer progression, was significantly higher in CAFs than in NFs. POSTN increased cell proliferation via NSCLC cells' ERK pathway activation and induced epithelial-mesenchymal transition (EMT), which improved migration in vitro. In addition, POSTN knockdown in CAFs suppressed these effects, and in vivo experiments demonstrated that the POSTN knockdown improved the sensitivity of EGFR-mutant NSCLC cells for osimertinib treatment. Collectively, our results showed that CAF-derived POSTN is involved in tumor growth, migration, EMT induction, and drug resistance in NSCLC. Targeting CAF-secreted POSTN could be a potential therapeutic strategy for NSCLC. KEY MESSAGES: • POSTN is significantly upregulated in CAFs compared to normal fibroblasts in NCSLC. • POSTN increases cell proliferation via activation of the NSCLC cells' ERK pathway. • POSTN induces EMT in NSCLC cells and improves the migration ability. • POSTN knockdown improves the sensitivity for osimertinib in EGFR-mutant NSCLC cells.

A Novel Non-Contact Detection and Identification Method for the Post-Disaster Compression State of Injured Individuals Using UWB Bio-Radar.

Building collapse leads to mechanical injury, which is the main cause of injury and death, with crush syndrome as its most common complication. During the post-disaster search and rescue phase, if rescue personnel hastily remove heavy objects covering the bodies of injured individuals and fail to provide targeted medical care, ischemia-reperfusion injury may be triggered, leading to rhabdomyolysis. This may result in disseminated intravascular coagulation or acute respiratory distress syndrome, further leading to multiple organ failure, which ultimately leads to shock and death. Using bio-radar to detect vital signs and identify compression states can effectively reduce casualties during the search for missing persons behind obstacles. A time-domain ultra-wideband (UWB) bio-radar was applied for the non-contact detection of human vital sign signals behind obstacles. An echo denoising algorithm based on PSO-VMD and permutation entropy was proposed to suppress environmental noise, along with a wounded compression state recognition network based on radar-life signals. Based on training and testing using over 3000 data sets from 10 subjects in different compression states, the proposed multiscale convolutional network achieved a 92.63% identification accuracy. This outperformed SVM and 1D-CNN models by 5.30% and 6.12%, respectively, improving the casualty rescue success and post-disaster precision.

Surface Functional Modification by Ti3 C2 Tx MXene on PLLA Nanofibers for Optimizing Neural Stem Cell Engineering.

Optimizing cell substrates by surface modification of neural stem cells (NSCs), for efficient and oriented neurogenesis, represents a promising strategy for treating neurological diseases. However, developing substrates with the advanced surface functionality, conductivity, and biocompatibility required for practical application is still challenging. Here, Ti3 C2 Tx MXene is introduced as a coating nanomaterial for aligned poly(l-lactide) (PLLA) nanofibers (M-ANF) to enhance NSC neurogenesis and simultaneously tailor the cell growth direction. Ti3 C2 Tx MXene treatment provides a superior conductivity substrate with a surface rich in functional groups, hydrophilicity, and roughness, which can provide biochemical and physical cues to support NSC adhesion and proliferation. Moreover, Ti3 C2 Tx MXene coating significantly promotes NSC differentiation into both neurons and astrocytes. Interestingly, Ti3 C2 Tx MXene acts synergistically with the alignment of nanofibers to promote the growth of neurites, indicating enhanced maturation of these neurons. RNA sequencing analysis further reveals the molecular mechanism by which Ti3 C2 Tx MXene modulates the fate of NSCs. Notably, surface modification by Ti3 C2 Tx MXene mitigates the in vivo foreign body response to implanted PLLA nanofibers. This study confirms that Ti3 C2 Tx MXene provides multiple advantages for decorating the aligned PLLA nanofibers to cooperatively improve neural regeneration.

Effects of bilirubin on the development and electrical activity of neural circuits.

In the past several decades, bilirubin has attracted great attention for central nervous system (CNS) toxicity in some pathological conditions with severely elevated bilirubin levels. CNS function relies on the structural and functional integrity of neural circuits, which are large and complex electrochemical networks. Neural circuits develop from the proliferation and differentiation of neural stem cells, followed by dendritic and axonal arborization, myelination, and synapse formation. The circuits are immature, but robustly developing, during the neonatal period. It is at the same time that physiological or pathological jaundice occurs. The present review comprehensively discusses the effects of bilirubin on the development and electrical activity of neural circuits to provide a systematic understanding of the underlying mechanisms of bilirubin-induced acute neurotoxicity and chronic neurodevelopmental disorders.

