Shining New Light on Biological Systems: Luminescent Transition Metal Complexes for Bioimaging and Biosensing Applications.

Luminescence imaging is a powerful and versatile technique for investigating cell physiology and pathology in living systems, making significant contributions to life science research and clinical diagnosis. In recent years, luminescent transition metal complexes have gained significant attention for diagnostic and therapeutic applications due to their unique photophysical and photochemical properties. In this Review, we provide a comprehensive overview of the recent development of luminescent transition metal complexes for bioimaging and biosensing applications, with a focus on transition metal centers with a d6, d8, and d10 electronic configuration. We elucidate the structure-property relationships of luminescent transition metal complexes, exploring how their structural characteristics can be manipulated to control their biological behavior such as cellular uptake, localization, biocompatibility, pharmacokinetics, and biodistribution. Furthermore, we introduce the various design strategies that leverage the interesting photophysical properties of luminescent transition metal complexes for a wide variety of biological applications, including autofluorescence-free imaging, multimodal imaging, organelle imaging, biological sensing, microenvironment monitoring, bioorthogonal labeling, bacterial imaging, and cell viability assessment. Finally, we provide insights into the challenges and perspectives of luminescent transition metal complexes for bioimaging and biosensing applications, as well as their use in disease diagnosis and treatment evaluation.

Exploiting the Potential of Iridium(III) bis-Nitrone Complexes as Phosphorogenic Bifunctional Reagents for Phototheranostics.

Cross-linking strategies have found wide applications in chemical biology, enabling the labeling of biomolecules and monitoring of protein-protein interactions. Nitrone exhibits remarkable versatility and applicability in bioorthogonal labeling due to its high reactivity with strained alkynes via the strain-promoted alkyne-nitrone cycloaddition (SPANC) reaction. In this work, four cyclometalated iridium(III) polypyridine complexes functionalized with two nitrone units were designed as novel phosphorogenic bioorthogonal reagents for bioimaging and phototherapeutics. The complexes showed efficient emission quenching, which is attributed to an efficient nonradiative decay pathway via the low-lying T1/S0 minimum energy crossing point (MECP), as revealed by computational studies. However, the complexes displayed significant emission enhancement and lifetime extension upon reaction with (1R,8S,9s)-bicyclo[6.1.0]non-4-yne (BCN) derivatives. In particular, they showed a remarkably higher reaction rate toward a bis-cyclooctyne derivative (bis-BCN) compared with its monomeric counterpart (mono-BCN). Live-cell imaging and (photo)cytotoxicity studies revealed higher photocytotoxicity in bis-BCN-pretreated cells, which is ascribed to the enhanced singlet oxygen (1O2) photosensitization resulting from the elimination of the nitrone-associated quenching pathway. Importantly, the cross-linking properties and enhanced reactivity of the complexes make them highly promising candidates for the development of hydrogels and stapled/cyclized peptides, offering intriguing photophysical, photochemical, and biological properties. Notably, a nanosized hydrogel (2-gel) demonstrated potential as a drug delivery system, while a stapled peptide (2-bis-pDIKK) exhibited p53-Mdm2 inhibitory activity related to apoptosis and a cyclized peptide (2-bis-RGD) showed cancer selectivity.

Pooled prevalence of depressive symptoms among medical students: an individual participant data meta-analysis.

