Genome-wide association study of cardiometabolic multimorbidity in the UK Biobank.

Considering the high prevalence and poor prognosis of cardiometabolic multimorbidity (CMM), identifying causal factors and actively implementing preventive measures is crucial. However, Mendelian randomization (MR), a key method for identifying the causal factors of CMM, requires knowledge of the effects of SNPs on CMM, which remain unknown. We first analyzed the genetic overlap of single cardiometabolic diseases (CMDs) using the latest genome-wide association study (GWAS) for evidential support and comparison. We observed strong positive genetic correlations and shared loci among all CMDs. Further, GWAS and post-GWAS analyses of CMM were performed in 407 949 European ancestry individuals from the UK Biobank. Eleven loci and 12 lead SNPs were identified. By comparison, we found these SNPs were a subset of SNPs associated with CMDs, including both shared and non-shared SNPs. Then, the polygenic risk score model predicted the risk of CMM (C-index = 0.62) and we identified candidate genes related to lipid metabolism and immune function. Finally, as an example, two-sample MR analysis based on the GWAS revealed potential causal effects of total cholesterol, serum urate, body mass index, and smoking on CMM. These results provide a basis for future MR research and inspire future studies on the mechanism and prevention of CMM.

Dihydroartemisinin-driven TOM70 inhibition leads to mitochondrial destabilization to induce pyroptosis against lung cancer.

Enhancement of malignant cell immunogenicity to relieve immunosuppression of lung cancer microenvironment is essential in lung cancer treatment. In previous study, we have demonstrated that dihydroartemisinin (DHA), a kind of phytopharmaceutical, is effective in inhibiting lung cancer cells and boosting their immunogenicity, while the initial target of DHA's intracellular action is poorly understood. The present in-depth analysis aims to reveal the influence of DHA on the highly expressed TOM70 in the mitochondrial membrane of lung cancer. The affinity of DHA and TOM70 was analyzed by microscale thermophoresis (MST), pronase stability, and thermal stability. The functions and underlying mechanism were investigated using western blots, qRT-PCR, flow cytometry, and rescue experiments. TOM70 inhibition resulted in mtDNA damage and translocation to the cytoplasm from mitochondria due to the disruption of mitochondrial homeostasis. Further ex and in vivo findings also showed that the cGAS/STING/NLRP3 signaling pathway was activated by mtDNA and thereby malignant cells underwent pyroptosis, leading to enhanced immunogenicity of lung cancer cells in the presence of DHA. Nevertheless, DHA-induced mtDNA translocation and cGAS/STING/NLRP3 mobilization were synchronously attenuated when TOM70 was replenished. Finally, DHA was demonstrated to possess potent anti-lung cancer efficacy in vitro and in vivo. Taken together, these data confirm that TOM70 is an important target for DHA to disturb mitochondria homeostasis, which further activates STING and arouses pyroptosis to strengthen immunogenicity against lung cancer thereupon. The present study provides vital clues for phytomedicine-mediated anti-tumor therapy.

Laser-triggered intelligent drug delivery and anti-cancer photodynamic therapy using platelets as the vehicle.

In our previous study, target drug delivery and treatment of malignant tumors have been achieved by using platelets as carriers loading nano-chemotherapeutic agents (ND-DOX). However, drug release from ND-DOX-loaded platelets is dependent on negative platelet activation by tumor cells, whose activation is not significant enough for the resulting drug release to take an effective anti-tumor effect. Exploring strategies to proactively manipulate the controlled release of drug-laden platelets is imperative. The present study innovatively revealed that photodynamic action can activate platelets in a spatiotemporally controlled manner. Consequently, based on the previous study, platelets were used to load iron oxide-polyglycerol-doxorubicin-chlorin e6 composites (IO-PG-DOX-Ce6), wherein the laser-triggered drug release ability and anti-tumor capability were demonstrated. The findings suggested that IO-PG-DOX-Ce6 could be stably loaded by platelets in high volume without any decrease in viability. Importantly and interestingly, drug-loaded platelets were significantly activated by laser irradiation, characterized by intracellular ROS accumulation and up-regulation of CD62p. Additionally, scanning electron microscopy (SEM) and hydrated particle size results also showed a significant aggregation response of laser irradiated-drug-loaded platelets. Further transmission electron microscopy (TEM) measurements indicated that the activated platelets released extracellularly their cargo drug after laser exposure, which could be taken up by co-cultured tumor cells. Finally, the co-culture model of drug-loaded platelets and tumor cells proved that laser-triggered delivery system of platelets could effectively damage the DNA and promote apoptosis of tumor cells. Overall, the present study discovers a drug-loaded platelets delivery using photodynamic effect, enabling laser-controlled intelligent drug delivery and anti-tumor therapy, which provides a novel and feasible approach for clinical application of cytopharmaceuticals.

