Long-term risks of respiratory diseases in patients infected with SARS-CoV-2: a longitudinal, population-based cohort study.

Background: In the post-pandemic era, growing apprehension exists regarding the potential sequelae of COVID-19. However, the risks of respiratory diseases following SARS-CoV-2 infection have not been comprehensively understood. This study aimed to investigate whether COVID-19 increases the long-term risk of respiratory illness in patients with COVID-19. Methods: In this longitudinal, population-based cohort study, we built three distinct cohorts age 37-73 years using the UK Biobank database; a COVID-19 group diagnosed in medical records between January 30th, 2020 and October 30th, 2022, and two control groups, a contemporary control group and a historical control group, with cutoff dates of October 30th, 2022 and October 30th, 2019, respectively. The follow-up period of all three groups was 2.7 years (the median (IQR) follow-up time was 0.8 years). Respiratory outcomes diagnosed in medical records included common chronic pulmonary diseases (asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary vascular disease (PVD), and lung cancer. For the data analysis, we calculated hazard ratios (HRs) along with their 95% CIs using Cox regression models, following the application of inverse probability weights (IPTW). Findings: A total of 3 cohorts were included in this study; 112,311 individuals in the COVID-19 group with a mean age (±SDs) of 56.2 (8.1) years, 359,671 in the contemporary control group, and 370,979 in the historical control group. Compared with the contemporary control group, those infected with SARS-CoV-2 exhibited elevated risks for developing respiratory diseases. This includes asthma, with a HR of 1.49 and a 95% CI 1.28-1.74; bronchiectasis (1.30; 1.06-1.61); COPD (1.59; 1.41-1.81); ILD (1.81; 1.38-2.21); PVD (1.59; 1.39-1.82); and lung cancer (1.39; 1.13-1.71). With the severity of the acute phase of COVID-19, the risk of pre-described respiratory outcomes increases progressively. Besides, during the 24-months follow-up, we observed an increasing trend in the risks of asthma and bronchiectasis over time. Additionally, the HR of lung cancer for 0-6 month follow-up was 3.07 (CI 1.73-5.44), and the association of lung cancer with COVID-19 disease disappeared at 6-12 month follow-up (1.06; 0.43-2.64) and at 12-24 months (1.02; 0.45-2.34). Compared to those with one SARS-CoV-2 infection, reinfected patients were at a higher risk of asthma (3.0; 1.32-6.84), COPD (3.07; 1.42-6.65), ILD (3.61; 1.11-11.8), and lung cancer (3.20; 1.59-6.45). Similar findings were noted when comparing with a historical cohort serving as a control group, including asthma (1.31; 1.13-1.52); bronchiectasis (1.53; 1.23-1.89); COPD (1.41; 1.24-1.59); ILD (2.53; 2.05-3.13); PVD (2.30; 1.98-2.66); and lung cancer (2.23; 1.78-2.79). Interpretation: Our research suggests that patients with COVID-19 may have an increased risk of developing respiratory diseases, and the risk increases with the severity of infection and reinfection. Even during the 24-month follow-up, the risk of asthma and bronchiectasis continued to increase. Hence, implementing appropriate follow-up strategies for these individuals is crucial to monitor and manage potential long-term respiratory health issues. Additionally, the increased risk in lung cancer in the COVID-19 individuals was probably due to the diagnostic tests conducted and incidental diagnoses. Funding: The National Natural Science Foundation of China of China Regional Innovation and Development Joint Foundation; National Natural Science Foundation of China; Program for High-level Foreign Expert Introduction of China; Natural Science Foundation for Distinguished Young Scholars of Guangdong Province; Guangdong Basic and Applied Basic Research Foundation; Climbing Program of Introduced Talents and High-level Hospital Construction Project of Guangdong Provincial People's Hospital; VA Clinical Merit and ASGE clinical research funds.

Risks of digestive diseases in long COVID: evidence from a population-based cohort study.