BACKGROUND: The methodological choice of aggregated estimates for meta-analysis may be notable for some common drawbacks, including variations in the cut-off values of depression, and lower statistical power for analyzing the associated factors. The study aimed to refine the precision of previous findings on the prevalence of depressive symptoms among medical students, through gathering individual participant data (IPD) as identified from our previous reviews. MATERIAL AND METHODS: In the present study, we searched MEDLINE, EMBASE, PsycINFO, WanFang, Scielo and LILACS to identify published systematic reviews and meta-analyses up to March 2018, then individual data was requested for further analysis (PROSPERO registration: CRD42018091917). The participants' age, sex, year of study, scores for depressive symptoms, and other predictor variables were requested. To pool the prevalence from the included studies, random-effects model (two-step method) was used. Multiple linear regression was used to examine the associated factors on the depression z-scores (one-step method). RESULTS: Of the 249 studies, the datasets of 34 studies were included. The crude prevalence was 19.4% (95% CI: 18.8%, 19.9%) by one-step method and the pooled prevalence was 18.1% (95% CI: 14.1%, 22.1%) by two-step method. Multiple linear regression revealed that being a female, older age, and senior year of study were significantly associated with the z-score. CONCLUSION: The pooled prevalence of depressive symptoms from the Individual Participant Data (IPD) meta-analysis was lower than the previous meta-analyses using aggregated data. Age, sex, and year of study were significantly associated with the depression z-score. IPD meta-analysis may provide a more accurate estimation of disease burden, and allow verification of associated factors.

Association of serum uric acid levels with cardiovascular and all-cause mortality in hypertensive patients in China: a cohort study.

PURPOSE: The present study aimed to assess the association of elevated serum uric acid (SUA) and hypouricemia with all-cause mortality and cardiovascular mortality in Chinese hypertensive patients. METHODS: In the present prospective cohort, 9325 hypertensive patients from Dongguan, China were enrolled from 2014 to 2018 for analysis. Participants were categorised by quintiles of SUA. The HRs and 95% CIs for the association between SUA, all-cause and cardiovascular mortality were evaluated using the multivariate Cox regression model. After adjusting for multiple confounders, restricted cubic spline analysis was conducted to demonstrate the shape of relationship. RESULTS: After a median follow-up of 4.18 years for 9325 participants, there were 409 (4.4%) and 151 (1.6%) reported cases of all-cause and cardiovascular mortality, respectively. By using the third quintile of SUA (6.68 mg/dL to <7.55 mg/dL for men, 5.63 mg/dL to <6.42 mg/dL for women) as reference, the highest quintiles of SUA were associated with an elevated risk of all cause (HR: 1.34, 95% CI 1.00 to 1.80) in the crude model, but the association was not significant after adjusting for multiple comparisons. The association between low SUA and mortality and the dose-response analysis on the non-linearity of SUA-mortality relationship were not statistically significant. CONCLUSIONS: Although the association between SUA levels, all-cause and cardiovascular disease mortality did not appear to be significant among Chinese hypertensive patients, the findings might be confounded by their medical conditions. Further studies are needed to verify the optimal SUA levels for hypertensive patients.

A Concerted Enzymatic and Bioorthogonal Approach for Extra- and Intracellular Activation of Environment-Sensitive Ruthenium(II)-Based Imaging Probes and Photosensitizers.

In this article, we report a novel targeting strategy involving the combination of an enzyme-instructed self-assembly (EISA) moiety and a strained cycloalkyne to generate large accumulation of bioorthogonal sites in cancer cells. These bioorthogonal sites can serve as activation triggers in different regions for transition metal-based probes, which are new ruthenium(II) complexes carrying a tetrazine unit for controllable phosphorescence and singlet oxygen generation. Importantly, the environment-sensitive emission of the complexes can be further enhanced in the hydrophobic regions offered by the large supramolecular assemblies, which is highly advantageous to biological imaging. Additionally, the (photo)cytotoxicity of the large supramolecular assemblies containing the complexes was investigated, and the results illustrate that cellular localization (extracellular and intracellular) imposes a profound impact on the efficiencies of photosensitizers.

Dual-emissive Iridium(III) Complexes as Phosphorescent Probes with Orthogonal Responses to Analyte Binding and Oxygen Quenching.