Predictive value of immune genomic signatures from breast cancer cohorts containing data for both response to neoadjuvant chemotherapy and prognosis after surgery.

BACKGROUND: Previous studies of immune genomic signatures (IGSs) in breast cancer have attempted to predict the response to chemotherapy or prognosis and were performed using different patient cohorts. The purpose of this study was to evaluate the predictive functions of various IGSs using the same patient cohort that included data for response to chemotherapy as well as the prognosis after surgery. METHODS: We applied five previously described IGS models in a public dataset of 508 breast cancer patients treated with neoadjuvant chemotherapy. The prognostic and predictive values of each model were evaluated, and their correlations were compared. RESULTS: We observed a high proportion of expression concordance among the IGS models (r: 0.56-1). Higher scores of IGSs were detected in aggressive breast cancer subtypes (basal and HER2-enriched) (P < 0.001). Four of the five IGSs could predict chemotherapy responses and two could predict 5-year relapse-free survival in cases with hormone receptor-positive (HR +) tumors. However, the models showed no significant differences in their predictive abilities for hormone receptor-negative (HR-) tumors. CONCLUSIONS: IGSs are, to some extent, useful for predicting prognosis and chemotherapy response; moreover, they show substantial agreement for specific breast cancer subtypes. However, it is necessary to identify more compelling biomarkers for both prognosis and response to chemotherapy in HR- and HER2 + cases.

Associations of cumulative depressive symptoms with subsequent cognitive decline and adverse health events: Two prospective cohort studies.

BACKGROUND: The course of depression is variable; however, few studies examined the relationship between long-term cumulative depressive symptoms and adverse health outcomes in the elderly. METHODS: In this cohort study, we used data from the Health and Retirement Study (HRS) over 24 years and the English Longitudinal Study of Ageing (ELSA) over 16 years. Cumulative depressive symptoms were estimated by calculating the areas under the curve based on the Center for Epidemiological Research Depression scale assessed at four examinations. Outcomes include cognitive decline, incident dementia, cardiovascular disease (CVD), cancer, and all-cause mortality. RESULTS: A total of 8284 American (mean age: 60.1 years; male: 35.4 %) and 4314 British (60.1 years; 42.4 %) were included in the analysis. The median follow-up was 16.1 years in the HRS and 9.9 years in the ELSA. Similar results were observed in two cohorts. Comparing with the first tertile of cumulative depressive symptoms, the third tertile experienced faster cognitive decline (p = 0.013 in the ELSA and p < 0.001 in the HRS), increased risk of dementia (both p < 0.001), CVD (both p < 0.001) and all-cause mortality (p = 0.002 in the HRS). Strong dose-response relationships were observed. We did not found clearly association between cumulative depressive symptoms and incident cancer. CONCLUSIONS: This study suggests that long-term cumulative depressive symptoms were associated with subsequent faster cognitive decline and greater risks for dementia, CVD and all-cause mortality, but not cancer. These findings provide insights on potential effective strategy that may improve health in the elderly, future clinical trials are needed to determine causality.

Development and validation of a deep learning algorithm based on fundus photographs for estimating the CAIDE dementia risk score.

BACKGROUND: the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) dementia risk score is a recognised tool for dementia risk stratification. However, its application is limited due to the requirements for multidimensional information and fasting blood draw. Consequently, an effective and non-invasive tool for screening individuals with high dementia risk in large population-based settings is urgently needed. METHODS: a deep learning algorithm based on fundus photographs for estimating the CAIDE dementia risk score was developed and internally validated by a medical check-up dataset included 271,864 participants in 19 province-level administrative regions of China, and externally validated based on an independent dataset included 20,690 check-up participants in Beijing. The performance for identifying individuals with high dementia risk (CAIDE dementia risk score ≥ 10 points) was evaluated by area under the receiver operating curve (AUC) with 95% confidence interval (CI). RESULTS: the algorithm achieved an AUC of 0.944 (95% CI: 0.939-0.950) in the internal validation group and 0.926 (95% CI: 0.913-0.939) in the external group, respectively. Besides, the estimated CAIDE dementia risk score derived from the algorithm was significantly associated with both comprehensive cognitive function and specific cognitive domains. CONCLUSIONS: this algorithm trained via fundus photographs could well identify individuals with high dementia risk in a population setting. Therefore, it has the potential to be utilised as a non-invasive and more expedient method for dementia risk stratification. It might also be adopted in dementia clinical trials, incorporated as inclusion criteria to efficiently select eligible participants.