What is the context?1. Platelets were applied to load IO-PG-DOX-Ce6, wherein the laser-triggered drug release and anti-tumor effect were investigated in vitro.2. The findings indicated that IO-PG-DOX-Ce6 could be stably loaded by platelets in high volume without any decrease in viability, which may attribute to the activation of autophagy in platelets.3. IO-PG-DOX-Ce6-loaded platelets could be significantly activated by laser irradiation (690 nm).4. Activated platelets released extracellularly their cargo drug after laser exposure, which could be taken up by co-cultured tumor cells5. The co-culture model of drug-loaded platelets and tumor cells proved that the laser-triggered delivery system of platelets could effectively damage the DNA and promote apoptosis of tumor cells.What is new?1. Platelets could be utilized as the vehicle to load photosensitizer-loaded-nano-drug.2. Photodynamic action can activate platelets in a spatiotemporally controlled manner, which could be a tool to regulate the activation of platelets.3. The laser-triggered activation of drug-loaded platelets allows for target release of cargo.4. The limitation of the current research is that only in vitro experiments were carried out to demonstrate our conclusions.What is impact?The present work provides a novel and feasible approach for the clinical application of cytopharmaceuticals.

Associations between consumption of three types of beverages and risk of cardiometabolic multimorbidity in UK Biobank participants: a prospective cohort study.

BACKGROUND: Although the association between beverages and a single cardiometabolic disease has been well studied, their role in disease progression from the single cardiometabolic disease state to cardiometabolic multimorbidity (CMM) state remains unclear. This study examined the associations between three types of beverages: sugar-sweetened beverages (SSBs), artificially sweetened beverages (ASBs), and pure fruit/vegetable juices, and the incidence of CMM in patients with a single cardiometabolic disease. METHODS: Our analysis included 37,994 participants from the UK Biobank who completed at least one dietary questionnaire and were diagnosed with only one cardiometabolic disease at the time of recruitment. Competing risk models were used to examine the association between the three types of beverages and incidence of CMM. We conducted analysis both in patients with any single cardiometabolic disease and in patients with specific cardiometabolic disease. RESULTS: During a median follow-up of 9.1 years (interquartile range [IQR] 9.0-9.8), a total of 6399 participants developed CMM. The consumption of SSBs and ASBs (>1 serving per day) was associated with a higher risk of CMM (SSBs: hazard ratio [HR] 1.19, 95% confidence interval [95% CI] 1.08-1.31; ASBs: HR 1.15, 95% CI 1.04-1.27). Intake of pure fruit/vegetable juices was inversely associated with the incidence of CMM (0-1 serving per day: HR 0.90, 95% CI 0.85-0.94; >1 serving per day: HR 0.90, 95% CI 0.81-0.99). However, the association of the high-level consumption of pure fruit/vegetable juices (>1 serving per day) was not statistically significant after correcting for multiple testing. In the analysis of patients with specific cardiometabolic diseases, positive associations were observed in patients with hypertension for SSBs consumption, while inverse associations persisted in patients with cardiovascular disease (coronary heart disease or stroke) and in hypertensive patients for pure fruit/vegetable juice consumption. CONCLUSIONS: Consuming >1 serving of SSBs and ASBs per day was associated with a higher risk of CMM in patients with a single cardiometabolic disease. In contrast, intake of pure fruit/vegetable juices was inversely associated with the risk of CMM. Our findings highlight the need to limit the use of SSBs and ASBs in patients with a single cardiometabolic disease.

Association between healthy lifestyle and the occurrence of cardiometabolic multimorbidity in hypertensive patients: a prospective cohort study of UK Biobank.