Phosphorescent probes often show sensitive response toward analytes at a specific wavelength. However, oxygen quenching usually occurs at the same wavelength and thus hinders the accurate detection of analytes. In this study, we have developed dual-emissive iridium(III) complexes that exhibit phosphorescence responses to copper(II) ions at a wavelength distinct from that where oxygen quenching occurs. The complexes displayed colorimetric phosphorescence response in aqueous solutions under different copper(II) and oxygen conditions. In cellular imaging, variation in oxygen concentration over a large range from 5 % to 80 % can modulate the intensity and lifetime of green phosphorescence without affecting the response of red phosphorescence toward intracellular copper(II) ions.

Luminescent and Photofunctional Transition Metal Complexes: From Molecular Design to Diagnostic and Therapeutic Applications.

There has been emerging interest in the exploitation of the photophysical and photochemical properties of transition metal complexes for diagnostic and therapeutic applications. In this Perspective, we highlight the major recent advances in the development of luminescent and photofunctional transition metal complexes, in particular, those of rhenium(I), ruthenium(II), osmium(II), iridium(III), and platinum(II), as bioimaging reagents and phototherapeutic agents, with a focus on the molecular design strategies that harness and modulate the interesting photophysical and photochemical behavior of the complexes. We also discuss the current challenges and future outlook of transition metal complexes for both fundamental research and clinical applications.

Photo- and Electrochemical Dual-Responsive Iridium Probe for Saccharide Detection.

Dual detection systems are of interest for rapid, accurate data collection in sensing systems and in vitro testing. We introduce an IrIII complex with a boronic acid receptor site attached to the 2-phenylpyridine ligand as an ideal probe with photo- and electrochemical signals that is sensitive to monosaccharide binding in aqueous solution. The complex displays orange luminescence at 618 nm, which is reduced by 70 and 40 % upon binding of fructose and glucose, respectively. The electro-chemiluminescent signal of the complex also shows a direct response to monosaccharide binding. The IrIII complex shows the same response upon incorporation into hydrogel matrices as in solution, thus demonstrating the potential of its integration into a device, as a nontoxic, simple-to-use tool to observe sugar binding over physiologically relevant pH ranges and saccharide concentrations. Moreover, the complex's luminescence is responsive to monosaccharide presence in cancer cells.

The relationship between famine exposure during early life and ascending aorta dilatation in adults.

The relationship between exposure to famine in early life and the risk of ascending aorta dilatation (AAD) in adulthood is still unclear; therefore, we aimed to examine the association in the Chinese population. We investigated the data of 2598 adults who were born between 1952 and 1964 in Guangdong, China. All enrolled subjects were categorised into five groups: not exposed to famine, exposed during fetal period, and exposed during early, mid or late childhood. AAD was assessed by cardiac ultrasound. Multivariate logistic regression and interaction tests were performed to estimate the OR and CI on the association between famine exposure and AAD. There were 2598 (943 male, mean age 58·3 ± 3·68 years) participants were enrolled, and 270 (10·4 %) subjects with AAD. We found that famine exposure (OR = 2·266, 95 % CI 1·477, 3·477, P = 0·013) was associated with elevated AAD after adjusting for multiple confounders. In addition, compared with the non-exposed group, the adjusted OR for famine exposure during fetal period, early, mid or late childhood were 1·374 (95 % CI 0·794, 2·364, P = 0·251), 1·976 (95 % CI 1·243, 3·181, P = 0·004), 1·929 (95 % CI 1·237, 3·058, P = 0·004) and 2·227 (95 % CI 1·433, 3·524, P < 0·001), respectively. Subgroup analysis showed that the effect of famine exposure on the association with AAD was more pronounced in female, current smokers, people with BMI ≥ 24 kg/m2 and hypertensive patients. We observed that exposure to famine during early life was linked to AAD in adulthood.

Efficacy of dietary supplements on improving sleep quality: a systematic review and meta-analysis.