BACKGROUND: In the post-pandemic era, a wide range of COVID-19 sequelae is of growing health concern. However, the risks of digestive diseases in long COVID have not been comprehensively understood. To investigate the long-term risk of digestive diseases among COVID patients. METHODS: In this large-scale retrospective cohort study with up to 2.6 years follow-up (median follow-up: 0.7 years), the COVID-19 group (n = 112,311), the contemporary comparison group (n = 359,671) and the historical comparison group (n = 370,979) predated the COVID-19 outbreak were built using UK Biobank database. Each digestive outcome was defined as the diagnosis 30 days or more after the onset of COVID-19 infection or the index date. Hazard ratios (HRs) and corresponding 95% confidence intervals (CI) were computed utilizing the Cox regression models after inverse probability weighting. RESULTS: Compared with the contemporary comparison group, patients with previous COVID-19 infection had higher risks of digestive diseases, including gastrointestinal (GI) dysfunction (HR 1.38 (95% CI 1.26 to 1.51)); peptic ulcer disease (HR 1.23 (1.00 to 1.52)); gastroesophageal reflux disease (GERD) (HR 1.41 (1.30 to 1.53)); gallbladder disease (HR 1.21 (1.06 to 1.38)); severe liver disease (HR 1.35 (1.03 to 1.76)); non-alcoholic liver disease (HR 1.27 (1.09 to 1.47)); and pancreatic disease (HR 1.36 (1.11 to 1.66)). The risks of GERD were increased stepwise with the severity of the acute phase of COVID-19 infection. Even after 1-year follow-up, GERD (HR 1.64 (1.30 to 2.07)) and GI dysfunction (HR 1.35 (1.04 to 1.75)) continued to pose risks to COVID-19 patients. Compared to those with one SARS-CoV-2 infection, reinfected patients were at a higher risk of pancreatic diseases (HR 2.57 (1.23 to 5.38)). The results were consistent when the historical cohort was used as the comparison group. CONCLUSIONS: Our study provides insights into the association between COVID-19 and the long-term risk of digestive system disorders. COVID-19 patients are at a higher risk of developing digestive diseases. The risks exhibited a stepwise escalation with the severity of COVID-19, were noted in cases of reinfection, and persisted even after 1-year follow-up. This highlights the need to understand the varying risks of digestive outcomes in COVID-19 patients over time, particularly those who experienced reinfection, and develop appropriate follow-up strategies.

Automatic echocardiographic evaluation of the probability of pulmonary hypertension using machine learning.

Echocardiography, a simple and noninvasive tool, is the first choice for screening pulmonary hypertension (PH). However, accurate assessment of PH, incorporating both the pulmonary artery pressures and additional signs for PH remained unsatisfied. Thus, this study aimed to develop a machine learning (ML) model that can automatically evaluate the probability of PH. This cohort included data from 346 (275 for training set and internal validation set and 71 for external validation set) patients with suspected PH patients and receiving right heart catheterization. Echocardiographic images on parasternal short axis-papillary muscle level (PSAX-PML) view from all patients were collected, labeled, and preprocessed. Local features from each image were extracted and subsequently integrated to build a ML model. By adjusting the parameters of the model, the model with the best prediction effect is finally constructed. We used receiver-operating characteristic analysis to evaluate model performance and compared the ML model with the traditional methods. The accuracy of the ML model for diagnosis of PH was significantly higher than the traditional method (0.945 vs. 0.892, p = 0.027 [area under the curve [AUC]]). Similar findings were observed in subgroup analysis and validated in the external validation set (AUC = 0.950 [95% CI: 0.897-1.000]). In summary, ML methods could automatically extract features from traditional PSAX-PML view and automatically assess the probability of PH, which were found to outperform traditional echocardiographic assessments.

Habitual fish oil use and risk of COVID-19-related outcomes: Evidence from a large scale cohort study and Mendelian randomization analysis.

BACKGROUND & AIMS: Previous findings for the effects of fish oil on COVID-19-related outcomes remain largely inconclusive and controversy persists. Large population-based studies in real-life settings are required to explore the impact of habitual fish oil use on Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, Coronavirus disease 2019 (COVID-19)-related hospitalization and death. To investigate the associations between habitual fish oil use and SARS-CoV-2infection, COVID-19-related outcome. METHODS: Cohort study based on the UK Biobank. 466,572 participants were enrolled. For Mendelian randomization (MR) study, single-nucleotide variants were selected for exposures of fish-oil-derived n-3 PUFAs, including docosapentaenoic acid (DPA). RESULTS: 146,969 (31.5%) participants reported their habitual fish oil use at baseline. Compared with non-fish-oil-users, the hazard ratios for habitual users were 0.97 (95% confidence interval [CI] 0.94 to 0.99) for SARS-CoV-2 infection, 0.92 (95% CI 0.85 to 0.98) for COVID-19-related hospitalization and 0.86 (95% CI 0.75 to 0.98) for COVID-19-related death. MR showed that a higher level of circulating DPA is casually associated with a lower risk of severe COVID-19 (IVW, odds ratio = 0.26, 95% CI 0.08-0.88, P = 0.030). CONCLUSIONS: In this large cohort, we found that habitual fish oil use was significantly associated with lower risks of SARS-CoV-2 infection, hospitalization and death from COVID-19. MR analyses further support a possible causal role of DPA, one of the components of fish oil and valid biomarkers of dietary intake, in reducing the risk of severe COVID-19.

