Healthy Lifestyles Modify the Association of Melatonin Receptor 1B Gene and Ischemic Stroke: A Family-Based Cohort Study in Northern China.

Limited research has reported the association between MTNR1B gene polymorphisms and ischemic stroke (IS), and there is insufficient evidence on whether adopting a healthy lifestyle can mitigate genetic risks in this context. This study aimed to investigate the associations between MTNR1B gene variants (rs10830963 and rs1387153) and IS, examining the potential effect of gene-lifestyle interactions on IS risk. Conducted in northern China, this family-based cohort study involved 5116 initially IS-free subjects. Genotype data for rs10830963 and rs1387153 in MTNR1B were collected. Eight modifiable lifestyle factors, including body mass index (BMI), smoking, alcohol consumption, dietary habits, physical activity, sedentary time, sleep duration, and chronotype, were considered in calculating healthy lifestyle scores. Multilevel Cox models were used to examine the associations between MTNR1B variants and IS. Participants carrying the rs10830963-G and rs1387153-T alleles exhibited an elevated IS risk. Each additional rs10830963-G allele and rs1387153-T allele increased the IS risk by 36% (HR = 1.36, 95% CI, 1.12-1.65) and 32% (HR = 1.32, 95% CI, 1.09-1.60), respectively. Participants were stratified into low, medium, and high healthy lifestyle score groups (1537, 2188, and 1391 participants, respectively). Genetic-lifestyle interactions were observed for rs10830963 and rs1387153 (p for interaction < 0.001). Notably, as the healthy lifestyle score increased, the effect of MTNR1B gene variants on IS risk diminished (p for trend < 0.001). This study underscores the association between the MTNR1B gene and IS, emphasizing that adherence to a healthy lifestyle can mitigate the genetic predisposition to IS.

Research progress on the antitumor effects of harmine.

Harmine is a naturally occurring ß-carboline alkaloid originally isolated from Peganum harmala. As a major active component, harmine exhibits a broad spectrum of pharmacological properties, particularly remarkable antitumor effects. Recent mechanistic studies have shown that harmine can inhibit cancer cell proliferation and metastasis through epithelial-to-mesenchymal transition, cell cycle regulation, angiogenesis, and the induction of tumor cell apoptosis. Furthermore, harmine reduces drug resistance when used in combination with chemotherapeutic drugs. Despite its remarkable antitumor activity, the application of harmine is limited by its poor solubility and toxic side effects, particularly neurotoxicity. Novel harmine derivatives have demonstrated strong clinical application prospects, but further validation based on drug activity, acute toxicity, and other aspects is necessary. Here, we present a review of recent research on the action mechanism of harmine in cancer treatment and the development of its derivatives, providing new insights into its potential clinical applications and strategies for mitigating its toxicity while enhancing its efficacy.

The cyclic AMP (cAMP) phosphodiesterase CpdA required for growth, biofilm formation, motility and pathogenicity of Edwardsiella piscicida.

Edwardsiella piscicida is a severe fish pathogen with wide host range, causing the huge economic losses in the aquaculture industry. Cyclic adenosine monophosphate (cAMP) as an important second messenger regulates the physiological and behavioral responses to environmental cues in eukaryotic and prokaryotic. The intracellular level of cAMP for effective activity is tightly controlled by the synthesis of adenylate cyclase, excretion and degradation of phosphodiesterase. In this study, we identified and characterized a class III cAMP phosphodiesterase, named as CpdA, in the E. piscicida. To investigate the role of CpdA in the physiology and pathogenicity, we constructed the in-frame deletion mutant of cpdA of E. piscicida, TX01ΔcpdA. The results showed that TX01ΔcpdA accumulated the higher intracellular cAMP concentration than TX01, indicating that CpdA exerted the hydrolysis of cAMP. In addition, compared to the TX01, the TX01ΔcpdA slowed growth rate, diminished biofilm formation and lost motility. More importantly, pathogenicity analysis confirmed that TX01ΔcpdA significantly impaired the ability of invading the epithelial cells, reproduction in macrophages, tissues dissemination and lethality for healthy tilapias. The most of lost properties of TX01ΔcpdA were restored partially or fully by the introduction of cpdA gene. These results suggest that cpdA is required for regulation of the physiology and virulence of E. piscicida.