Gene Expression Profiling between Patient Groups with High and Low Ki67 Levels after Short-term Preoperative Aromatase Inhibitor Treatment for Breast Cancer.

According to a recent report, a low Ki67 level after short-term preoperative hormone therapy (post-Ki67) might suggest a more favorable prognosis compared with a high post-Ki67 level in patients with hormone receptorpositive/human epidermal growth factor 2-negative (HR+/HER2-) breast cancer with high levels of Ki67. This study aimed to evaluate the pre-treatment genetic differences between these two patient groups. Forty-five luminal B-like patients were stratified into two groups, namely, a group with high (H→H) and one with low (H→L) Ki67 levels after short-term preoperative aromatase inhibitor (AI) treatment. We compared pre-treatment gene expression profiles between the two groups. In gene level analysis, there was no significant difference between the two groups by the class comparison test. In pathway analysis, five metabolism-related gene sets were significantly upregulated in the H→L group (p≤0.05). In the search for novel targets, five genes (PARP, BRCA2, FLT4, CDK6, and PDCD1LG2) showed significantly higher expression in the H→H group (p≤0.05). Several metabolism-related pathways were associated with sensitivity to AI. In the future, it will be necessary to seek out new therapeutic strategies for the poor prognostic group with high post-Ki67.

Enhanced Electrochemiluminescence of Graphitic Carbon Nitride by Adjustment of Carbon Vacancy for Supersensitive Detection of MicroRNA.

Herein, a supersensitive biosensor was constructed by using graphitic carbon nitride with a carbon vacancy (VC-g-C3N4) as an efficient electrochemiluminescence (ECL) emitter for detection of microRNA-21 (miRNA-21). Impressively, VC-g-C3N4 could be prepared by formaldehyde (HCHO)-assisted urea ploycondensation, and the concentration of the carbon vacancy could be controlled by adjusting the dosage of HCHO to improve the ECL performance, in which the carbon vacancy could improve the charge carrier transfer to enhance the conductivity and it also could be used as an electron trap to prevent electrode passivation and facilitate the adsorption of coreactant S2O82- to accelerate its reduction. Compared with original g-C3N4, the introduction of carbon vacancies resulted in a significant enhancement of the ECL efficiency of VC-g-C3N4. With the aid of improved cascade strand displacement amplification (IC-SDA), the ECL biosensor realized sensitive detection of miRNA-21 with a low detection limit of 3.34 aM. This successful strategy promoted the development of g-C3N4 in the ECL field to construct the sensitive biosensor for molecular and disease diagnoses.

Effects of Cuisine-Based Chinese Heart-Healthy Diet in Lowering Blood Pressure Among Adults in China: Multicenter, Single-Blind, Randomized, Parallel Controlled Feeding Trial.

BACKGROUND: More than one-fifth of the world's population consumes Chinese cuisines regularly, but no evidence-based healthy diets fitting the Chinese food culture are available for implementation. METHODS: A multicenter, patient- and outcome assessor-blind, randomized feeding trial was conducted among 265 participants with 130 to 159 mm Hg baseline systolic blood pressure (SBP) for 4 major Chinese cuisines (Shangdong, Huaiyang, Cantonese, Szechuan). After a 7-day run-in period on a control diet matching the usual local diets, participants were randomized to continue with the control diet or the cuisine-based Chinese heart-healthy diet for another 28 days. The primary outcome was SBP, and secondary outcomes included diastolic blood pressure and food preference score. Linear regression models were used to estimate the intervention effects and adjustments for the center. The incremental cost per 1 mm Hg reduction in SBP was also calculated. RESULTS: A total of 265 participants were randomized (135 on the Chinese heart-healthy diet and 130 on the control diet), with 52% women, mean age of 56.5±9.8 years, and mean SBP and diastolic blood pressure of 139.4±8.3 and 88.1±8.0 mm Hg, respectively, at baseline. The change in SBP and diastolic blood pressure from baseline to the end of the study in the control group was -5.0 (95% CI, -6.5 to -3.5) mm Hg and -2.8 (95% CI, -3.7 to -1.9) mm Hg, respectively. The net difference of change between the 2 groups in SBP and diastolic blood pressure were -10.0 (95% CI, -12.1 to -7.9) mm Hg and -3.8 (95% CI, -5.0 to -2.5) mm Hg, respectively. The effect size did not differ among cuisines (P for interaction=0.173). The mean food preference score was 9.5 (with 10 the best preferred) at baseline, and the net change during intervention was 0.1 (95% CI, -0.1 to 0.2; P=0.558). The incremental cost-effectiveness ratio per 1 mm Hg SBP reduction was CNY 0.4 (USD 0.06) per day. No difference in the number of adverse events was found between the 2 groups (P=0.259), and none of the adverse events was associated with the intervention. CONCLUSIONS: The Chinese heart-healthy diet is effective, palatable, and cost-effective in reducing blood pressure in Chinese adults with high blood pressure, with a clinically significant effect applicable across major Chinese cuisine cultures. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03882645.