Associations of habitual glucosamine use with SARS-CoV-2 infection and hospital admission and death with COVID-19: Evidence from a large population based cohort study.

The coronavirus disease 2019 (COVID-19) pandemic has led to a fundamental number of morbidity and mortality worldwide. Glucosamine was indicated to help prevent and control RNA virus infection preclinically, while its potential therapeutic effects on COVID-19-related outcomes are largely unknown. To assess the association of habitual glucosamine use with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, hospital admission, and mortality with COVID-19 in a large population based cohort. Participants from UK Biobank were reinvited between June and September 2021 to have SARS-CoV-2 antibody testing. The associations between glucosamine use and the risk of SARS-CoV-2 infection were estimated by logistic regression. Hazard ratios (HRs) and 95% confidence intervals (CIs) for COVID-19-related outcomes were calculated using COX proportional hazards model. Furthermore, we carried out propensity-score matching (PSM) and stratified analyses. At baseline, 42 673 (20.7%) of the 205 704 participants reported as habitual glucosamine users. During median follow-up of 1.67 years, there were 15 299 cases of SARS-CoV-2 infection, 4214 cases of COVID-19 hospital admission, and 1141 cases of COVID-19 mortality. The fully adjusted odds ratio of SARS-CoV-2 infection with glucosamine use was 0.96 (95% CI: 0.92-1.01). The fully adjusted HR were 0.80 (95% CI: 0.74-0.87) for hospital admission, and 0.81 (95% CI: 0.69-0.95) for mortality. The logistic regression and Cox proportional hazard analyses after PSM yielded consistent results. Our study demonstrated that habitual glucosamine use is associated with reduced risks of hospital admission and death with COVID-19, but not the incidence of SARS-CoV-2 infection.

Machine learning for clustering and postclosure outcome of adult CHD-PAH patients with borderline hemodynamics.

BACKGROUND: Patients with uncorrected isolated simple shunts associated pulmonary arterial hypertension (PAH) had increased mortality. Treatment strategies for borderline hemodynamics remain controversial. This study aims to investigate preclosure characteristics and its association with postclosure outcome in this group of patients. METHODS: Adults with uncorrected isolated simple shunts associated PAH were included. Peak tricuspid regurgitation velocity<2.8 m/sec with normalized cardiac structures was defined as the favorable study outcome. We applied unsupervised and supervised machine learning for clustering analysis and model constructions. RESULTS: Finally, 246 patients were included. During a median follow-up of 414days, 58.49% (62/106) of patients with pretricuspid shunts achieved favorable outcome while 32.22% (46/127) of patients with post-tricuspid shunts. In unsupervised learning, two clusters were identified in both types of shunts. Generally, the oxygen saturation, pulmonary blood flow, cardiac index, dimensions of the right and left atrium, were the major features that characterized the identified clusters. Specifically, mean right atrial pressure, right ventricular dimension, and right ventricular outflow tract helped differentiate clusters in pretricuspid shunts while age, aorta dimension, and systemic vascular resistance helped differentiate clusters for post-tricuspid shunts. Notably, cluster 1 had better postclosure outcome than cluster 2 (70.83% vs 32.55%, p < .001 for pretricuspid and 48.10% vs 16.67%, p < .001 for post-tricuspid). However, models constructed from supervised learning methods did not achieve good accuracy for predicting the postclosure outcome. CONCLUSIONS: There were two main clusters in patients with borderline hemodynamics, in which one cluster had better postclosure outcome than the other.

Systolic Blood Pressure and Cardiovascular Risk in Normotensive Adults.

