Associations between sleep-behavioral traits and healthspan: A one-sample Mendelian randomization study based on 388,909 participants of the UK-Biobank.

BACKGROUND: Although the association between sleep behavior and morbidity and mortality risk has been reported before, there is still uncertainty whether the observed associations are causal or confounding. Therefore, we investigated the causal relationships between sleep-behavioral traits and terminated healthspan risk using Mendelian randomization (MR). METHODS: We conducted a one-sample MR analysis to evaluate causality between six sleep-behavioral traits (sleep duration, chronotype/morningness, napping, sleeplessness/insomnia, and getting up from bed) and risk of healthspan termination among 388, 909 UK Biobank (UKB) participants. Instrumental variables for sleep behaviors (N = 590) were obtained from recent genome-wide association studies (GWAS). We defined healthspan based on eight predominant health-terminating events associated with longevity (congestive heart failure, myocardial infarction, chronic obstructive pulmonary disease, stroke, dementia, diabetes, cancer, and death). We further constructed a sleep score and a weighted genetic risk score to increase the predictive ability of the sleep-behavioral traits. Cox regression models and Inverse Probability Treatment Weighting (IPTW) were implemented, followed by MR to assess causation. We used inverse-variance-weighted MR to estimate causal effects, and weighted-median and MR-egger for sensitivity analysis to test the pleiotropic effects. RESULTS: In IPTW, we observed a decreased risk of terminated healthspan for healthy sleep behaviors such as 'sleep duration 7-8h/d' (Hazard ratio, HR = 0.93; 95 % confidence interval, CI: 0.92-0.96; P < 0.001); 'morningness' (HR = 0.95; 95%CI: 0.93-0.98; P < 0.01); 'napping' (HR = 0.93; 95%CI: 0.91-0.94; P < 0.001); 'easy getting up from bed' (HR = 0.91; 95%CI: 0.88-0.93; P < 0.001); and, 'never/rarely experience sleeplessness/insomnia' (HR = 0.94; 95%CI: 0.92-0.96; P < 0.001). MR results further indicated causal associations between healthy sleep duration (OR = 0.98; 95%CI: 0.97-1.00; P = 0.036) and insomnia (OR = 1.02; 95%CI: 1.01-1.03; P < 0.001) with terminated healthspan. MR-egger did not suggest any potential pleiotropy. CONCLUSION: This study supports abnormal sleep duration and insomnia as potential causal risk factors for terminated healthspan. Thus, healthy sleep behavior is valuable for the extension of healthspan, and well-designed and tailored sleep health interventions are warranted.

A two-stage genome-wide association study identified four potential early-onset nonsmall cell lung cancer risk loci based on 26,652 participants in Chinese population.

Early-onset lung cancer is rare with an increasing incidence rate. Although several genetic variants have been identified for it with candidate gene approaches, no genome-wide association study (GWAS) has been reported. In this study, a two-stage strategy was adopted: firstly we performed a GWAS to identify variants associated with early-onset nonsmall-cell lung cancer (NSCLC) risk using 2556 cases (age ≤ 50 years) and 13,327 controls by logistic regression model. To further discriminate younger cases from older ones, we took a case-case analysis for the promising variants with above early-onset cases and 10,769 cases (age > 50 years) by Cox regression model. After combining these results, we identified four early-onset NSCLC susceptibility loci at 5p15.33 (rs2853677, odds ratio [OR] = 1.48, 95% confidence interval [CI]: 1.36-1.60, Pcase-control = 3.58 × 10-21 ; hazard ratio [HR] = 1.10, 95% CI: 1.04-1.16, Pcase-case = 6.77 × 10-4 ), 5p15.1 (rs2055817, OR = 1.24, 95% CI: 1.15-1.35, Pcase-control = 1.39 × 10-7 ; HR = 1.08, 95% CI: 1.02-1.14, Pcase-case = 6.90 × 10-3 ), 6q24.2 (rs9403497, OR = 1.24, 95% CI: 1.15-1.35, Pcase-control = 1.61 × 10-7 ; HR = 1.11, 95% CI: 1.05-1.17, Pcase-case = 3.60 × 10-4 ) and 12q14.3 (rs4762093, OR = 1.31, 95% CI: 1.18-1.45, Pcase-control = 1.90 × 10-7 ; HR = 1.10, 95% CI: 1.03-1.18, Pcase-case = 7.49 × 10-3 ). Except for 5p15.33, other loci were found to be associated with NSCLC risk for the first time. All of them had stronger effects in younger patients than in older ones. These results provide a promising overview for early-onset NSCLC genetics.