Online Exploring the Gaseous Oil Fumes from Oleic Acid Thermal Oxidation by Synchrotron Radiation Photoionization Mass Spectrometry.

Cooking oil fumes are an intricate and dynamic mixture containing a variety of poisonous and hazardous substances, and their real-time study remains challenging. Based on tunable synchrotron radiation photoionization mass spectrometry (SR-PIMS), isomeric/isobaric compounds in the gaseous oil fumes from oleic acid thermal oxidation were determined in real time and distinguished by photoionization efficiency (PIE) curve simulation combined with multiple linear regression (MLR) analysis. A series of common carcinogens such as formaldehyde, acetaldehyde, acrolein, and several unreported chemicals including diethyl ether and formylcyclohexane were successfully characterized. Moreover, time-resolved profiles of certain components in gaseous oil fumes were monitored for 55 h. Distinct evolutionary processes were observed, indicating the consumption and formation of parent molecules, intermediates, and final products.

Study on the thermal oxidation of oleic, linoleic and linolenic acids by synchrotron radiation photoionization mass spectrometry.

RATIONALE: Cooking oil fumes contain numerous hazardous and carcinogenic chemicals, posing potential threats to human health. However, the sources of these species remain ambiguous, impeding health risk assessment, pollution control and mechanism research. METHODS: To address this issue, the thermal oxidation of three common unsaturated fatty acids (UFAs), namely oleic, linoleic and linolenic acids, present in vegetable oils was investigated. The volatile and semi-volatile products were comprehensively characterized by online synchrotron radiation photoionization mass spectrometry (SR-PIMS) with two modes, which were validated and complemented using offline gas chromatography (GC)/MS methods. Tunable SR-PIMS combined with photoionization efficiency curve simulation enabled the recognition of isomers/isobars in gaseous fumes. RESULTS: SR-PIMS revealed over 100 products, including aldehydes, alkenes, furans, aromatic hydrocarbons, etc., such as small molecules of formaldehyde, acetaldehyde, acrolein, ethylene and furan, which are not readily detected by conventional GC/MS; and some unreported fractions, e.g. ketene, 4-ethylcyclohexene and cycloundecene(E), were also observed. Furthermore, real-time monitoring of product emissions during the thermal oxidation of the three UFAs via SR-PIMS revealed that linolenic acid may be the major source of acrolein. CONCLUSION: SR-PIMS has been demonstrated as a powerful technique for online investigation of cooking oil fumes. This study achieved comprehensive characterization of volatile and semi-volatile products from the thermal oxidation of oleic, linoleic and linolenic acids, facilitating the traceability of species in cooking fumes and aiding in exploring the thermal reactions of different vegetable oils.

Prevalence and trends of polypharmacy in U.S. adults, 1999-2018.

BACKGROUND: Polypharmacy is one of the most important health issues for its potential impacts on disease burden and healthcare costs. The aim of this study was to update a comprehensive picture of prevalence and trends in polypharmacy over 20 years in U.S. adults. METHODS: Participants included 55,081 adults aged ≥ 20 from the National Health and Nutrition Examination Survey, January 1, 1999, through December 31, 2018. The simultaneously use of ≥ 5 drugs in one individual was defined as polypharmacy. National prevalence and trends in polypharmacy were evaluated among U.S. adults within different demo-socioeconomic status and pre-existing diseases. RESULTS: From 1999-2000 to 2017-2018, the overall percentages of adults with polypharmacy remained on the rise, increasing from 8.2% (7.2-9.2%) to 17.1% (15.7-18.5%) (average annual percentage change [AAPC] = 2.9%, P = .001). The polypharmacy prevalence was considerably higher in the elderly (from 23.5% to 44.1%), in adults with heart disease (from 40.6% to 61.7%), and in adults with diabetes (from 36.3% to 57.7%). Also, we observed a greater increase rate of polypharmacy in men (AAPC = 4.1%, P < .001), in the Mexican American (AAPC = 6.3%, P < .001), and in the non-Hispanic Black (AAPC = 4.4%, P < .001). CONCLUSIONS: From 1999-2000 to 2017-2018, the prevalence of polypharmacy is continually increasing in U.S. adults. The polypharmacy was especially higher in the older, in patients with heart disease, or diabetes. The high prevalence urges the healthcare providers and health policymakers to manage polypharmacy among specific population groups.