OBJECTIVE: To examine the association of systolic blood pressure (SBP) and cardiovascular risk in normotensive adults. PATIENTS AND METHODS: This study analyzed data from 7 prospective cohorts between September 29, 1948, and December 31, 2018. Complete information on history of hypertension and baseline blood pressure measurements were required for inclusion. We excluded individuals younger than 18 years old, those with a history of hypertension, and patients with baseline SBP measurements of less than 90 mm Hg or 140 mm Hg or higher. Cox proportional hazards regression and restricted cubic spline models were used to evaluate the hazards of cardiovascular outcomes. RESULTS: A total of 31,033 participants were included. The mean ± SD age was 45.3±14.8 years, 16,693 of the participants (53.8%) were female, and the mean ± SD SBP was 115.8±11.7. Over a median follow-up of 23.5 years, 7005 cardiovascular events occurred. Compared with those who had SBP levels of 90 to 99 mm Hg, participants with SBP levels of 100 to 109, 110 to 119, 120 to 129, and 130 to 139 mm Hg experienced 23% (hazard ratio [HR], 1.23; 95% CI, 1.07 to 1.42), 53% (HR, 1.53; 95% CI, 1.33 to 1.76), 87% (HR, 1.87; 95% CI, 1.62 to 2.16), and 117% (HR, 2.17; 95% CI, 1.87 to 2.52) increased risks of cardiovascular events, respectively. Compared with follow-up SBP of 90 to 99 mm Hg, the HRs for cardiovascular events were 1.25 (95% CI, 1.02 to 1.54), 1.93 (95% CI, 1.58 to 2.34), 2.55 (95% CI, 2.09 to 3.10), and 3.39 (95% CI, 2.78 to 4.14), respectively, for follow-up SBP levels of 100 to 109, 110 to 119, 120 to 129, and 130 to 139 mm Hg. CONCLUSION: In adults without hypertension, there is a stepwise increase in risk of cardiovascular events, with increasing SBP starting at levels as low as 90 mm Hg.

Dental Diseases Increase Risk of Aortic Arch Calcification Independent of Renal Dysfunction in Older Adults: Shenzhen Community Cohort Study.

Many studies have documented that dental diseases were associated with an increased risk of cardiovascular diseases. Aortic arch calcification (AoAC) is a powerful predictor of cardiovascular diseases. However, whether the status of dental health is associated with AoAC is still unknown. 9463 participants over the age of 60 from Shenzhen community centers were included in the cross-sectional analysis. Physical examination data, blood biochemical tests, and AoAC scores calculated by chest radiography were collected and analyzed. Among them, 2630 participants were followed up for AoAC progression up to 36 months. Participants with AoAC suffered more tooth loss than those without AoAC (77.62% vs. 72.91%; p < 0.001). Association rule analysis suggested a strong association between dental diseases and AoAC. Tooth loss or decay increased the risk of AoAC progression (HR 1.459; 95%CI 1.284−1.658) after adjusting other risk factors including renal dysfunction. Dental diseases are potential predictors for AoAC in elderly people, which are independent of renal dysfunction.

Machine learning in a real-world PFO study: analysis of data from multi-centers in China.

PURPOSE: The association of patent foreman ovale (PFO) and cryptogenic stroke has been studied for years. Although device closure overall decreases the risk for recurrent stroke, treatment effects varied across different studies. In this study, we aimed to detect sub-clusters in post-closure PFO patients and identify potential predictors for adverse outcomes. METHODS: We analyzed patients with embolic stroke of undetermined sources and PFO from 7 centers in China. Machine learning and Cox regression analysis were used. RESULTS: Using unsupervised hierarchical clustering on principal components, two main clusters were identified and a total of 196 patients were included. The average age was 42.7 (12.37) years and 64.80% (127/196) were female. During a median follow-up of 739 days, 12 (6.9%) adverse events happened, including 6 (3.45%) recurrent stroke, 5 (2.87%) transient ischemic attack (TIA) and one death (0.6%). Compared to cluster 1 (n = 77, 39.20%), patients in cluster 2 (n = 119, 60.71%) were more likely to be male, had higher systolic and diastolic blood pressure, higher body mass index, lower high-density lipoprotein cholesterol and increased proportion of presence of atrial septal aneurysm. Using random forest survival (RFS) analysis, eight top ranking features were selected and used for prediction model construction. As a result, the RFS model outperformed the traditional Cox regression model (C-index: 0.87 vs. 0.54). CONCLUSIONS: There were 2 main clusters in post-closure PFO patients. Traditional cardiovascular profiles remain top ranking predictors for future recurrence of stroke or TIA. However, whether maximizing the management of these factors would provide extra benefits warrants further investigations.

Association of nutritional status and mortality risk in patients with primary pulmonary hypertension.