Determinants of Voluntary Counseling and Testing Service Uptake Among Adult Sub-Saharan Africans: A Systematic Review and Meta-Analysis.

Objective: To examine the major determinants of VCT service uptake among adults in SSA. Methods: Electronic databases were searched to identify eligible English language publications. Reporting of the study selection procedure was done according to PRISMA and the selected articles were also critically appraised. Results: We found 8 significant determinants of VCT uptake among adults in SSA, such as less physical access [OR (Odds ratio): 0.77 (95% CI (Confidence interval): 0.62-0.96), p < 0.01], older age [OR: 1.36 (95% CI: 1.08-1.73), p < 0.01], higher education level [OR: 1.60 (95% CI: 1.24-2.05), p < 0.01], high knowledge of HIV and VCT awareness [OR: 1.40 (95% CI: 1.03-1.90), p < 0.01], unprotected sexual practices [OR: 1.75 (95% CI: 1.18-2.58), p < 0.01], discussion on HIV among partners and others [OR: 1.76 (95% CI: 1.10-2.81), p < 0.01], other STIs [OR: 1.40 (95% CI: 1.00-1.98), p < 0.01], and divorced/separated [OR: 1.39 (95% CI: 1.12-1.72), p < 0.01]. Conclusion: This study showed that 8 determinants were significantly associated with VCT service uptake in SSA. Thus, HIV interventions and policy initiatives should be tailored to these determinants to ensure scale-up of VCT service uptake in SSA.

Investigation of the relationships between sleep behaviors and risk of healthspan termination: a prospective cohort study based on 323,373 UK-Biobank participants.

OBJECTIVES: To examine the associations between four sleep behaviors and the risk of healthspan termination. METHODS: This study included 323,373 participants, free of terminated healthspan at baseline, from the UK-Biobank (UKB). We applied multivariable-adjusted Cox regression models to estimate the risk of terminated healthspan based on four sleep behaviors (insomnia/sleeplessness, napping, daytime sleepiness, and difficulty getting up from bed), which were self-reported and measured on Likert scales from "usually" to "never/rarely" experiences. In this study, healthspan was defined based on eight events that are strongly associated with longevity (congestive heart failure, myocardial infarction, chronic obstructive pulmonary disease, stroke, dementia, diabetes, cancer, and death). RESULTS: Participants who reported the following unhealthy sleep behaviors had a significantly higher risk of terminated healthspan: "usually experience sleeplessness/insomnia" (HR = 1.05, 95% CI: 1.03-1.07; P < 0.001); "usually nap" (HR = 1.22, 95% CI: 1.18-1.26; P < 0.01); "excessive daytime sleepiness" (HR = 1.25, 95% CI: 1.19-1.32; P < 0.001); and "difficult getting up from bed" (HR = 1.08, 95% CI: 1.05-1.10; P < 0.001). The corresponding population attributable risk percentage (PAR%) indicated that about 7% of healthspan termination in this cohort would have been eliminated if all participants had healthy sleep behaviors. CONCLUSION: Participants who reported "usually experience sleeplessness/insomnia," "usually nap," "excessive daytime sleepiness," and "difficult getting up from bed" had increased risk of shortened healthspan. Therefore, adherence to healthy sleep behavior is significant for the extension of healthspan.