BACKGROUND: Cardiometabolic multimorbidity (CMM) is becoming increasingly common in patients with hypertension, and it is well established that healthy lifestyle plays a key role in the prevention of hypertension. However, the association between combined lifestyle factors and CMM in patients with hypertension is uncertain. METHODS: This prospective analysis included the data (obtained from the UK biobank) of participants with hypertension who did not have coronary heart disease (CHD), stroke, or diabetes. The outcome was the occurrence of CMM, defined as ≥ 1 disease of CHD, stroke, and diabetes that occurred in participants with hypertension. Four lifestyle factors (smoking, alcohol consumption, diet, and physical activity) were assessed using a weighted healthy lifestyle score, and participants were divided into four groups: the very unhealthy, unhealthy, healthy, and very healthy groups. The flexible parameter Royston-Parmar proportional hazard model was used to estimate hazard ratios (HRs) between lifestyles and CMM, as well as the difference in CMM-free life expectancy. RESULTS: During a median follow-up of 12.2 years, 9812 (18.4%) of the 53,397 hypertensive patients occurred CMM. Compared with the very unhealthy group, the very healthy group had a 41% reduction in the risk for CMM in hypertensive patients and a 32-50% reduction in the risk for specific cardiometabolic diseases such as CHD, stroke, and diabetes. For each lifestyle factor, non-smoking had the greatest protective effect against CMM (HR: 0.64, 95% confidence interval (CI) 0.60-0.68). A lifestyle combining multiple healthy factors extended CMM-free life expectancy (e.g., six years longer at age 45 years for participants in the very healthy group). CONCLUSIONS: Combined healthy lifestyle factors were associated with a lower risk for CMM in hypertensive patients. This suggests that combined healthy lifestyle should be supported to decrease disease burden.

Associations of baseline use of fish oil with progression of cardiometabolic multimorbidity and mortality among patients with hypertension: a prospective study of UK Biobank.

PURPOSE: The role of fish oil in the prognosis of hypertensive patients is unknown. This study investigated the associations of fish oil supplementation with the progression of cardiometabolic multimorbidity (CMM) and mortality among patients with hypertension. METHODS: Based on UK Biobank, we enrolled participants with hypertension and free of other cardiometabolic diseases. The exposure was baseline use of fish oil derived from questionnaires at baseline. The primary outcomes were the incidence of CMM and all-cause mortality. Competing risk models and flexible parametric proportion-hazards models were fitted to assess the adjusted hazard ratios (HRs) for the risk of CMM and mortality outcomes, respectively. RESULTS: Among 81,579 participants involved [50.37%, men; mean age, 59.38 years (standard deviation, 7.23 years)], 15,990 CMM events and 6456 all-cause deaths were reported (median follow-up, 12.23 years). In multivariable-adjusted models, baseline use of fish oil was associated with 8% lower risk of CMM [95% confidence interval (95% CI) 0.89-0.96, P < 0.001] and 10% lower risk of all-cause mortality (95% CI 0.85-0.95, P < 0.001). CONCLUSION: In individuals with hypertension, baseline use of fish oil was associated with a reduced risk of CMM and all-cause mortality, and further clinical trials are needed to prove this hypothesis.

Use of fish oil and mortality of patients with cardiometabolic multimorbidity: A prospective study of UK biobank.

BACKGROUND AND AIMS: Cardiometabolic multimorbidity (CMM) has risen as a global issue of public health, with an in-creasing prevalence and more severe clinical prognosis. This study aimed to estimate the association between use of fish oil and mortality among patients with CMM. METHODS AND RESULTS: In this prospective study based on UK Biobank, participants with ≥2 of cardiometabolic diseases (CMDs, including coronary heart disease [CHD], diabetes, hypertension, and stroke in this study) at recruitment were included. Use of fish oil was derived from touchscreen questionnaires at baseline. All-cause and cardiovascular mortality were accessed via electronic health-related records. Kaplan-Meier curves and flexible parametric Royston-Parmar proportion-hazard models were fitted to assess the as-sociations of fish-oil use with all-cause, cardiovascular mortality, and related life expectancy alterations. Among 30 068 participants from UK Biobank (67.9% men; mean age 61.75 years), 5357 deaths were reported during 12.03 years of follow-up. For patients with CMM, use of fish oil was associated with a 17% lower risk of all-cause mortality (95% confidence interval [95% CI] 0.78-0.88, P < 0.001), and 19% lower risk of cardiovascular mortality (95% CI 0.72-0.90, P < 0.001) in multivariable-adjusted models. At 45 years old, using fish oil was associated with 1.66 years of life expectancy gained. CONCLUSION: Among patients with CMM, use of fish oil was associated with a significantly reduced risk of all-cause, cardiovascular mortality, and prolonged life expectancy.