Association of Metformin Use with Iron Deficiency Anemia in Urban Chinese Patients with Type 2 Diabetes.

BACKGROUND: Previous evidence yielded contradictory findings on the relationship between metformin and anemia. This study aims to assess whether metformin use is associated with iron-deficiency anemia (IDA) risk in patients with type 2 diabetes (T2D) in Beijing, China. METHODS: Overall, 60,327 newly diagnosed T2D patients were included based on a historical cohort study design. The information pertaining to these patients was gathered from the Beijing Medical Claim Data for Employees Database. These patients were then categorized into the metformin and non-metformin groups and matched on a 1:1 propensity score based on their initial antidiabetic prescription. The Cox proportional hazards models were utilized to calculate the incidences and the hazard ratios (HRs). RESULTS: The study enrolled 27,960 patients with type 2 diabetes, with 13,980 patients in each of the initial glucose-lowering prescription groups: metformin and non-metformin. During a median follow-up period of 4.84 years, 4832 patients developed IDA. The incidence of IDA was significantly lower in the metformin group (26.08/1000 person-years) than in the non-metformin group (43.20/1000 person-years). Among the three groups divided by the proportion of days covered by metformin, we found a negative correlation between the proportion of days covered by metformin and the risk of IDA. The risk of IDA in patients with a proportion of days covered by metformin of <20%, 20-79%, and ≥80% was 0.43 (0.38, 0.48), 0.37 (0.34, 0.42), and 0.91 (0.85, 0.98), respectively, compared to the non-metformin group. We also performed subgroup analyses and sensitivity analyses: the incidence of IDA in the metformin group was lower than that in the non-metformin group in all subgroups, and the protective effect was more significant in subgroups of patients aged ≥65, with Charlson comorbidity index (CCI) ≥2, and with gastric acid inhibitor use. CONCLUSIONS: In Chinese patients with T2DM, metformin treatment was associated with a decreased risk of IDA admission, and this risk responded positively to the proportion of days covered by metformin. These findings suggest that metformin may have a pleiotropic effect on IDA in patients with type 2 diabetes. Our study has important clinical implications for the management of patients with diabetes and other conditions that increase the risk of IDA.

Brachial-ankle pulse wave velocity is a stronger predictor than blood pressure for atherosclerotic cardiovascular diseases and all-cause mortality: a cohort study.

Whether brachial-ankle pulse wave velocity (baPWV) is a better predictive indicator than blood pressure (BP) for atherosclerotic cardiovascular diseases (ASCVD) events and all-cause mortality in the general population has not yet been established. The current study included 47,659 participants from the Kailuan cohort in China, who underwent the baPWV test and were free of ASCVD, atrial fibrillation, and cancer at baseline. The hazard ratios (HRs) of ASCVD and all-cause mortality were evaluated using the Cox proportional hazards model. The predictive ability of baPWV, systolic BP (SBP), and diastolic BP (DBP) for ASCVD and all-cause mortality was evaluated using the area under the curve (AUC) and concordance index (C-index). Within the median follow-up period of 3.27 and 3.32 person-years, 885 ASCVD events and 259 deaths occurred, respectively. The HRs of ASCVD and all-cause mortality increased with the increase of baPWV, SBP, and DBP. When baPWV, SBP, and DBP were analyzed as continuous variables, the adjusted HRs were 1.29 (95% CI, 1.22-1.37), 1.28 (95% CI, 1.20-1.37), and 1.26 (95% CI, 1.17-1.34) for each standard deviation increase, respectively. The AUC and C-index for baPWV in predicting ASCVD and all-cause mortality were 0.744 and 0.750, respectively, while those for SBP were 0.697 and 0.620, those for DBP were 0.666 and 0.585. The AUC and C-index of baPWV were higher than those of SBP and DBP (P < 0.001). Therefore, baPWV is an independent predictor of ASCVD and all-cause mortality in the general Chinese population, and its predictive ability is superior to that of BP. baPWV is a more ideal screening method for ASCVD in large-scale population.