Drug repositioning of tranilast to sensitize a cancer therapy by targeting cancer-associated fibroblast.

Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment that mediate resistance of cancer cells to anticancer drugs. Tranilast is an antiallergic drug that suppresses the release of cytokines from various inflammatory cells. In this study, we investigated the inhibitory effect of tranilast on the interactions between non-small cell lung cancer (NSCLC) cells and the CAFs in the tumor microenvironment. Three EGFR-mutant NSCLC cell lines, two KRAS-mutant cell lines, and three CAFs derived from NSCLC patients were used. To mimic the tumor microenvironment, the NSCLC cells were cocultured with the CAFs in vitro, and the molecular profiles and sensitivity to molecular targeted therapy were assessed. Crosstalk between NSCLC cells and CAFs induced multiple biological effects on the NSCLC cells both in vivo and in vitro, including activation of the STAT3 signaling pathway, promotion of xenograft tumor growth, induction of epithelial-mesenchymal transition (EMT), and acquisition of resistance to molecular-targeted therapy, including EGFR-mutant NSCLC cells to osimertinib and of KRAS-mutant NSCLC cells to selumetinib. Treatment with tranilast led to inhibition of IL-6 secretion from the CAFs, which, in turn, resulted in inhibition of CAF-induced phospho-STAT3 upregulation. Tranilast also inhibited CAF-induced EMT in the NSCLC cells. Finally, combined administration of tranilast with molecular-targeted therapy reversed the CAF-mediated resistance of the NSCLC cells to the molecular-targeted drugs, both in vitro and in vivo. Our results showed that combined administration of tranilast with molecular-targeted therapy is a possible new treatment strategy to overcome drug resistance caused by cancer-CAF interaction.

The trajectories of depressive symptoms and subsequent incident dementia, coronary heart diseases, stroke and all-cause mortality.

BACKGROUND: Evidence suggests the occurrence of depressive symptoms in mid- to late-life inflates the risk for ageing-related morbidity compared to people without depressive symptoms. The eventual association between depressive symptoms in mid- to late-life and long-term (over 10-year) risks for incident dementia, coronary heart disease (CHD), stroke, and morbidity is to be established. METHODS: This longitudinal cohort study utilized Health and Retirement Study (HRS) of U.S residents aged ≥ 50 years who were interviewed every 2-year during follow-up (average follow-up: 11.6 ± 2.85 years). Trajectories of depressive symptoms were assessed by the Center for Epidemiologic Studies Depression (CES-D) scale from 1994 to 2000 at baseline. Incident dementia, CHD, stroke and all-cause mortality were determined from 2000 to 2018. RESULTS: Among 7810 individuals who were free from dementia, CHD and stroke, five trajectories of depressive symptoms were identified: non-depressed (36.7 %), mild (48.8 %), worsening (7.8 %), improving (4.1 %) and persistent (2.7 %). Compared with those in the non-depressed group, participants with mild, worsening and persistent depressive symptoms had significantly greater hazards of incident dementia (multivariable adjusted hazard ratios and 95 % confidence intervals: 1.32 [1.17-1.48], 1.58 [1.30-1.93], 2.82 [2.17-3.67], respectively), CHD (1.13 [1.03-1.24], 1.47 [1.25-1.73], 1.34 [1.03-1.74], respectively), stroke (1.30 [1.12-1.52], 1.58 [1.23-2.04], 1.71 [1.16-2.53], respectively) and all-cause mortality (1.17 [1.07-1.27], 1.46 [1.27-1.68], 1.66 [1.35-2.06], respectively). The hazards of incident events, except for CHD, were not significantly greater in individuals with improving depressive symptoms. CONCLUSIONS: The present findings suggest even sub-clinical threshold depressive symptoms were associated with the hazards of ageing related diseases while such associations were not significant with managed depressive symptoms.