PURPOSE: Different dietary supplements aimed at improving sleep quality are available on the market, but there has not been a comprehensive review to evaluate the efficacy of these dietary supplements on subjective sleep quality. We aimed to summarise up-to-date research evidence and to identify the types of dietary supplement that improve subjective sleep quality. METHODS: Multiple databases (Ovid Emcare, Ovid MEDLINE (R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and APA PsycInfo) were used for searching papers published until August 2020. The changes in sleep quality indices, intervention duration and sample size were extracted from every paper. To analyse the effect of dietary supplements on sleep quality, a random effects model with mean difference (MD) and 95% CI was adopted. The heterogeneity across studies was measured by I2 statistics. The quality of included studies was evaluated by Cochrane's risk of bias tool. RESULTS: Thirty-one randomised controlled trials of dietary supplements were included. Subjective sleep quality was significantly improved by supplementation of amino acids (MD -1.27, 95% CI -2.35 to -0.20; I2=0%), melatonin (MD -1.21, 95% CI -2.17 to -0.24; I2=79%) and vitamin D (MD -1.63, 95% CI -3.15 to -0.10; I2=85%). Although not all studies provided adequate data for meta-analysis, we also discussed how magnesium, zinc, resveratrol and nitrate supplementation may improve sleep quality. CONCLUSIONS: Amino acids, vitamin D and melatonin supplements were significantly beneficial to improve sleep quality. However, high heterogeneity and wide confidence levels were observed in vitamin D and melatonin. Further research on the effect of magnesium, zinc, resveratrol and nitrate supplementation on improving sleep quality is required.

Phosphorogenic Iridium(III) bis-Tetrazine Complexes for Bioorthogonal Peptide Stapling, Bioimaging, Photocytotoxic Applications, and the Construction of Nanosized Hydrogels.

The dual functionality of 1,2,4,5-tetrazine as a bioorthogonal reactive unit and a luminescence quencher has shaped tetrazine-based probes as attractive candidates for luminogenic labeling of biomolecules in living systems. In this work, three cyclometalated iridium(III) complexes featuring two tetrazine units were synthesized and characterized. Upon photoexcitation, the complexes were non-emissive but displayed up to 3900-fold emission enhancement upon the inverse electron-demand Diels-Alder (IEDDA) [4+2] cycloaddition with (1R,8S,9s)-bicyclo[6.1.0]non-4-yne (BCN) substrates. The rapid reaction kinetics (k2 up to 1.47×104  M-1 s-1 ) of the complexes toward BCN substrates allowed effective peptide labeling. The complexes were also applied as live cell bioimaging reagents and photocytotoxic agents. One of the complexes was utilized in the preparation of luminescent nanosized hydrogels that exhibited interesting cargo delivery properties.

Aggregation and Supramolecular Self-Assembly of Low-Energy Red Luminescent Alkynylplatinum(II) Complexes for RNA Detection, Nucleolus Imaging, and RNA Synthesis Inhibitor Screening.

As an important nuclear substructure, the nucleolus has received increasing attention because of its significant functions in the transcription and processing of ribosomal RNA in eukaryotic cells. In this work, we introduce a proof-of-concept luminescence assay to detect RNA and to accomplish nucleolus imaging with the use of the supramolecular self-assembly of platinum(II) complexes. Noncovalent interactions between platinum(II) complexes and RNA can be induced by the introduction of a guanidinium group into the complexes, and accordingly, a high RNA affinity can be achieved. Interestingly, the aggregation affinities of platinum(II) complexes enable them to display remarkable luminescence turn-on upon RNA binding, which is a result of the strengthening of noncovalent Pt(II)···Pt(II) and π-π stacking interactions. The complexes exhibit not only intriguing spectroscopic changes and luminescence enhancement after RNA binding but also specific nucleolus imaging in cells. As compared to fluorescent dyes, the low-energy red luminescence and large Stokes shifts of platinum(II) complexes afford a high signal-to-background autofluorescence ratio in nucleolus imaging. Additional properties, including long phosphorescence lifetimes and low cytotoxicity, have endowed the platinum(II) complexes with the potential for biological applications. Also, platinum(II) complexes have been adopted to monitor the dynamics of the nucleolus induced by the addition of RNA synthesis inhibitors. This capability allows the screening of inhibitors and can be advantageous for the development of antineoplastic agents. This work provides a novel strategy for exploring the application of platinum(II) complex-based cell imaging agents based on the mechanism of supramolecular self-assembly. It is envisaged that platinum(II) complexes can be utilized as valuable probes because of the aforementioned appealing advantages.