Neiella litorisoli sp. nov., an alginate lyase: producing bacterium from South China Sea, and proposal of Echinimonadaceae fam. nov. in the order Alteromonadales.

A Gram-stain-negative, rod-shaped bacterium, designated HB171785T, was isolated from soil sample collected from Qishui Bay, Hainan, China. The strain grew optimally at pH 7-8, 37-40 °C and with NaCl 3-4%. The predominant isoprenoid quinone was found to be Q-8 and the major fatty acids were C16:0, C16:1 ω7c/C16:1 ω6c, C18:1 ω7c/C18:1 ω6c and C12:0 3OH. The polar lipids contained diphosphatidylglycerol, phosphatidylglycerol, and phosphatidylethanolamine. The size of the draft genome was 4.32 Mbp with G + C content 49.7%. Phylogenetic analysis of 16S rRNA gene sequence indicated that the closest phylogenetically related species were Neiella marina j221T, "Neiella holothuriorum" 126 and Echinimonas agarilytica KMM 6351T with the similarities of 98.2, 96.0 and 95.0%, respectively. The phylogenetic tree based on 16S rRNA gene and phylogenomic tree based on core genome showed that strain HB171785T clustered together with N. marina j221T, with the highest values of average nucleotide identity (82.9%) and digital DNA-DNA hybridization (25.4%). The combined phylogenetic relatedness, phenotypic and genotypic features supported the conclusion that strain HB171785T represents a novel species of the genus Neiella, for which the name Neiella litorisoli sp. nov. is proposed. The type strain is HB171785T (= MCCC 1K04625T = KCTC 82319T). In addition, Echinimonadaceae fam. nov. in the order Alteromonadales was proposed.

Polypharmacy, chronic kidney disease, and mortality among older adults: A prospective study of National Health and nutrition examination survey, 1999-2018.

Introduction: Polypharmacy might contribute to a range of adverse outcomes, which could get worse in the elderly with chronic kidney disease (CKD). Evidence on polypharmacy, CKD, and mortality is scarce. We aimed to investigate the prospective association between polypharmacy, CKD and all-cause and cause-specific mortality in adults aged ≥65 years. Methods: A total of 13,513 adults from the National Health and Nutrition Examination Surveys were included, following up from 1999 to 2018 until December 31, 2019. The simultaneous use of ≥5 medications by one individual was defined as polypharmacy. Survey-weighted Cox proportional hazard models were used to estimate the hazard ratio (HRs) for mortality from all-cause, cardiovascular diseases (CVD), and cancer after adjusting for potential confounding factors. Results: Among the elderly with CKD, we identified 3,825 total deaths (1,325 CVD and 714 cancer) during a median follow-up of 7.7 years. Participants with polypharmacy had a 27% (HR = 1.27 [1.15, 1.39]) and 39% (HR = 1.39 [1.19, 1.62]) higher risk of all-cause and CVD mortality, respectively, but not for cancer mortality. Compared with the elderly with no polypharmacy and no CKD, the corresponding HRs (95%CIs) for all-cause mortality were 1.04 (0.96, 1.14) for those with no polypharmacy but CKD, 1.24 (1.11, 1.39) for with polypharmacy but no CKD, and 1.34 (1.21, 1.49) for those with both polypharmacy and CKD. A similar pattern was detected for CVD mortality. Discussion: Polypharmacy was associated with elevated risks of all-cause and CVD mortality among the elderly CKD patients. More evidence-based approaches should be promoted for the appropriate deprescribing in the older adults with CKD.

Lifestyle, Genetic Susceptibility, and the Risk of Idiopathic Pulmonary Fibrosis: A Large Prospective Cohort Study.