Malnutrition plays a crucial role in pulmonary hypertension (PH). The prognostic nutritional index (PNI) is a reliable indicator for nutritional status assessment. However, its relationship with mortality risk in PH patients has not yet been investigated. This study analyzed data from the Patient Registry for Primary PH. PNI was calculated through albumin and lymphocyte counts. Subjects with missing data for PNI calculation were excluded. The primary endpoint was all-cause mortality. Cox proportional hazard model was used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs). Of the 317 patients records available in the registry, we finally included 136 patients. The average age of the included subjects was 40.56 (14.91) years and 63.24% (86/136) were female. In our analysis of Cox regression, per 1-point increment of PNI was associated with 4% decreased risk of mortality in PH patients (age- and sex-adjusted HR: 0.96, 95% CI: 0.93-0.98, p = 0.002). We further categorized these subjects by quartiles of PNI. Compared to quartile 4, the age- and sex-adjusted HRs of death for quartiles 1, 2, and 3 were 2.39 (95% CI: 1.21-4.72, p = 0.01), 2.25 (95% CI: 1.15-4.39, p = 0.02), and 1.72 (95% CI: 0.84-3.52, p = 0.14). In addition, logistic regression analyses suggested a positive correlation of PNI with total lung capacity (ß = 0.98, p = 0.002) and forced expiratory volume in 1 min (ß = 1.53, p = 0.03). This study demonstrates that low PNI was associated with an increased risk of death in PH patients. These findings help to enlighten our understanding of the nutritional status and adverse outcomes in PH patients.

Functional analysis of nuclear receptor HR96 gene in Bombyx mori exposed to phoxim.

The nuclear receptor (NRs) gene family functions as ligand-dependent transcription factors in a variety of animals, which participates in a variety of biological processes, such as cell differentiation, metabolic regulation, reproduction, development, insect metamorphosis. In this study, a nuclear receptor HR96 gene in silkworm Bombyx mori (BmHR96) was identified, and the responses of BmHR96 gene to 20-hydroxyecdysone (20E), three insecticides, and two disinfectants were analyzed and its function in phoxim exposure was explored.  Quantitative real-time polymerase chain reaction indicated that the expression of BmHR96 mRNA was the highest in ovary of 5th instar Day 3 silkworm larvae and in silk gland of the wandering stage. The expression patterns of BmHR96 gene in ovary, head, testis, and midgut of different stages were different. After injecting 20E into B. mori, the expression of BmHR96 mRNA had no significant difference compared with control. Three insecticides and two disinfectants were used to treat B. mori, respectively, and it was found that they had different influence patterns on the expression level of BmHR96. siRNA of BmHR96 was injected into silkworm larvae and the expression of BmHR96 was decreased significantly after injecting 72 h. After silencing of BmHR96, B. mori was fed with phoxim-treated leaves. The results showed that the mortality of B. mori after silencing of BmHR96 was significantly higher than the control. Our results indicated that HR96 plays an important role in regulating the stress response of phoxim.

Magnesium and Zinc Intake Ratio Mediates the Increase of Coronary Artery Calcification through Upregulating Interleukin 6.

The relation between dietary minerals and coronary artery calcification (CAC) has been emphasized. However, the effects of multiple dietary minerals on CAC progression remain unclear. This study Investiagetes the effect of combined dietary mineral intake on the progression of CAC. We analyzed a population-based cohort with 6814 participants from the Multi-Ethnic Study of Atherosclerosis (MESA). CAC scores were measured at baseline and subsequent follow-up examinations by Multi-detector computed tomography (MDCT) scans with Agatston scores. Then, the progression of CAC was defined through increased CAC scores in the follow-up from the baseline exam. The results revealed that the dietary intake of individual minerals did not show significant differences across CAC progression vs non progression groups. However, participants with CAC progression had an increased Magnesium (Mg):Zinc (Zn) ratio (P < 0.05). This effect was significant in logistic regression after adjusting for multiple established risk factors of CAC progression (OR 1.050; 95% CI 1.003, 1.099; P = 0.038). The increased risk of CAC associated with Mg/Zn was mediated through an increase level of IL-6, which increased with association to the Mg: Zn ratio. In conclusion, the dietary of Mg: Zn ratio, rather than individual mineral intake is associated with increased risk of CAC progression, which is mediated by pro-calcific IL-6. Therefore, the consideration of dietary intake of Zn and Mg together would play a cardio protective role among CAC patients.

Capsaicin Attenuates Arterial Calcification Through Promoting SIRT6-Mediated Deacetylation and Degradation of Hif1α (Hypoxic-Inducible Factor-1 Alpha).