Molecular Design of Bioorthogonal Probes and Imaging Reagents Derived from Photofunctional Transition Metal Complexes.

For more than 15 years, bioorthogonal chemistry has received increasing attention due to its successful applications in the detection and imaging of biomolecules in their native biological environments. The method typically proceeds with the incorporation of a biological substrate appended with a bioorthogonal functional group (chemical reporter), followed by the introduction of the substrate to biological systems. Biomolecules containing the substrate are then recognized by an exogenously delivered bioorthogonal probe. Despite the fact that many useful chemical reporters and bioorthogonal reactions have been developed, most of the bioorthogonal probes reported thus far are fluorescent dyes. A limitation is that stringent washing is required due to the interference caused by the background fluorescence of unreacted probes. Thus, fluorogenic probes with turn-on emission properties upon bioorthogonal labeling have been designed as an alternative strategy. These probes are highly appealing because excellent images can be obtained without the need for washing steps. Nearly all fluorogenic bioorthogonal probes designed are essentially organic dyes, their emission is limited to fluorescence, and the utilization of the probes is confined to bioimaging applications. Recently, there has been a growing interest in the bioimaging and therapeutic applications of luminescent inorganic and organometallic transition metal complexes due to their intriguing photophysical and photochemical properties, high membrane permeability, controllable cellular uptake, intracellular localization, and cytotoxicity. We anticipate that photofunctional transition metal complexes can be exploited as valuable bioorthogonal probes due to these appealing advantages. In this Account, we introduce the molecular design, photophysical and photochemical properties, and biological applications of various bioorthogonal probes and imaging reagents based on photofunctional transition metal complexes. The presence of a cationic metal center significantly enhances the bioorthogonal reactivity of the probes, yet their stability in aqueous solutions can be maintained. Interestingly, some of these metal complexes are strategically modified to display phosphorogenic properties, that is, phosphorescence turn-on upon bioorthogonal labeling reactions. Importantly, these probes not only exhibit favorable photophysical properties after bioorthogonal labeling, but also efficient photoinduced singlet oxygen (1O2) generation. This interesting bioorthogonal reaction-triggered photosensitization capability allows the modulation of 1O2 generation efficiency and contributes to the development of controllable photocytotoxic agents. The exploration of transition metal complex-based probes not only significantly widens the scope of bioorthogonal labeling but also further highlights the unique advantages of these complexes in the design of theranostic reagents. The development of these innovative reagents is expected to contribute to the basic understanding of biological processes in living systems and provide exciting opportunities for new diagnostic and therapeutic applications.

Luminescent Neutral Cyclometalated Iridium(III) Complexes Featuring a Cubic Polyhedral Oligomeric Silsesquioxane for Lipid Droplet Imaging and Photocytotoxic Applications.