BACKGROUND: Lifestyle is an important contributor of age-related chronic disease, but the association between lifestyle and the risk of idiopathic pulmonary fibrosis (IPF) remains unknown. The extent to which genetic susceptibility modifies the effects of lifestyle on IPF also remains unclear. RESEARCH QUESTION: Is there a joint effect or interaction of lifestyle and genetic susceptibility on the risk of developing IPF? STUDY DESIGN AND METHODS: This study included 407,615 participants from the UK Biobank study. A lifestyle score and a polygenic risk score were constructed separately for each participant. Participants were then classified into three lifestyle categories and three genetic risk categories based on the corresponding score. Cox models were fitted to assess the association of lifestyle and genetic risk with the risk of incident IPF. RESULTS: With favorable lifestyle as the reference group, intermediate lifestyle (hazard ratio, 1.384; 95% CI, 1.218-1.574) and unfavorable lifestyle (hazard ratio, 2.271; 95% CI, 1.852-2.785) were significantly associated with an increased risk of IPF. For the combined effect of lifestyle and polygenic risk score, participants with unfavorable lifestyle and high genetic risk had the highest risk of IPF (hazard ratio, 7.796; 95% CI, 5.482-11.086) compared with those with favorable lifestyle and low genetic risk. Moreover, approximately 32.7% (95% CI, 11.3-54.1) of IPF risk could be attributed to the interaction of an unfavorable lifestyle and high genetic risk. INTERPRETATION: Exposure to unfavorable lifestyle significantly increased the risk of IPF, particularly in those with high genetic risk.

A novel approach for quantitative determination of cellulose content in tobacco via 2D HSQC NMR spectroscopy.

Cellulose is an important component of tobacco (Nicotiana tabacum L.) cell walls, which can be precursors for many harmful compounds in smoke. Traditional cellulose content analysis methods involve sequential extraction and separation steps, which are time-consuming and environmentally unfriendly. In this study, a novel method was first introduced to analyze cellulose content in tobacco via two-dimensional heteronuclear single quantum coherence (2D HSQC) NMR spectroscopy. The method was based on derivatization approach to allow the dissolution of insoluble polysaccharide fractions of tobacco cell walls in DMSO­d6/pyridine-d5 (4:1 v/v) for NMR analysis. The NMR results suggested that besides the main NMR signals of cellulose, partial signals of hemicellulose including mannopyranose, arabinofuranose, and galactopyranose units could also be identified. In addition, the utilization of relaxation reagents has proved to be an effective way to improve the sensitivity of 2D NMR spectroscopy, which was beneficial for quantification of biological samples with limited quantities. To overcome the limitations of quantification using 2D NMR, the calibration curve of cellulose with 1,3,5-trimethoxybenzene as internal reference was constructed and thus the accurate measurement of cellulose in tobacco was achieved. Compared with the chemical method, the interesting method was simple, reliable, and environmentally friendly, which provided a new insight for quantitative determination and structure analysis of plant macromolecules in complex samples.

Metabacillus arenae sp. nov., isolated from seashore sand.

A Gram-stain-positive, non-motile, rod-shaped, facultatively anaerobic bacterium, designated as IB182487T, was isolated from a seashore sand sample collected from Zhaoshu Island, PR China. Strain IB182487T grew at pH 6.0-10.0 (optimum, pH 8.0), 4-45 °C (optimum, 25-30 °C) and with 0-17 % (w/v) NaCl (optimum, 2-10 %). Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain IB182487T belonged to the genus Metabacillus and was closely related to Metabacillus idriensis SMC 4352-2T, (96.6 %), Metabacillus indicus LMG 22858T (96.5 %), Metabacillus niabensis DSM 17723T (96.3 %) and Metabacillus halosaccharovorans DSM 25387T (96.1 %). Strain IB182487T had meso-diaminopimelic acid as the diagnostic diamino acid in the cell-wall peptidoglycan and contained menaquinone MK-7 as the predominant isoprenoid quinone. Its polar lipids consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, two unidentified phospholipids and three unidentified glycolipids. The major cellular fatty acids of strain IB182487T were iso-C15 : 0 and anteiso-C15 : 0. The whole genome average nucleotide identity and digital DNA-DNA hybridization analysis between the isolate and its closely related type strains demonstrated that the strain significantly differed from other Metabacillus species. The genomic DNA G+C content of strain IB182487T was 37.4 mol%. On the basis of phenotypic and chemotaxonomic properties, phylogenetic relatedness as well as genomic characteristics, strain IB182487T represents a novel species of the genus Metabacillus, for which the name Metabacillus arenae sp. nov. is proposed. The type strain of M. arenae is IB182487T (=MCCC 1K04629T=JCM 34523T).

Genetic susceptibility and lifestyle modify the association of long-term air pollution exposure on major depressive disorder: a prospective study in UK Biobank.