BACKGROUND: Sustained Hif1α (hypoxic-inducible factor-1 alpha) accumulation plays a central role in osteogenic transdifferentiation and subsequent calcification. Capsaicin, the potent agonist of TRPV1 (transient receptor potential vanilloid type 1), was found to mitigate hypoxic-related injury and reverse phenotypic switch of vascular smooth muscle cells. However, its role in arterial calcification and the underlying mechanisms remain unexplored. METHODS: We used data from Multi-Ethnic Study of Atherosclerosis to examine the association of coronary artery calcification and chili consumption. Chronic kidney disease mice and high phosphate-induced vascular smooth muscle cells calcification models were established to investigate the anticalcification effect of capsaicin, evaluated by calcium deposition and changes in phenotype markers. RESULTS: Chili consumption was negatively correlated with coronary artery calcification and conferred a smaller progression burden during follow-up. Capsaicin reduced calcium deposition and osteogenic transdifferentiation both in vivo and in vitro. Using siTRPV1 (small interfering RNA and the antagonist of TRPV1), the anticalcification effect of capsaicin was abrogated. Hif1α was increased in phosphate-treated vascular smooth muscle cells and its degradation was accelerated by capsaicin. Retaining Hif1α stability using cobalt chloride (CoCl2) or MG132 abolished the protective effect of capsaicin. We further identified an increased expression of SIRT6 (Sirtuin 6) in response to capsaicin and confirmed the physical interaction between SIRT6 and Hif1α. Acetylated Hif1α was decreased, whereas hydroxylated Hif1α was increased under capsaicin treatment. Using immunohistochemistry analysis, we observed increased SIRT6 and reduced Hif1α in both SIRT6 transgenic and capsaicin-treated chronic kidney disease mice. CONCLUSIONS: Capsaicin facilitates deacetylation and degradation of Hif1α by upregulating SIRT6, which inhibits osteogenic transdifferentiation and protects against arterial calcification. These data highlight a promising therapeutic target for the management of arterial calcification.

SIRT6 protects vascular smooth muscle cells from osteogenic transdifferentiation via Runx2 in chronic kidney disease.

Vascular calcification (VC) is regarded as an important pathological change lacking effective treatment and associated with high mortality. Sirtuin 6 (SIRT6) is a member of the Sirtuin family, a class III histone deacetylase and a key epigenetic regulator. SIRT6 has a protective role in patients with chronic kidney disease (CKD). However, the exact role and molecular mechanism of SIRT6 in VC in patients with CKD remain unclear. Here, we demonstrated that SIRT6 was markedly downregulated in peripheral blood mononuclear cells (PBMCs) and in the radial artery tissue of patients with CKD with VC. SIRT6-transgenic (SIRT6-Tg) mice showed alleviated VC, while vascular smooth muscle cell-specific (VSMC-specific) SIRT6 knocked-down mice showed severe VC in CKD. SIRT6 suppressed the osteogenic transdifferentiation of VSMCs via regulation of runt-related transcription factor 2 (Runx2). Coimmunoprecipitation (co-IP) and immunoprecipitation (IP) assays confirmed that SIRT6 bound to Runx2. Moreover, Runx2 was deacetylated by SIRT6 and further promoted nuclear export via exportin 1 (XPO1), which in turn caused degradation of Runx2 through the ubiquitin-proteasome system. These results demonstrated that SIRT6 prevented VC by suppressing the osteogenic transdifferentiation of VSMCs, and as such targeting SIRT6 may be an appealing therapeutic target for VC in CKD.

Inflammatory Cells Accelerated Carotid Artery Calcification via MMP9: Evidences From Single-Cell Analysis.

Background: Vascular calcification (VC) is an important predictor of prognosis in atherosclerosis, the phenotypic transformation of vascular smooth muscle cells (VSMCs) is thought to be a process of VC. However, the implications and potential mechanisms for VSMCs phenotypic transition remain unknown. Methods: To study the transformation of vascular smooth muscle cells (VSMCs) in the calcification early period, we analyzed single-cell sequencing data from carotid artery calcified core and paracellular tissue, based on the results of enrichment analysis and protein-protein interaction analysis. Upstream transcription factors were tracked and finally the results were validated using the MESA database. Results: We successfully identified a subpopulation of inflammatory macrophage-like VSMCs and determined that MMP9 is an important factor in the phenotypic transformation of VSMCs. We found that RELA regulates MMP9 expression and that knockdown of RELA attenuated MMP9 expression and reduced the expression of BMP2 and the macrophage marker LGALS3 in vascular smooth muscle in inflammatory states, while serum levels of MMP9 correlated significantly with the inflammatory response. Conclusion: This study reveals that the phenotypic transformation of VSMCs can be regulated by modulating MMP9, providing a new idea for the early treatment of VC.

Comprehensive analysis of proton pump inhibitors and risk of digestive tract cancers.