New neutral iridium(III) complexes featuring a cubic polyhedral oligomeric silsesquioxane (POSS) unit, [Ir(N∧C)2(L1-POSS)] [HN∧C = 2-phenylpyridine (Hppy; 1), 2-phenylbenzothioazole (Hbt; 2), and 2-(1-naphthyl)benzothiazole (Hbsn; 3); L1-POSS = (E)-4-[(2-hydroxybenzylidene)amino]benzyl 3-heptakis(isobutyl)POSS-propyl carbamate], were designed and synthesized. Their POSS-free counterparts, [Ir(N∧C)2(L1)] [L1 = (E)-N-(4-hydroxymethylphenyl)-1-(2-hydroxyphenyl)methanimine; HN∧C = Hppy (1a), Hbt (2a), and Hbsn (3a)], and the poly(ethylene glycol) (PEG) derivatives [Ir(N∧C)2(L1-PEG)] [L1-PEG = (E)-4-[(2-hydroxybenzylidene)amino]benzyl 3-[2-[ω-methoxypoly(1-oxapropyl)]ethyl]carbamate; HN∧C = Hppy (1b), Hbt (2b), and Hbsn (3b)] were also prepared. The photophysical, photochemical, and biological properties of the POSS complexes were compared with those of their POSS-free and PEG-modified counterparts. Upon irradiation, all of these complexes displayed orange-to-red emission and long emission lifetimes under ambient conditions. The bsn complexes 3, 3a, and 3b exhibited the highest singlet oxygen (1O2) generation quantum yields (ΦΔ = 0.85-0.86) in aerated CH3CN. Laser-scanning confocal microscopy images revealed that complexes 1-3 and 1a-3a showed exclusive lipid-droplet staining upon cellular uptake, while the PEG derivatives 1b-3b displayed lysosomal localization. Complex 3 was utilized to study various lipid-droplet-related biological events including lipid-droplet accumulation under oleic acid stimulation, the movement of lipid droplets, and preadipocyte differentiation. Notably, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays indicated that the ppy complexes 1 and 1b and the bt complexes 2 and 2b were noncytotoxic both in the dark and upon irradiation at 450 nm for 5 min (IC50 > 200 µM), while the bsn complexes 3, 3a, and 3b showed low dark cytotoxicity (IC50 = 52.9 to >200 µM) and high photocytotoxicity (IC50 = 1.1-5.3 µM). The cellular uptake, internalization mechanisms, and cell death pathways of these complexes were also investigated. This work not only offers promising luminescent probes for lipid droplets through the structural modification of iridium(III) complexes but also paves the way to the construction of new reagents for theranostics.

Serum 25-hydroxyvitamin D, frailty, and mortality among the Chinese oldest old: Results from the CLHLS study.

BACKGROUND AND AIMS: In this study, the aim is to explore whether frailty status modified the associations of serum 25(OH)D levels with all-cause and cause-specific mortality in the oldest old Chinese population. METHODS AND RESULTS: A total of 1411 participants aged at least 80 years were enrolled in the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Information on serum 25(OH)D level, frailty status, and covariates were examined at baseline. All-cause and cause-specific mortality status were ascertained during the follow-up survey conducted in 2017-2018 by using the ICD-10 codes. Cox proportional hazard models with stratified analyses were performed to evaluate potential associations. Over a median follow-up of 3.2 years, 722 (51.2%) participants were deceased, including 202 deaths due to circulatory diseases, and 520 deaths due to noncirculatory causes. After multivariable adjustment, the lowest quartile of serum 25(OH)D levels (Hazard Ratios (95% Confidence Intervals), 1.85 (1.45-2.36), 1.85 (1.45-2.36), 1.73 (1.31-2.29), respectively) and frailty (Odd Ratios (95% Confidence Intervals), 1.91 (1.60-2.29), 2.67 (1.90-3.74), 1.64 (1.31-2.05)) were associated with significantly higher risk of all-cause mortality, circulatory mortality, and noncirculatory mortality, respectively. In addition, we observed significant interactions among 25(OH)D and frailty on the risk of all-cause and cause-specific mortality (all P-interaction < 0.001). Similar results were found in sensitivity analyses by excluding participants who died in the first year of follow-up and using clinical cutoffs of serum 25(OH)D levels. CONCLUSION: Low serum 25(OH)D levels were associated with higher risk of all-cause and cause-specific mortality among the oldest old of the Chinese population, and the associations were significantly stronger in individuals with frailty.