Sex-Specific Associations of Testosterone and Genetic Factors With Health Span.

Background: Previous studies have suggested associations between testosterone, genetic factors, and a series of complex diseases, but the associations with the lifespan phenotype, such as health span, remain unclear. Methods: In this prospective cohort study, we analyzed 145,481 men and 147,733 women aged 38-73 years old from UK Biobank (UKB) to investigate the sex-specific associations of total testosterone (TT), free testosterone (FT), or polygenic risk score (PRS) with health span termination (HST) risk. At baseline, serum testosterone levels were measured. HST was defined by eight events strongly associated with longevity. PRS, an efficient tool combining the effect of common genetic variants to discriminate genetic risk of complex phenotypes, was constructed by 12 single-nucleotide polymorphisms related to health span from UKB (P ≤ 5.0 × 10-8). We used multivariable Cox regression models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: With a median follow-up time of 7.70 years, 26,748 (18.39%) men and 18,963 (12.84%) women had HST. TT was negatively associated with HST in men [HR per standard deviation (SD) increment of log-TT: 0.92, 95% CI: 0.88-0.97]. Inversely, both TT (HR per SD increment of log-TT: 1.05, 95% CI: 1.02-1.08) and FT (HR per SD increment of log-FT: 1.08, 95% CI: 1.05-1.11) presented an increased risk of HST in women. PRS was positively associated with HST risk (quintile 5 versus quintile 1, men, HR: 1.19, 95% CI: 1.15-1.24; women, HR: 1.21, 95% CI: 1.16-1.27). Moreover, men with high TT and low genetic risk showed the lowest HST risk (HR: 0.80, 95% CI: 0.73-0.88), whereas HST risk for women with both high TT and genetic risk increased obviously (HR: 1.32, 95% CI: 1.19-1.46). Similar joint effects were observed for FT in both genders. Conclusions: We observed sex-specific associations that testosterone was negatively associated with HST risk in men and positively associated with HST risk in women. Genetic factors increased the HST risk, suggesting that participants with both high genetic risk and abnormal testosterone levels (high level in women or low level in men) should be the target for early intervention. Although our findings highlight the associations between testosterone and health span, further mechanistic studies and prospective trials are warranted to explore the causation behind.

Investigation of Causal Effect of Type 2 Diabetes Mellitus on Lung Cancer: A Mendelian Randomization Study.

BACKGROUND: Although several observational studies have attempted to investigate the association between type 2 diabetes mellitus (T2DM) and lung cancer risk, the results are controversial. Here, we intend to examine whether there is a causal association between T2DM and lung cancer risk. MATERIALS AND METHODS: We conducted a Mendelian randomization (MR) study to systematically investigate the effect of T2DM on lung cancer among 13,327 cases and 13,328 controls. A weighted genetic risk score (wGRS) was constructed as a proxy instrument by using 82 previously reported T2DM-related single nucleotide polymorphisms (SNPs). The logistic regression model was utilized to estimate associations of T2DM-related SNPs and wGRS with lung cancer risk. Sensitivity analyses were also performed to assess the robustness of the observed associations. RESULTS: We found no evidence for a causal relationship between T2DM and lung cancer risk (odds ratio, OR = 0.96, 95% confidence interval: 0.91-1.01, p = 0.96), and the association did not vary among populations of different age, sex, smoking status, and histological type. Sensitivity analyses (e.g., MR-Egger test) suggest that pleiotropic effects did not bias the result. CONCLUSION: In this MR study with a large number of lung cancer cases, we found no evidence to support the causal role of T2DM in lung cancer risk. Further large-scale prospective studies are warranted to replicate our findings.

Associations Between Sleep Quality and Health Span: A Prospective Cohort Study Based on 328,850 UK Biobank Participants.