Improving low-accuracy protein structures using enhanced sampling techniques.

In this paper, we report results of using enhanced sampling and blind selection techniques for high-accuracy protein structural refinement. By combining a parallel continuous simulated tempering (PCST) method, previously developed by Zang et al. [J. Chem. Phys. 141, 044113 (2014)], and the structure based model (SBM) as restraints, we refined 23 targets (18 from the refinement category of the CASP10 and 5 from that of CASP12). We also designed a novel model selection method to blindly select high-quality models from very long simulation trajectories. The combined use of PCST-SBM with the blind selection method yielded final models that are better than initial models. For Top-1 group, 7 out of 23 targets had better models (greater global distance test total scores) than the critical assessment of structure prediction participants. For Top-5 group, 10 out of 23 were better. Our results justify the crucial position of enhanced sampling in protein structure prediction and refinement and demonstrate that a considerable improvement of low-accuracy structures is achievable with current force fields.

Assessment of Bidirectional Relationships between Frailty and Mental Disorders: A Bidirectional Mendelian Randomization Study.

OBJECTIVES: Although observational studies have reported the association between frailty and mental disorders, the causality remains unclear. We aimed to evaluate the bidirectional causal association between frailty levels and mental disorders using a 2-sample Mendelian randomization (MR) analysis. DESIGN: A bidirectional, 2-sample Mendelian randomization (MR) analysis. SETTING AND PARTICIPANTS: Instrumental variables were obtained from large-scale genome-wide association study (GWAS) of a European-descent population for frailty index (FI, n = 175,226), Fried Frailty Score (FFS, n = 386,565), major depressive disorder (MDD, n = 674,452), bipolar disorder (n = 353,899), anxiety and stress-related disorder (ASRD, n = 31,880), and schizophrenia (n = 127,906). METHODS: Two-sample MR analyses were conducted using inverse variance-weighted method, with sensitivity analyses using MR-Egger, weighted median, and simple median methods. RESULTS: Per SD increase in genetically predicted FI and FFS increased the risk of MDD [odds ratio (OR) 1.56, 95% CI 1.27-1.94, P = 3.65 × 10-5, and OR 1.67, 95% CI 1.26-2.20, P = 3.02 × 10-4, respectively]. Per-SD increase in genetically predicted FI also increased the risk of ASRD (OR 2.76, 95% CI 1.36-5.60, P = .005). No significant effect was observed for frailty levels on the risk of bipolar disorder and schizophrenia. In the reverse direction, genetically predicted MDD was associated with higher FI (ß 0.182, 95% CI 0.087-0.277, P = 1.79 × 10-4) and FFS (ß 0.121, 95% CI 0.087-0.155, P = 4.43 × 10-12). No reliable evidence supported the effects of genetically predicted bipolar disorder, ASRD, or schizophrenia on frailty levels. CONCLUSIONS AND IMPLICATIONS: A bidirectionally causal association exists between frailty levels and MDD, and higher FI is associated with a higher risk of ASRD. No reliable evidence suggested the causal associations of other mental disorders with frailty. Our findings provided evidence for introduction of psychological-related strategies in management of frailty.

Parental cardiometabolic multimorbidity and subsequent cardiovascular incidence in middle-aged adults: A prospective cohort study.

Background: The prevalence of cardiometabolic multimorbidity, defined as the coexistence of two or three cardiometabolic diseases (CMDs), including coronary heart disease (CHD), diabetes, and stroke, has increased rapidly in recent years, but the additive association between parental cardiometabolic multimorbidity and cardiovascular incidence in middle-aged adults remains unclear. Methods: All the data analysed in this study were derived from the UK Biobank, and a total of 71,923 participants aged 40-55 years old without CVD were included in the main analyses. A weighted score was developed and grouped participants into four parental CMDs patterns: non-CMD, low burden, middle burden, and high burden. Cox proportional hazard models were used to estimate the associations between parental CMDs pattern and CVD incidence before 65 years old. Improvement in CVD risk prediction by adding parental CMDs pattern to a basic model was evaluated. Results: Among the 71,923 participants, 3070 CVD events were observed during a median 12.04 years of follow-up. Compared to non-CMD groups, adults in high burden group had a 94% (73-117%) increased risk of CVD. The restricted cubic spline analysis revealed an exposure-response association between parental CMDs burden and risk of CVD (Pnonlinear = 0.24). Additionally, models involving parental CMDs pattern showed slightly improvements in CVD risk prediction, especially for CHD. Conclusion: An increased burden of parental CMDs was associated with an increased risk of CVD incidence in middle-aged adults. Parental CMDs pattern may provide valuable information in primary prevention of CVD in middle-aged adults.