BACKGROUND: Evidence linking air pollution to major depressive disorder (MDD) remains sparse and results are heterogeneous. In addition, the evidence about the interaction and joint associations of genetic risk and lifestyle with air pollution on incident MDD risk remains unclear. We aimed to examine the association of various air pollutants with the risk of incident MDD and assessed whether genetic susceptibility and lifestyle influence the associations. METHODS: This population-based prospective cohort study analyzed data collected between March 2006 and October 2010 from 354,897 participants aged 37 to 73 years from the UK Biobank. Annual average concentrations of PM2.5, PM10, NO2, and NOx were estimated using a Land Use Regression model. A lifestyle score was determined based on a combination of smoking, alcohol drinking, physical activity, television viewing time, sleep duration, and diet. A polygenic risk score (PRS) was defined using 17 MDD-associated genetic loci. RESULTS: During a median follow-up of 9.7 years (3,427,084 person-years), 14,710 incident MDD events were ascertained. PM2.5 (HR: 1.16, 95% CI: 1.07-1.26; per 5 µg/m3) and NOx (HR: 1.02, 95% CI: 1.01-1.05; per 20 µg/m3) were associated with increased risk of MDD. There was a significant interaction between the genetic susceptibility and air pollution for MDD (P-interaction < 0.05). Compared with participants with low genetic risk and low air pollution, those with high genetic risk and high PM2.5 exposure had the highest risk of incident MDD (PM2.5: HR: 1.34, 95% CI: 1.23-1.46). We also observed an interaction between PM2.5 exposure and unhealthy lifestyle (P-interaction < 0.05). Participants with the least healthy lifestyle and high air pollution exposures had the highest MDD risk when compared to those with the most healthy lifestyle and low air pollution (PM2.5: HR: 2.22, 95% CI: 1.92-2.58; PM10: HR: 2.09, 95% CI: 1.78-2.45; NO2: HR: 2.11, 95% CI: 1.82-2.46; NOx: HR: 2.28, 95% CI: 1.97-2.64). CONCLUSIONS: Long-term exposure to air pollution is associated with MDD risk. Identifying individuals with high genetic risk and developing healthy lifestyle for reducing the harm of air pollution to public mental health.

Long-term Exposure to Ambient Air Pollutants and Increased Risk of Pneumonia in the UK Biobank.

BACKGROUND: Short-term exposure to air pollution has been linked to pneumonia risk. However, evidence on the long-term effects of air pollution on pneumonia morbidity is scarce and inconsistent. We investigated the associations of long-term air pollutant exposure with pneumonia and explored the potential interactions with smoking. RESEARCH QUESTION: Is long-term exposure to ambient air pollution associated with the risk of pneumonia, and does smoking modify the associations? STUDY DESIGN AND METHODS: We analyzed data in 445,473 participants without pneumonia within 1 year before baseline from the UK Biobank. Annual average concentrations of particulate matter (particulate matter with a diameter < 2.5 µm [PM2.5] and particulate matter with a diameter < 10 µm [PM10]), nitrogen dioxide (NO2), and nitrogen oxides (NOx) were estimated using land-use regression models. Cox proportional hazards models were used to assess the associations between air pollutants and pneumonia incidence. Potential interactions between air pollution and smoking were examined on both additive and multiplicative scales. RESULTS: The hazard ratios of pneumonia for each interquartile range increase in PM2.5, PM10, NO2, and NOx concentrations were 1.06 (95% CI, 1.04-1.08), 1.10 (95% CI, 1.08-1.12), 1.12 (95% CI, 1.10-1.15), and 1.06 (95% CI, 1.04-1.07), respectively. There were significant additive and multiplicative interactions between air pollution and smoking. Compared with individuals who had never smoked with low air pollution exposure, individuals who had ever smoked with high air pollution exposure had the highest pneumonia risk (PM2.5: hazard ratio [HR], 1.78; 95% CI, 1.67-1.90; PM10: HR, 1.94; 95% CI, 1.82-2.06; NO2: HR, 2.06; 95% CI, 1.93-2.21; NOx: HR, 1.88; 95% CI, 1.76-2.00). The associations between air pollutants and pneumonia risk persisted in participants exposed to air pollutants concentrations meeting the European Union limits. INTERPRETATION: Long-term exposure to air pollutants was associated with an increased risk of pneumonia, especially in individuals who smoke.