OBJECTIVE: To examine the associations between sleep quality and health span using a prospective cohort design based on the UK Biobank (UKB). MATERIALS AND METHODS: This longitudinal cohort study enrolled 328,850 participants aged between 37 and 73 years from UKB to examine the associations between sleep quality and risk of terminated health span. End of health span was defined by eight events strongly associated with longevity (cancer, death, congestive heart failure, myocardial infarction, chronic obstructive pulmonary disease, stroke, dementia, and diabetes), and a sleep score was generated according to five sleep behavioral factors (sleep duration, chronotype, sleeplessness, daytime sleepiness, and snoring) to characterize sleep quality. The hazard ratio (HR) and 95% confidence intervals (CIs) were calculated by multivariate-adjusted Cox proportional hazards model. Moreover, we calculated population attributable risk percentage (PAR%) to reflect the public health significance of healthy sleep quality. RESULTS: Compared with poor sleep quality, participants with healthy sleep quality had a 15% (HR: 0.85, 95% CI: 0.81-0.88) reduced risk of terminated health span, and those of less-healthy sleep quality had a 12% (HR: 0.88, 95% CI: 0.85-0.92) reduced risk. Linear trend results indicated that the risk of terminated health span decreased by 4% for every additional sleep score. Nearly 15% health span termination events in this cohort would have been prevented if a healthy sleep behavior pattern was adhered to (PAR%: 15.30, 95% CI: 12.58-17.93). CONCLUSION: Healthy sleep quality was associated with a reduced risk of premature end of health span, suggesting healthy sleep behavior may extend health span. However, further studies are suggested for confirmation of causality and potential mechanism.

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma.

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

Construction of Multicolor Upconversion Nanotheranostic Agent for in-situ Cooperative Photodynamic Therapy for Deep-Seated Malignant Tumors.

Upconversion nanoparticles (UCNPs)-based photodynamic nanotheranostic agents could address the main drawbacks of photosensitizer molecules (PSs) including instability in aqueous solution and rapid clearance. Due to the relatively weak luminescence intensity of UCNPs and insufficient reactive oxygen species (ROSs), UCNPs-based photodynamic therapy (UCNPs-PDT) was discounted for deep-seated tumors. Thus, we proposed a PSs-modulated sensitizing switch strategy. Indocyanine green (ICG) as an NIR organic dye was proved to effectively enhance the luminescence intensity of UCNPs. Herein, four-color UCNPs were coated with a silica layer which loaded ICG and PSs while the thickness of silica layer was controlled to assist the sensitization function of ICG and activation of PSs. Under the drive of mitochondria-targeting ligand, the prepared nanotheranostic agent would accumulate in the mitochondria where ROSs were in-situ produced and then cell apoptosis was induced. Due to the cooperative PDT and high tissue-penetration depth of NIR laser, the prepared upconversion nanotheranostic agent could achieve significant inhibition on the deep-seated tumors.

Effects of Commemorations and Postdonation Services on Public Willingness to Donate Bodies in China.

Multiple body donation programs have been established throughout China over the last 20 years, but these programs remain challenged by an insufficient supply of cadavers for medical education. The commemoration of body donors is a feature of many successful programs, and adopting this practice throughout the country could be an important element of raising public awareness and encouraging body donation among the public. The present study aimed to investigate public views on the commemoration of whole-body donors and postdonation services in China by analyzing the factors that influence participants' willingness to donate. A survey was conducted using convenience sampling with a non-probability sampling method, and data were analyzed using chi-square and post hoc multiple comparisons tests. A total of 1,800 questionnaires were distributed, 1,717 were returned, and 1,605 were considered valid. Of the respondents, 20.87% were willing to donate, and 64.80% thought that it is necessary to commemorate donors. The results of multiple comparisons demonstrated that the elderly and those with a higher educational level were more willing to donate than participants in other groups. Education was also found to influence views on donation memorial activities, and the chi-square test revealed that conducting commemorations and improving postdonation services can promote the establishment of successful donor programs in China and improve the social acceptance of body donation.