Association between Longitudinal Change of Sleep Patterns and the Risk of Cardiovascular Diseases.

STUDY OBJECTIVES: To investigate the role of longitudinal change of sleep patterns in the incidence of cardiovascular diseases (CVD). METHODS: Based on UK Biobank, a total of 18,172 participants were enrolled. Five dimensions of healthy sleep including early chronotype, sleep 7-8 hours/day, free of insomnia, no snoring, and no frequent excessive daytime sleepiness were used to generate a healthy sleep score (HSS) ranging from 0 to 5. Corresponding to the HSS of 0-1, 2-3, and 4-5, the poor, intermediate, and healthy sleep pattern were defined. Based on changes of HSS across assessment 1 and 2, we calculated the absolute difference of HSS. For the change of sleep patterns, we categorized five profiles (stable healthy, worsening, stable intermediate, optimizing, and stable poor sleep patterns). The outcomes were incidence of CVD including coronary heart disease (CHD) and stroke. We assessed the adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) by Cox hazard models. RESULTS: Compared with participants with stable poor pattern, those who improved their sleep pattern or maintained the healthy sleep pattern had a 26% and 32% lower risk of CVD, respectively. Stable healthy sleep pattern was associated with a 29% and 44% reduced risk of CHD and stroke. Per unit longitudinal increment of the HSS was related to an 8% lower risk of CVD and CHD. Compared with individuals with constant HSS, those with decreased HSS had a 13% higher risk of developing CVD. CONCLUSION: Optimizing sleep pattern and maintaining the healthy sleep pattern may reduce the risk of CVD.

Design and Optimization of Thin-Walled Main Support Structure for Space Camera Based on Additive Manufacturing.

In order to solve the design requirements of high stiffness and lightweight for the primary support structure of a wide-field auroral imager, we propose a solution for designing and optimizing a large-scale complex thin-walled structure using additive manufacturing. Firstly, we devise an integrated thin-walled structure and test material for the main support. Secondly, shape optimization is achieved via the optimization of the lateral slope angle of the primary support based on Timoshenko cantilever beam theory. Additionally, an active fitting optimization algorithm is proposed for the purpose of refining the wall thickness of the thin-walled structure. Then, we determine the structural design of the main support. This primary support is manufactured via selective laser melting (SLM). Following processing, the structure size is 538 mm × 400 mm × 384 mm, and the mass is 7.78 kg. Finally, frequency scanning experiments indicate that, in the horizontal direction, there is a natural frequency of 105.97 Hz with an error rate of approximately 3% compared to finite element analysis results. This research confirms that our large-scale complex, thin-walled main support structure design meets all design requirements.

Source-specific ecological risk analysis and critical source identification of heavy metal(loid)s in the soil of typical abandoned coal mining area.

Long-term coal mining activities in abandoned coal mining areas have resulted in the migration of large quantities of heavy metals into the surrounding soil environment, posing a threat to the regional ecological environment. This study focuses on the surface soil collected from a typical abandoned coal mining area. Methods such as the pollution index (PI) and potential ecological risk index (RI) were used to comprehensively evaluate the pollution levels and ecological risks of soil heavy metals. Geostatistical analysis and the APCS-MLR model were used to quantify the sources of soil heavy metals, and Nemerow integrated ecological risk (NIRI) model was coupled to apportion the ecological risks from different pollution sources. The results indicate that the average concentrations of Cd, As, and Zn are 4.58, 2.44, and 1.67 times the soil background values, respectively, while the concentrations of other heavy metals are below the soil background values. The soil of study area is strongly polluted by heavy metals, with the pollution level and ecological risk of Cd being significantly higher than those of other heavy metals. The NIRI calculation results show that the overall comprehensive ecological risk level is considerable, with sample points classified as relatively considerable, moderate, and low at 60.53 %, 36.84 %, and 2.63 %, respectively. The sources of soil heavy metals can be categorized into four types: traffic activities, natural sources, coal gangue accumulation, and a combined source of coal mining and agricultural activities, with contribution rates of 35.3 %, 36.1 %, 19.5 %, and 9.1 %, respectively. The specific source ecological risk assessment results indicate that coal gangue accumulation contributes the most to ecological risk (36.4 %) and should be prioritized for pollution control, with Cd being the priority control element for ecological risk. The findings provide theoretical support for the refined management of soil heavy metal pollution in abandoned coal mining areas.

