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Abstract Time in target range (TTR) and blood pressure variability (BPV) of systolic blood pressure (SBP) are independent risk factors for major adverse cardiovascular events (MACE) and all‐cause mortality in hypertensive patients. However, the association of the combination of low TTR and high BPV of SBP with the risk of MACE and all‐cause mortality is unclear. This study sought to investigate the combined effect of the TTR and BPV on the risk of MACE and all‐cause mortality in patients with hypertension. A total of 11 496 hypertensive patients from the Kailuan cohort study were included in our study. All participants were divided into four groups according to their TTR and BPV levels. Cox proportional hazards regression models were used to calculate the hazard ratios (HRs) and 95% confidence interval (CI) for incident MACE and all‐cause mortality. During a median follow‐up of 5.64 years, 839 MACEs (included 99 cases of myocardial infarction, 591 cases of stroke, and 191 cases of heart failure) and 621 deaths occurred. Compared with the high‐TTR and low‐BPV group, the HRs (95% CI) of MACE and all‐cause mortality were 1.309 (1.025–1.671) and 1.842 (1.373–2.473) for the high‐TTR and high‐BPV group, 1.692 (1.347–2.125) and 1.731 (1.298–2.309) for the low‐TTR & low‐BPV group, 2.132 (1.728–2.629) and 2.247 (1.722–2.932) for the low‐TTR & high‐BPV group. Our study suggests that the combination of low TTR and high BPV of SBP was associated with a higher risk of MACE and all‐cause mortality in patients with hypertension.

Abstract Background Elongin A (ELOA), our previous work revealed, serves as a novel tumor suppressor in colorectal cancer. However, the function and mechanism of ELOA in other cancer types, including gastric cancer (GC), remain to be elucidated. Methods The expression of ELOA was measured by quantitative reverse transcription‐polymerase chain reaction and western blot. The effects of ELOA on GC growth and metastasis were assessed through a series of in‐vitro and in‐vivo assays. Furthermore, the potential mechanism of ELOA was revealed by RNA sequencing, dual luciferase reporter assay, chromatin immunoprecipitation, and rescue experiments in GC. Results We uncovered increased expression of ELOA in GC tissues compared with paired normal tissues via bioinformatic analyses and our sample detection. Enhanced ELOA expression in GC tissues was obviously correlated with poor tumor differentiation, lymph node metastasis, advanced tumor stage, and a poor prognosis. A series of functional experiments showed that ELOA promoted the proliferation and metastasis of GC. Mechanistically, we revealed that the decreased levels of miR‐490‐3p caused the upregulation of ELOA in GC. Both RNA‐seq and ChIP assays revealed that ELOA transcriptionally activated retinol‐binding protein 1 (RBP1) by binding to its promotor. Furthermore, specific knockdown of RBP1 reduced the tumor‐promoting ability of ELOA in GC cells. Conclusions In summary, our findings demonstrate that ELOA exerts oncogenic properties by activating RBP1 expression, providing the basis for a promising therapeutic target in GC.

Background Cardiac conduction diseases can lead to life‐threatening outcomes. However, the evidence on risk factors for conduction disease that is needed to underpin prevention strategies is limited. The present study aimed to determine the association between type 2 diabetes and cardiac conduction diseases. Methods and Results This study included 101 080 participants free of prevalent diabetes and cardiac conduction diseases at baseline from the Kailuan Study. All participants were monitored biennially until December 31, 2020. During follow‐up, 14 397 participants were diagnosed as having type 2 diabetes. For each case subject, 1 control subject was randomly selected, matched for age (±1 year) and sex. The final analysis comprised 10 744 case‐control pairs. Cox regression models with age as the underlying time scale were used. During a median follow‐up of 5.46 years, 571 incident events occurred, including 164 atrioventricular blocks, 414 bundle‐branch blocks (BBBs), 274 right BBBs, and 210 left BBBs. After adjustment for potential confounders, participants with type 2 diabetes diagnosed had greater relative risks for most outcomes relative to controls, with hazard ratios of 1.42 (95% CI, 1.18–1.67) for conduction diseases, 1.40 (95% CI, 1.00–1.96) for atrioventricular blocks, 1.43 (95% CI, 1.16–1.75) for BBBs, and 1.69 (95% CI, 1.15–2.49) for left BBBs. In contrast, no association between diabetes and right BBB was observed. Conclusions In this study, participants with type 2 diabetes are at an increased risk of cardiac conduction disease but not associated with the development of right BBB.