Sandwich-Structured Upconversion Nanoprobes Coated with a Thin Silica Layer for Mitochondria-Targeted Cooperative Photodynamic Therapy for Solid Malignant Tumors.

Upconversion nanoparticles-based photodynamic nanotheranostic agents (UCNPs-PDT) have received great interest due to improved tissue penetration, weak autofluorescence, and low biotoxicity. However, conventional UCNPs-PDT are often limited by low energy transfer efficiency from UCNPs to photosensitizer (PS) molecules and insufficient generation and limited diffusion distance of reactive oxygen species (ROSs). Herein, an "all in one" nanotheranostic agent has been developed which has multicolor sandwich-structured UCNPs (SWUCNPs) as the core, a thin silica layer with a mitochondria-targeted group for loading dual PS as the medium layer, and polyethylene glycol-folic acid (PEG-FA) chains as the outer layer. Multicolor SWUCNPs simultaneously achieve two-photon fluorescence imaging and serve as energy donor for dual PS molecules. The thin luminescence layer and silica layer control most UCNPs activators and PS molecules in the effective energy transfer distance to guarantee a high energy transfer efficiency. Via FA-mediated endocytosis, the nanotheranostic agent is selectively endocytosed by cancer cells, is released from the endosome/lysosome, targets the mitochondria, and in situ produces ROSs under excitation from NIR, leading to significant mitochondria-mediated cell apoptosis. Furthermore, the established nanotheranostic agent shows tumor targetability, increased generation of ROSs, high PDT efficacy, significant cell apoptosis, minimal systemic cytotoxicity, and efficacious in vivo tumor inhibition.

Construction of a targeted photodynamic nanotheranostic agent using upconversion nanoparticles coated with an ultrathin silica layer.

Two-activator codoped UCNPs served as energy donors and photosensitizers entrapped in an ultrathin silica layer served as energy acceptors to establish LRET-based photodynamic therapy with the advantages of shortened donor-to-acceptor distance and enhanced LRET efficiency. The exterior PEG-FA ligand further enhanced the biocompatibility and targetability to cancer cells and the tumor section.

Synthesis, self-assembly, and in vitro toxicity of fatty acids-modified Bletilla striata polysaccharide.

Hydrophobic modification of Bletilla striata polysaccharide (BSP) was performed by grafting fatty acids to BSP backbone and then characterized on their physicochemical properties. All neutral derivatives were able to self-assemble into spherical particles within the size range of 250-400 nm, their size and critical micelle concentration decreased with increasing hydrophobicity and substitution degree of the fatty acids. Also, the BSP-stearic acid conjugates showed a preferable performance on hemolysis test and cytotoxicity analysis on HepG2 cells, which suggested their potential application as a drug delivery vector.

Silymarin-Loaded Nanoparticles Based on Stearic Acid-Modified Bletilla striata Polysaccharide for Hepatic Targeting.

Silymarin has been widely used as a hepatoprotective drug in the treatment of various liver diseases, yet its effectiveness is affected by its poor water solubility and low bioavailability after oral administration, and there is a need for the development of intravenous products, especially for liver-targeting purposes. In this study, silymarin was encapsulated in self-assembled nanoparticles of Bletilla striata polysaccharide (BSP) conjugates modified with stearic acid and the physicochemical properties of the obtained nanoparticles were characterized. The silymarin-loaded micelles appeared as spherical particles with a mean diameter of 200 nm under TEM. The encapsulation of drug molecules was confirmed by DSC thermograms and XRD diffractograms, respectively. The nanoparticles exhibited a sustained-release profile for nearly 1 week with no obvious initial burst. Compared to drug solutions, the drug-loaded nanoparticles showed a lower viability and higher uptake intensity on HepG2 cell lines. After intravenous administration of nanoparticle formulation for 30 min to mice, the liver became the most significant organ enriched with the fluorescent probe. These results suggest that BSP derivative nanoparticles possess hepatic targeting capability and are promising nanocarriers for delivering silymarin to the liver.