Indocyanine green-loaded platelet activated by photodynamic and photothermal effects for selective control of wound repair.

OBJECTIVE: Prompt and effective wound repair is an essential strategy to promote recovery and prevent infection in patients with various types of trauma. Platelets can release a variety of growth factors upon activation to facilitate revascularization and tissue repair, provided that their activation is uncontrollable. The present study is designed to explore the selective activation of platelets by photodynamic and photothermal effects (PDE/PTE) as well as the trauma repair mediated by PDE/PTE. MATERIALS AND METHODS: In the current research, platelets were extracted from the blood of mice. Indocyanine green (ICG) was applied to induce PDE/PTE. The uptake of ICG by platelets was detected by laser confocal microscopy and flow cytometry. The cellular integrity was measured by microscopy. The reactive oxygen species (ROS) generation and temperature of platelets were assayed by 2,7-Dichlorodihydrofluorescein diacetate (DCFH-DA) and temperature detector. The activation of platelets was measured by western blots (WB), dynamic light scattering (DLS), and scanning electron microscopy (SEM). The release of growth factor was detected by enzyme-linked immuno sorbent assay (Elisa), wherein the in vitro cell proliferation was investigated by 5-Ethynyl-2'-deoxyuridine (EDU) assay. The wound infection rates model and histological examination were constructed to assay the ICG-loaded platelet-mediated wound repair. RESULTS: Platelets could load with ICG, a kind of photodynamic and photothermal agent, as carriers and remain intact. Near-infrared (NIR) laser irradiation of ICG-loaded platelets (ICG@PLT) facilitated higher temperature and ROS generation, which immediately activated ICG@PLT, as characterized by increased membrane p-selectin (CD62p), cyclooxygenase-2 (COX-2), thromboxane A2 receptor (TXA2R) expression, elevated hydrated particle size, and prominent aggregation in platelets. Further investigation revealed that massive insulin-like growth factor (IGF) and platelet-derived growth factor (PDGF) were released from the activated ICG@PLT, which also promoted the proliferation of endothelial cells and keratinocytes in co-culture. In consequence, activated platelets and increased neovascularization could be observed in rats with wound infection treated by ICG@PLT in the presence of NIR. More impressively, the hydrogel containing ICG@PLT accelerated wound healing and suppressed inflammation under NIR, exhibiting excellent wound repair properties. CONCLUSION: Taken together, the current work identified that platelets could be activated by PDE/PTE and thereby release growth factor, potentiating wound repair in a controlled manner.

The association between sleep characteristics and the risk of all-cause mortality among individuals with cardiometabolic multimorbidity: a prospective study of UK Biobank.