Early-life exposure to the Chinese famine and risk of carotid intima-media thickness increased in adulthood.

BACKGROUND AND AIMS: Little was known about the effect of famine exposure on carotid intima-media thickness (cIMT). The present study aimed to explore the relationship in a Chinese population. METHODS AND RESULTS: Participants were divided into five groups: not exposed to famine, exposed to famine in fetal, early, mid or late childhood. Elevated cIMT was defined as a thickness of >0.9 mm measured by carotid ultrasound. Multivariate logistic regression was performed to calculate odds ratio (OR) and confidence interval (CI) between famine exposure and cIMT. A total of 2637 (970 male, mean age 59.1 ± 3.65 years) participants were recruited, and 491 (18.62%) of them had elevated cIMT. When compared with the non-exposure group, the fully adjusted ORs for increased cIMT for exposure in fetal, early, mid to late childhood were 1.321 (95%CI: 0.872, 1.994, P = 0.186), 1.713 (95% CI: 1.188, 2.483, P = 0.004), 2.359 (95% CI: 1.674, 3.357, P < 0.001) and 2.485 (95% CI: 1.773, 3.518, P < 0.001), respectively. Subgroup analyses showed that the exposure to famine did not interact with body mass index, gender, smoking status, hypertension and diabetes history on its effect on cIMT. CONCLUSION: Our findings indicated that early-life exposure to the Chinese famine might be associated with an increased risk of increased cIMT in adulthood.

The association of blood lipid parameters variability with ischemic stroke in hypertensive patients.

BACKGROUND AND AIMS: The relationship between lipid variability and stroke among patients with hypertension were inconclusive. We aimed to investigate the association of lipid variability with ischemic stroke in hypertensive patients. METHODS AND RESULTS: This retrospective cohort study included 4995 individuals with hypertension between 2013 and 2015, and recorded their status of ischemic stroke until the end of 2018. The variability in total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured using the standard deviation (SD), coefficient of variation (CV), variability independent of the mean (VIM) and average absolute difference between successive values (ASV). Multivariate Cox proportional hazards models with hazard ratios (HRs) and 95% confidence interval (CI) were performed. There were 110 cases of ischemic stroke during a median follow up of 4.2 years. The multivariable adjusted HRs and 95% CIs comparing the highest versus the lowest quartiles of SD of TC, LDL-C, HDL-C and TG were 4.429 (95% CI: 2.292, 8.560), 2.140 (95% CI: 1.264, 3.621), 1.368 (95% CI: 0.793, 2.359) and 1.421 (95% CI: 0.800, 2.525), respectively. High variability in TC and LDL-C were associated with a higher risk for ischemic stroke. Similarly, the results were consistent when calculating variability of TC and LDL-C using CV, ASV and VIM, and in various subgroup analyses. CONCLUSION: Higher variability of TC and LDL-C associated with the risk of ischemic stroke among hypertensive patients. These findings suggest reducing variability of lipid parameters may decrease adverse outcomes.

Effects of waist to height ratio, waist circumference, body mass index on the risk of chronic diseases, all-cause, cardiovascular and cancer mortality.