Background Mitochondrial abnormalities exist in gastrocnemius muscle of people with peripheral artery disease (PAD). Whether abnormalities in mitochondrial biogenesis and autophagy are associated with greater ischemia or walking impairment in PAD is unknown. Methods and Results Protein markers of mitochondrial biogenesis and autophagy and the abundance of mitochondrial electron transport chain complexes were quantified in gastrocnemius muscle biopsies from people with and without PAD. Their 6‐minute walk distance and 4‐m gait speed were measured. Sixty‐seven participants (mean age 65.0 years [±6.8], 16 [23.9%] women, 48 [71.6%] Black) were enrolled, including 15 with moderate to severe PAD (ankle brachial index [ABI]

Background Supervised exercise therapy (SET) is the first‐line therapy for walking impairment in peripheral artery disease (PAD). This study evaluated the association between attendance at SET and improved walking performance, compared with a control group, in PAD. Methods and Results Data from 2 randomized clinical trials of SET for PAD were combined. In each trial, participants were randomized to 3 times weekly supervised treadmill exercise or an attention control group for 6 months (maximum, 77 exercise sessions). Participants randomized to SET were categorized into tertiles, according to the proportion of exercise sessions they attended. Results adjusted for age, sex, race, baseline walking performance, comorbidities, and other potential confounders. A total of 272 participants with PAD (mean age, 67.9±9.3 years; 44% women; 61% Black race) were included. For participants randomized to SET, tertiles of attendance rates at exercise sessions were as follows: 11% to 68% (N=45), 69% to

Background Peripheral artery disease (PAD) is associated with gastrocnemius muscle abnormalities. However, the biological pathways associated with gastrocnemius muscle dysfunction and their associations with progression of PAD are largely unknown. This study characterized differential gene and microRNA (miRNA) expression in gastrocnemius biopsies from people without PAD compared with those with PAD. Participants with PAD included those with and without PAD progression. Methods and Results mRNA and miRNA sequencing were performed to identify differentially expressed genes, differentially expressed miRNAs, mRNA‐miRNA interactions, and associated biological pathways for 3 sets of comparisons: (1) PAD progression (n=7) versus non‐PAD (n=7); (2) PAD no progression (n=6) versus non‐PAD; and (3) PAD progression versus PAD no progression. Immunohistochemistry was performed to determine gastrocnemius muscle fiber types and muscle fiber size. Differentially expressed genes and differentially expressed miRNAs were more abundant in the comparison of PAD progression versus non‐PAD compared with PAD with versus without progression. Among the top significant cellular pathways in subjects with PAD progression were muscle contraction or development, transforming growth factor‐beta, growth/differentiation factor, and activin signaling, inflammation, cellular senescence, and notch signaling. Subjects with PAD progression had increased frequency of smaller Type 2a gastrocnemius muscle fibers in exploratory analyses. Conclusions Humans with PAD progression exhibited greater differences in the number of gene and miRNA expression, biological pathways, and Type 2a muscle fiber size compared with those without PAD. Fewer differences were observed between people with PAD without progression and control patients without PAD. Further study is needed to confirm whether the identified transcripts may serve as potential biomarkers for diagnosis and progression of PAD.

Background In people with lower‐extremity peripheral artery disease, the effects of exercise on patient‐reported outcomes remain unclear. Methods and Results Four hundred four people with peripheral artery disease in 3 clinical trials were randomized to exercise (N=205) or a control group (N=199) and completed the 6‐minute walk and the Walking Impairment Questionnaire distance score (score 0–100, 100=best) at baseline and 6‐month follow‐up. Compared with the control group, exercise improved 6‐minute walk distance by +39.8 m (95% CI, 26.8–52.8, P