STUDY OBJECTIVES: To investigate the implications of both sleep factors and sleep patterns on the prognosis of cardiometabolic multimorbidity. METHODS: From UK Biobank, individuals with cardiometabolic multimorbidity , defined as the coincidence of at least 2 cardiometabolic diseases (hypertension, diabetes mellitus, coronary heart disease, and stroke) were included in this study. Four low-risk sleep factors, including early chronotype, sleep 7-8 h/d, free of insomnia, and no frequent excessive daytime sleepiness, were used to generate a healthy sleep score ranging from 0 to 4. Participants with a score of 0-1, 2, 3-4 were clustered into groups with poor, intermediate, and healthy sleep pattern, respectively. We assessed the adjusted hazard ratios and 95% confidence intervals for all-cause mortality using the Cox proportional hazards model. RESULTS: Among included 35,757 participants, the mean age (standard deviation)) was 61.82 (6.3) years. After full adjustment, early chronotype, sleep 7-8 h/d, no frequent excessive daytime sleepiness, and free of insomnia were independently associated with 8%, 12%, 11%, and 8% lower risk of all-cause mortality among all persons with cardiometabolic multimorbidity. We found the fully adjusted hazard ratio (95% confidence interval) for all-cause mortality was 0.90 (0.88-0.92) for a 1-point increase in the healthy sleep score. Compared with the reference group, participants with the intermediate and healthy sleep pattern had 9% and 23% lower risk of all-cause death, respectively, in the fully adjusted model. CONCLUSIONS: A healthy sleep pattern combining 4 low-risk sleep factors could be regarded as a healthy lifestyle for individuals with cardiometabolic multimorbidity to lower the risk of all-cause mortality. CITATION: He L, Ma T, Cheng X, Bai Y. The association between sleep characteristics and the risk of all-cause mortality among individuals with cardiometabolic multimorbidity: a prospective study of UK Biobank. J Clin Sleep Med. 2023;19(4):651-658.

Frailty, an Independent Risk Factor in Progression Trajectory of Cardiometabolic Multimorbidity: A Prospective Study of UK Biobank.

BACKGROUND: Although frailty was associated with cardiometabolic diseases (CMDs, including coronary heart disease, stroke, and diabetes here), there was no systematic analyses estimating its role in incidence, progression, and prognosis of cardiometabolic multimorbidity (CMM). METHODS: We included 351 205 participants without CMDs at baseline in UK Biobank. Occurrences of first CMD, CMM, and death were recorded. We used multistate models to assess transition-specific role of baseline frailty measured by frailty phenotype and frailty index in CMM progression trajectory from no disease to single CMD, CMM, and death. Association between changes in frailty and outcomes was investigated among 17 264 participants. RESULTS: Among 351 205 participants (44.0% male, mean age 56.55 years), 8 190 (2.3%) had frail phenotype, and 13 615 (3.9%) were moderate/severe frail according to the frailty index. During median follow-up of 13.11 years, 41 558 participants experienced ≥1 CMD, 4 952 had CMM, and 20 670 died. In multistate models, frail phenotype-related hazard ratios were 1.94 and 2.69 for transitions from no CMD to single disease and death, 1.63 and 1.67 for transitions from single CMD to CMM and death, and 1.57 for transitions from CMM to death (all p < .001). Consistent results were observed for frailty index. Improvement of frailty reduced the risk of CMD progression and death. CONCLUSIONS: Frailty is an independent risk factor for all transitions of CMM progression trajectory. Frailty-targeted management is a potential strategy for primary and secondary prevention of CMM beyond chronological age.

Computed tomographic manifestations of celiac ganglia between hypertensive and non-hypertensive population.

The celiac ganglion (CG) is associated with the sympathetic nervous system (SNS) and plays an important role in the pathogenesis of hypertension. The characteristics of the CG in patients with hypertension remain unknown. The aim of our study was to explore the differences in celiac ganglia (CGs) characteristics between hypertensive and non-hypertensive populations using computed tomography (CT). CGs manifestations on multidetector row CT in 1003 patients with and without hypertension were retrospectively analyzed. The morphological characteristics and CT values of the left CGs were recorded. The CT values of the ipsilateral adrenal gland (AG) and crus of the diaphragm (CD) were also measured. The left CG was located between the left AG and CD, and most CGs were long strips. The frequency of visualization of the left CGs was higher in the hypertension group than in the non-hypertension group (p < .05). There were no significant differences in the maximum diameter, size, and shape ratio of the left CGs between the two groups (p > .05). Except for the left CG in the arterial phase, the CT values of the left CG and AG in the non-hypertensive group were higher than those in the hypertension group (p < .05). The venous phase enhancement of the left CG in the non-hypertension group was significantly higher than that in the hypertension group (p < .05). Our findings reveal that CGs have characteristic manifestations in the hypertensive population. As important targets of the SNS, CGs have the potential to regulate blood pressure.

Delving Deeper Into Pixel Prior for Box-Supervised Semantic Segmentation.