BACKGROUND: For the past two decades, dispute on whether proton pump inhibitor (PPI) leads to digestive tract cancer remains, and emerging studies in recent years still demonstrate inconsistent results, which continues to perpetuate concerns over the safety of PPI use. We performed a systematic review and meta-analysis, with comprehensive evaluation by Bradford Hill criteria of causation, to assess the effect of PPI use on digestive tract cancers. METHODS: Medline, Embase and Web of Science databases were searched for observational studies published up to 15th January 2021. Pooled relative risks (RRs) were estimated via random effects models. Cumulative defined daily dose- and duration-risk relationships using restricted cubic spline and fractional polynomial models were investigated. Bradford Hill criteria were applied to evaluate causation. PROSPERO Registration: CRD42020211103. RESULTS: Thirty-two publications containing 4,355,254 participants were included. PPI use is associated with an increased risk of overall digestive tract cancers (RR = 1.63, 95% confidence interval (CI) 1.33 to 2.00). PPI use is correlated with increased risks of gastric cancer (RR = 1.78, 95% CI 1.38 to 2.31), pancreatic cancer (RR = 1.72, 95% CI 1.05 to 2.82) and liver cancer (RR = 1.62, 95% CI 1.04 to 2.52), but not of esophageal cancer (RR = 2.06, 95% CI 0.65 to 6.57) and colorectal cancer (RR = 1.24, 95% CI 0.93 to 1.66). The association between PPI and digestive tract cancers is stronger in people with minimal exposure. When cumulative defined daily dose or duration increases, the risks decline and become non-significant. Evaluation by Bradford Hill criteria indicates weak evidence of causation. CONCLUSIONS: A causal relationship between PPI use and digestive tract cancers is not supported by the evidence in the current review. Concerns over carcinogenic side-effects of PPI might be unfounded.

Longitudinal change in lung function and subsequent risks of cardiovascular events: evidence from four prospective cohort studies.

BACKGROUND: Lung function is constantly changing over the life course. Although the relation of cross-sectional lung function measure and adverse outcomes has been reported, data on longitudinal change and subsequent cardiovascular (CV) events risks are scarce. Therefore, this study is to determine the association of longitudinal change in lung function and subsequent cardiovascular risks. METHODS: This study analyzed the data from four prospective cohorts. Subjects with at least two lung function tests were included. We calculated the rate of forced respiratory volume in 1 s (FEV1) and forced vital capacity (FVC) decline for each subject and categorized them into quartiles. The primary outcome was CV events, defined as a composite of coronary heart disease (CHD), chronic heart failure (CHF), stroke, and any CV death. Cox proportional hazards regression and restricted cubic spline models were applied. RESULTS: The final sample comprised 12,899 participants (mean age 48.58 years; 43.61% male). Following an average of 14.79 (10.69) years, 3950 CV events occurred. Compared with the highest FEV1 quartile (Q4), the multivariable HRs for the lowest (Q1), 2nd (Q2), and 3rd quartiles (Q3) were 1.33 (95%CI 1.19, 1.49), 1.30 (1.16, 1.46), and 1.07 (0.95, 1.21), respectively. Likewise, compared with the reference quartile (Q4), the group that experienced a faster decline in FVC had higher HRs for CV events (1.06 [95%CI 0.94-1.20] for Q3, 1.15 [1.02-1.30] for Q2, and 1.28 [1.14-1.44] for Q1). The association remained robust across a series of sensitivity analyses and nearly all subgroups but was more evident in subjects < 60 years. CONCLUSIONS: We observed a monotonic increase in risks of CV events with a faster decline in FEV1 and FVC. These findings emphasize the value of periodic evaluation of lung function and open new opportunities for disease prevention.

Association between cardiovascular risk factors and colorectal cancer: A systematic review and meta-analysis of prospective cohort studies.

BACKGROUND: Emerging data have suggested colorectal cancer (CRC) often coexists with cardiovascular diseases, but whether cardiovascular risk factors play a role in CRC remains unclear. We performed a systematic review and meta-analysis to better illustrate the associations between cardiovascular risk factors and CRC. METHODS: We searched EMBASE, MEDLINE and Web of Science databases from inception up to June 14, 2020. Prospective cohort studies were included if they evaluated the association between at least one of cardiovascular risk factors and CRC incidence, containing sufficient data to obtain relative risk (RR) and 95% confidence interval (CI). We performed separate meta-analyses for each cardiovascular risk factor using random-effect model. PROSPERO registration number: CRD42020175537. FINDINGS: Data from 84 studies, reporting 52, 348, 827 individuals and 384, 973 incident cases were included in the analysis. Overall, the risk of CRC was 1.31(95% CI, 1.21-1.42) for obesity, 1.14 (95% CI, 1.09-1.20) for per 5 kg/m2 increase in body mass index, 1.18 (95% CI, 1.14-1.23) for former smoker, 1.20 (95% CI, 1.11-1.30) for current smoker, 1.25 (95% CI, 1.16-1.35) for diabetes, 1.07 (95% CI, 1.02-1.12) for hypertension. The summary RRs of CRC for the highest versus lowest quartiles of total cholesterol, triglyceride, low-density lipoprotein were 1.12 (95% CI, 1.03-1.22), 1.18 (95% CI, 1.04-1.35), 0.85 (95% CI, 0.62-1.17) respectively and the pooled RR for the lowest versus highest quartile of high-density lipoprotein was 1.14 (95% CI, 1.02-1.28). INTERPRETATION: Unfavorable cardiovascular risk factors are associated with increased risk of CRC, which may provide novel insight into the screening strategies of CRC in patient with these risk factors.