BACKGROUND: Given the fat redistribution in later stages of life, how the associations between abdominal obesity and the risk of morbidity and mortality have changed with age have not been elucidated, especially for waist to height ratio (WHtR). OBJECTIVE: To compare the strength of association between obesity indices and chronic diseases at baseline, and the subsequent mortality risk among US adults. METHODS: We included 21 109 participants from National Health and Nutrition Examination Survey 1999-2014. We performed logistic regression and receiver operating curve analysis to examine the discriminatory power of obesity indicators on cardiometabolic diseases and cancer at baseline. Sex-stratified and age-stratified Cox models were constructed to explore the prospective association between obesity indices and all-cause, cardiovascular and cancer mortality. RESULTS: Elevated WHtR, elevated waist circumference (WC) and body mass index (BMI)-classified obesity are associated with higher odds of hypertension (OR: 1.37-2.13), dyslipidemia (OR: 1.06 to 1.75, all p<0.05) and diabetes (OR: 1.40-3.16, all p<0.05). WHtR had significantly better discriminatory power to predict cardiometabolic health than BMI, especially for diabetes (area under the curve: 0.709 vs 0.654). After multivariable adjustment, all obesity indicators are associated with lower risk of all-cause mortality among females aged ≥65 years (HR: 0.64 to 0.85), but the association was only significant for BMI when obesity indicators were mutually adjusted (HR: 0.79). CONCLUSIONS: WHtR and WC appeared to be the better indicators for cardiometabolic health than BMI. However, BMI had a stronger and inverse association with a greater risk of all-cause mortality among older females.

Relationship between body mass index and ischaemic stroke in Chinese elderly hypertensive patients.

BACKGROUND: Despite obesity being a major risk factor for ischaemic stroke (IS), the association between body mass index (BMI) and IS in patients with hypertension remains uncertain. OBJECTIVE: To assess the association between BMI and IS among elderly hypertensive patients in China. METHODS AND RESULTS: We recruited 3500 hypertensive patients aged ≥60 between 1 January 2010 and 31 December 2011 in China and ascertained their stroke status until December 2016. Multivariate Cox regression was used to evaluate the association between BMI and IS with interaction tests for exposure and covariates. A total of 3315 subjects (mean age 71.41±7.20 years, 44.5% were men) were included for data analysis. During an average follow-up period of 5.5 years, there were 206 onset cases (6.21%) of IS. When BMI was treated as a continuous variable, it was positively associated with the incidence of new onset IS (HR=1.14; 95% CI: 1.05 to 1.34; p=0.005) after adjusting for potential confounders. Meanwhile, when BMI was treated as a categorical variable, the highest category (≥28 kg/m2) was strongly associated with an increased risk for IS compared with normal BMI category (18.5 to 24 kg/m2) (HR=1.36, 95% CI: 1.09 to 1.80; p<0.001) in the fully adjusted model. Subgroup and interaction analysis also demonstrated that BMI independently associated with IS among males, smokers, alcohol drinkers, diabetic patients, people with uncontrolled blood pressure, decreased estimated glomerular filtration rate and those aged ≥70 years. CONCLUSION: BMI was significantly associated with IS and was an independent risk of IS in Chinese elderly hypertensive patients.

Association between pulse pressure and ischaemic stroke in elderly patients with hypertension.

BACKGROUND: The association between pulse pressure (PP) and the risk of first ischaemic stroke (IS) is inconsistent. Therefore, we evaluated the association between PP and the risk of first IS among elderly hypertensive population in China. METHODS: This was a retrospective cohort study. Patients with hypertension and aged ≥60 years were recruited. Multivariate Cox regression was performed to evaluate the association between PP and the risk of IS. We further stratified the regression models into subgroups and test for interaction to assess whether the associations were modified by other covariates. RESULTS: A total of 3315 patients with hypertension (44.49% male; mean age 71.41±7.20 years) were included, and 206 cases of IS occurred with a median follow-up of 5.5 years. The results showed that per SD mm Hg increment in PP was associated with a 17% (95% CI 1.05 to 1.40, p=0.0172) increased risk of IS. Moreover, the HR of IS for the highest quartile of PP was 1.46 (95% CI 1.18 to 1.73, p=0.0011, p for trend <0.001) comparing with the lowest quartile of PP. Subgroup analysis showed that population aged ≥70 years, male, patients with smoking or drinking habit, diabetes at baseline, being overweight, with uncontrolled blood pressure or did not take antihypertensive drugs have a higher risk for IS. CONCLUSIONS: We found that PP was significantly associated with IS and was an independent risk factor for IS.