Background Peripheral artery disease (PAD) is a manifestation of atherosclerosis characterized by reduced blood flow to the lower extremities and mobility loss. Preliminary evidence suggests PAD damages skeletal muscle, resulting in muscle impairments that contribute to functional decline. We sought to determine whether PAD is associated with an altered macrophage profile in gastrocnemius muscles and whether muscle macrophage populations are associated with impaired muscle phenotype and walking performance in patients with PAD. Methods and Results Macrophages, satellite cells, and extracellular matrix in gastrocnemius muscles from 25 patients with PAD and 7 patients without PAD were quantified using immunohistochemistry. Among patients with PAD, both the absolute number and percentage of cluster of differentiation (CD) 11b+CD206+ M2‐like macrophages positively correlated to satellite cell number (r=0.461 [P=0.023] and r=0.416 [P=0.042], respectively) but not capillary density or extracellular matrix. The number of CD11b+CD206− macrophages negatively correlated to 4‐meter walk tests at normal (r=−0.447, P=0.036) and fast pace (r=−0.510, P=0.014). Extracellular matrix occupied more muscle area in PAD compared with non‐PAD (8.72±2.19% versus 5.30±1.03%, P

Background Patients with peripheral artery disease (PAD) undergo frequent episodes of ischemia‐reperfusion in lower extremity muscles that may negatively affect mitochondrial health and are associated with impaired mobility. We hypothesized that skeletal muscle from PAD patients will show high mitochondrial DNA heteroplasmy, especially in regions more susceptible to oxidative damage, such as the displacement loop, and that the degree of heteroplasmy will be correlated with the severity of ischemia and mobility impairment. Methods and Results Mitochondrial mutations and deletions and their relative abundance were identified by targeted mitochondrial DNA sequencing in biopsy specimens of gastrocnemius muscle from 33 PAD (ankle brachial index 0.9) subjects aged ≥60 years. The probability of heteroplasmy per DNA base was significantly higher for PAD subjects than non‐PAD within each region. In adjusted models, PAD was associated with higher heteroplasmy than non‐PAD (P=0.003), but the association was limited to microheteroplasmy, that is heteroplasmy found in 1% to 5% of all mitochondrial genomes (P=0.004). Heteroplasmy in the displacement loop and coding regions were significantly higher for PAD than non‐PAD subjects after adjustment for age, sex, race, and diabetes mellitus (P=0.037 and 0.004, respectively). Low mitochondrial damage, defined by both low mitochondrial DNA copy number and low microheteroplasmy, was associated with better walking performance. Conclusions People with PAD have higher “low frequency” heteroplasmy in gastrocnemius muscle compared with people without PAD. Among people with PAD, those who had evidence of least mitochondrial damage, had better walking performance than those with more mitochondrial damage. Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT02246660.

Background Among people with lower extremity peripheral artery disease, obesity is associated with faster functional decline than normal weight. The association of weight loss with functional decline in peripheral artery disease is unknown. Methods and Results Adults with an ankle‐brachial index

Background The effects of race on response to medical therapy in people with peripheral artery disease (PAD) are unknown. Methods and Results In the PROPEL (Progenitor Cell Release Plus Exercise to Improve Functional Performance in PAD) Trial, PAD participants were randomized to 1 of 4 groups for 6 months: supervised treadmill exercise+granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) (Group 1), exercise+placebo (Group 2), attention control+GM‐CSF (Group 3), or attention control+placebo (Group 4). Change in 6‐minute walk distance was measured at 12‐ and 26‐week follow‐up. In these exploratory analyses, groups receiving GM‐CSF (Groups 1 and 3), placebo (Groups 2 and 4), exercise (Groups 1 and 2), and attention control (Groups 2 and 4) were combined, maximizing statistical power for studying the effects of race on response to interventions. Of 210 PAD participants, 141 (67%) were black and 64 (30%) were white. Among whites, GM‐CSF improved 6‐minute walk distance by +22.0 m (95% CI: −4.5, +48.5, P=0.103) at 12 weeks and +44.4 m (95% CI: +6.9, +82.0, P=0.020) at 26 weeks, compared with placebo. Among black participants, there was no effect of GM‐CSF on 6‐minute walk distance at 12‐week (P=0.26) or 26‐week (−5.0 m [−27.5, +17.5, P=0.66]) follow‐up, compared with placebo. There was an interaction of race on the effect of GM‐CSF on 6‐minute walk change at 26‐week follow‐up (P=0.018). Exercise improved 6‐minute walk distance in black (P=0.006) and white (P=0.034) participants without interaction. Conclusions GM‐CSF improved 6‐minute walk distance in whites with PAD but had no effect in black participants. Further study is needed to confirm racial differences in GM‐CSF efficacy in PAD. Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT01408901.