Association between oral contraceptive use and incident heart failure.

AIMS: Oral contraceptives (OCs) are widely used in women of reproductive age, but their influences on heart failure (HF) development have yet to be reported. This study was performed to assess HF risk associated with OC use. METHODS AND RESULTS: We studied women participating in the Multi-Ethnic Study of Atherosclerosis with available data on OC use. Inverse probability of treatment weighting analyses were used to reduce baseline imbalances. Cox proportional hazards models were applied to evaluate the associations of OC use and HF risk. The primary analysis comprised a total of 3594 participants [average age 62.10 (10.24) years]. During an average follow-up of 12.45 (3.75) years, 138 incident HF occurred. In unadjusted Cox model, OC use was associated with a decreased risk of HF [hazard ratio (HR) = 0.45, 95% confidence interval (CI) 0.31-0.64, P < 0.001]. However, in multivariable-adjusted and inverse probability of treatment weighting models, the results were attenuated and became non-significant (HR = 0.96, 95% CI 0.63-1.48, P = 0.86 and HR = 0.79, 95% CI 0.45-1.40, P = 0.43, respectively). Duration of OC use was not related to increased risks of HF. When stratifying HF into subtypes, similar associations were observed. In multivariable-adjusted regression models, OC use was positively associated with left ventricular end-diastolic mass [coefficient (ß) = 3.04, P = 0.006] and stroke volume (ß = 1.76, P = 0.01 for the left ventricle; ß = 2.17, P = 0.005 for the right ventricle) but had no impact on left ventricular ejection fraction (ß = 0.09, P = 0.75) and right ventricular ejection fraction (ß = 0.33, P = 0.25). CONCLUSIONS: Oral contraceptive use in women of reproductive age does not portend increased risk of HF. However, whether the formulations or dosages differently impact this association should be further investigated.

Body mass index trajectories during mid to late life and risks of mortality and cardiovascular outcomes: Results from four prospective cohorts.

BACKGROUND: Our understanding of the weight-outcome association mainly comes from single-time body mass index (BMI) measurement. However, data on long-term trajectories of within-person changes in BMI on diverse study outcomes are sparse. Therefore, this study is to determine the associations of individual BMI trajectories and cardiovascular outcomes. METHODS: The present analysis was based on data from 4 large prospective cohorts and restricted to participants aged ≥45 years with at least two BMI measurements. Hazard ratios (HR) and 95% confidence intervals(95%CI) for each outcome according to different BMI trajectories were calculated in Cox regression models. FINDINGS: The final sample comprised 29,311 individuals (mean age 58.31 years, and 77.31% were white), with a median 4 BMI measurements used in this study. During a median follow-up of 21.16 years, there were a total of 10,192 major adverse cardiovascular events (MACE) and 11,589 deaths. A U-shaped relation was seen with all study outcomes. Compared with maintaining stable weight, the multivariate adjusted HR for MACE were 1.53 (95%CI 1.40-1.66), 1.26 (95%CI 1.16-1.37) and 1.08 (95%CI 1.02-1.15) respectively for rapid, moderate and slow weight loss; 1.01 (95%CI 0.95-1.07), 1.13 (95%CI 1.05-1.21) and 1.29 (95%CI 1.20-1.40) respectively for slow, moderate and rapid weight gain. Identical patterns of association were observed for all other outcomes. The development of BMI differed markedly between the outcome-free individuals and those who went on to experience adverse events, generally beginning to diverge 10 years before the occurrence of the events. INTERPRETATION: Our findings may signal an underlying high-risk population and inspire future studies on weight management. FUNDING: National Natural Science Foundation of China, Guangdong Natural Science Foundation.