Weakly supervised semantic segmentation (WSSS) based on bounding box annotations has attracted considerable recent attention and has achieved promising performance. However, most of existing methods focus on generation of high-quality pseudo labels for segmented objects using box indicators, but they fail to fully explore and exploit prior from bounding box annotations, which limits performance of WSSS methods, especially for fine parts and boundaries. To overcome above issues, this paper proposes a novel Pixel-as-Instance Prior (PIP) for WSSS methods by delving deeper into pixel prior from bounding box annotations. Specifically, the proposed PIP is built on two important observations on pixels around bounding boxes. First, since objects are usually irregularity and tightly close to bounding boxes (dubbed irregular-filling prior), so each row or column of bounding boxes basically have at least one pixel belonging to foreground objects and background, respectively. Second, pixels near the bounding boxes tend to be highly ambiguous and more difficult to classify (dubbed label-ambiguity prior). To implement our PIP, a constrained loss alike multiple instance learning (MIL) and a labeling-balance loss are developed to jointly train WSSS models, which regards each pixel as a weighted positive or negative instance while considering more effective prior (i.e., irregular-filling and label-ambiguity priors) from bounding box annotations in an efficient way. Note that our PIP can be flexibly integrated with various WSSS methods, while clearly improving their performance with negligible computational overload in training stage. The experiments are conducted on most widely used PASCAL VOC 2012 and Cityscapes benchmarks, and the results show that our PIP has a good ability to improve performance of various WSSS methods, while achieving very competitive results.

On the dynamics and control of a squirrel locking its head/eyes toward a fixed spot for safe landing while its body is tumbling in air.

An arboreal mammal such as a squirrel can amazingly lock its head (and thus eyes) toward a fixed spot for safe landing while its body is tumbling in air after unexpectedly being thrown into air. Such an impressive ability of body motion control of squirrels has been shown in a recent YouTube video, which has amazed public with over 100 million views. In the video, a squirrel attracted to food crawled onto an ejection device and was unknowingly ejected into air by the device. During the resulting projectile flight, the squirrel managed to quickly turn its head (eyes) toward and then keeps staring at the landing spot until it safely landed on feet. Understanding the underline dynamics and how the squirrel does this behavior can inspire robotics researchers to develop bio-inspired control strategies for challenging robotic operations such as hopping/jumping robots operating in an unstructured environment. To study this problem, we implemented a 2D multibody dynamics model, which simulated the dynamic motion behavior of the main body segments of a squirrel in a vertical motion plane. The inevitable physical contact between the body segments is also modeled and simulated. Then, we introduced two motion control methods aiming at locking the body representing the head of the squirrel toward a globally fixed spot while the other body segments of the squirrel were undergoing a general 2D rotation and translation. One of the control methods is a conventional proportional-derivative (PD) controller, and the other is a reinforcement learning (RL)-based controller. Our simulation-based experiment shows that both controllers can achieve the intended control goal, quickly turning and then locking the head toward a globally fixed spot under any feasible initial motion conditions. In comparison, the RL-based method is more robust against random noise in sensor data and also more robust under unexpected initial conditions.

Trends in the Prevalence of Cardiometabolic Multimorbidity in the United States, 1999-2018.

Cardiometabolic multimorbidity (co-existence of ≥1 cardiometabolic diseases) is increasingly common, while its prevalence in the U.S. is unknown. We utilized data from 10 National Health and Nutrition Examination Survey (NHANES) two-year cycles in U.S. adults from 1999 to 2018. We reported the age-standardized prevalence of cardiometabolic multimorbidity in 2017-2018 and analyzed their trends during 1999-2018 with joinpoint regression models. Stratified analyses were performed according to gender, age, and race/ethnicity. In 2017-2018, the prevalence of cardiometabolic multimorbidity was 14.4% in the U.S., and it was higher among male, older, and non-Hispanic Black people. The three most common patterns were hypertension and diabetes (7.5%); hypertension, diabetes, and CHD (2.2%); and hypertension and CHD (1.8%). During 1999-2018, the prevalence of cardiometabolic multimorbidity in U.S. adults increased significantly, with an averaged two-year cycle percentage change (AAPC) of 3.6 (95% CI: 2.1 to 5.3). The increasing trend was significant for both genders, most age groups except for 60-79 years, and non-Hispanic White people. For common patterns, the trend was increasing for hypertension and diabetes and hypertension, diabetes, and CHD, while it was decreasing for hypertension and CHD. Our findings provide evidence that cardiometabolic multimorbidity has risen as an austere issue of public health in the U.S.