Background It is currently unknown whether 6 months of supervised treadmill exercise has a durable benefit on 6‐minute walk performance, even after exercise is completed, in people with peripheral artery disease. Methods and Results A total of 156 participants with peripheral artery disease were randomized to 1 of 3 groups: supervised treadmill exercise, supervised resistance training, or attention control. Participants received supervised sessions during months 1 to 6 and telephone contact during months 6 to 12. Primary outcomes were change in 6‐minute walk distance and short physical performance battery at 6‐month follow‐up and have been reported previously. Secondary outcomes were change in 6‐minute walk and short physical performance battery at 12‐month follow‐up and are reported here. A group of 134 participants (86%) completed the 12‐month follow‐up. At 6‐month follow‐up, compared with control, 6‐minute walk distance improved in the treadmill exercise group (+36.1 m, 95% CI=13.9‐58.3, P=0.001). Between 6‐ and 12‐month follow‐up, 6‐minute walk distance significantly declined (−28.6 m, 95% CI=−52.6 to −4.5, P=0.020) and physical activity declined −272 activity units (95% CI=−546 to +2, P=0.052) in the treadmill exercise group compared with controls. At 12‐month follow‐up, 6 months after completing supervised treadmill exercise, change in 6‐minute walk distance was not different between the treadmill exercise and control groups (+7.5, 95% CI=−17.5 to +32.6, P=0.56). There were no differences in short physical performance battery change between either exercise group and control at 6‐month or 12‐month follow‐up. Conclusions A 6‐month supervised treadmill exercise intervention that improved 6‐minute walk distance at 6‐month follow‐up did not have persistent benefit at 12‐month follow‐up. These results do not support a durable benefit of supervised treadmill exercise in peripheral artery disease. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Identifier: NCT00106327.

The weighted sum and genetic algorithm-based hybrid method (WSGA-based HM), which has been applied to multiobjective orbit optimizations, is negatively influenced by human factors through the artificial choice of the weight coefficients in weighted sum method and the slow convergence of GA. To address these two problems, a cluster and principal component analysis-based optimization method (CPC-based OM) is proposed, in which many candidate orbits are gradually randomly generated until the optimal orbit is obtained using a data mining method, that is, cluster analysis based on principal components. Then, the second cluster analysis of the orbital elements is introduced into CPC-based OM to improve the convergence, developing a novel double cluster and principal component analysis-based optimization method (DCPC-based OM). In DCPC-based OM, the cluster analysis based on principal components has the advantage of reducing the human influences, and the cluster analysis based on six orbital elements can reduce the search space to effectively accelerate convergence. The test results from a multiobjective numerical benchmark function and the orbit design results of an Earth observation satellite show that DCPC-based OM converges more efficiently than WSGA-based HM. And DCPC-based OM, to some degree, reduces the influence of human factors presented in WSGA-based HM.

BackgroundWe compared the incidence of depression, defined by a Geriatric Depression Score (GDS) ≥6, between people with versus without peripheral artery disease (PAD). We determined whether depressive symptoms were associated with increased mortality in people with and without PAD. Methods and ResultsNine hundred and fifty‐one PAD patients and 478 non‐PAD patients were recruited from Chicago medical centers and followed prospectively. At baseline and annually, participants completed the GDS (0–15 scale, score ≥6=depression) and 6‐minute walk. Cause of death was confirmed with death certificates. The prevalence of a GDS ≥6 at baseline was 186/951 (19.6%) among PAD versus 63/478 (13.2%) among non‐PAD participants (P=0.003). During a mean follow‐up of 2.7±1.2 years, 122/712 (17.1%) of participants with PAD versus 51/403 (12.7%) without PAD developed a GDS ≥6 (P=0.047). Adjusting for age, sex, race, comorbidities, and other confounders, PAD participants had an increased rate of developing a GDS ≥6 compared to non‐PAD participants (hazard ratio=1.54 (95% CI=1.05–2.25, P=0.026). This association was not statistically significant after adjusting for 6‐minute walk (P=0.258). Among PAD participants, a baseline GDS ≥6 was associated with increased all‐cause mortality, adjusting for confounders (hazard ratio=1.57, 95% CI=1.12–2.21, P=0.009). This association was not significant after adjusting for 6‐minute walk (P=0.224). ConclusionsPeople with PAD have a higher incidence of depressive symptoms than people without PAD. In PAD, depressive symptoms are associated with increased all‐cause and cardiovascular mortality. These associations are explained in part by poorer 6‐minute walk among people with PAD and among depressed people with PAD, respectively.