Associations between multimorbidity and frailty transitions among older Americans.

BACKGROUND: The associations of multimorbidity patterns with transitions between frailty states remain unclear in older individuals. METHODS: We used data from the National Health and Aging Trends Study 2011-2019. Frailty was measured annually using the Fried frailty phenotype. Multimorbidity patterns at baseline were identified using latent class analysis based on 14 chronic conditions. We used the semi-Markov multi-state model to investigate the influences of multimorbidity characterized by condition counts and patterns on subsequent frailty transitions over follow-ups. RESULTS: Among 9450 participants aged ≥65 years at baseline, 34.8% were non-frail, 48.1% were pre-frail and 17.0% were frail. Over a median follow-up of 4.0 years, 16 880 frailty transitions were observed, with 10 527 worsening and 6353 improving. For 7675 participants with multimorbidity, four multimorbidity patterns were identified: osteoarticular pattern (62.4%), neuropsychiatric-sensory pattern (17.2%), cardiometabolic pattern (10.3%) and complex multimorbidity pattern (10.1%). Compared with no disease, multimorbidity was significantly associated with an increased risk of worsening transitions, including from non-frail to pre-frail (hazard ratio [HR] = 1.35; 95% confidence interval [CI] = 1.21-1.52), from non-frail to frail (HR = 1.68; 95% CI = 1.04-2.73), from pre-frail to frail (HR = 2.19; 95% CI = 1.66-2.90) and from pre-frail to death (HR = 1.64; 95% CI = 1.11-2.41). Compared with the osteoarticular pattern, neuropsychiatric-sensory, cardiometabolic and complex multimorbidity patterns had a significantly higher risk of worsening frailty (all P < 0.05). CONCLUSIONS: Multimorbidity was associated with dynamic transitions between frailty states and death among older American adults, and the associations varied across multimorbidity patterns. The findings could offer significant implications for public health policymakers in planning interventions and healthcare resources. They also might inform clinicians regarding providing targeted clinical treatment and health management based on multimorbidity patterns of older people.

A comprehensive single cell data analysis of lymphoblastoid cells reveals the role of super-enhancers in maintaining EBV latency.

We probed the lifecycle of Epstein-Barr virus (EBV) on a cell-by-cell basis using single cell RNA sequencing (scRNA-seq) data from nine publicly available lymphoblastoid cell lines (LCLs). While the majority of LCLs comprised cells containing EBV in the latent phase, two other clusters of cells were clearly evident and were distinguished by distinct expression of host and viral genes. Notably, both were high expressors of EBV LMP1/BNLF2 and BZLF1 compared to another cluster that expressed neither gene. The two novel clusters differed from each other in their expression of EBV lytic genes, including glycoprotein gene GP350. The first cluster, comprising GP350- LMP1hi cells, expressed high levels of HIF1A and was transcriptionally regulated by HIF1-α. Treatment of LCLs with Pevonedistat, a drug that enhances HIF1-α signaling, markedly induced this cluster. The second cluster, containing GP350+ LMP1hi cells, expressed EBV lytic genes. Host genes that are controlled by super-enhancers (SEs), such as transcription factors MYC and IRF4, had the lowest expression in this cluster. Functionally, the expression of genes regulated by MYC and IRF4 in GP350+ LMP1hi cells were lower compared to other cells. Indeed, induction of EBV lytic reactivation in EBV+ AKATA reduced the expression of these SE-regulated genes. Furthermore, CRISPR-mediated perturbation of the MYC or IRF4 SEs in LCLs induced the lytic EBV gene expression, suggesting that host SEs and/or SE target genes are required for maintenance of EBV latency. Collectively, our study revealed EBV-associated heterogeneity among LCLs that may have functional consequence on host and viral biology.

The association between vision impairment and cognitive outcomes in older adults: a systematic review and meta-analysis.

OBJECTIVES: To provide a quantitative synthesis of studies on the relationship between vision impairment (VI) and cognitive outcomes in older adults. METHOD: A systematic search was undertaken of relevant databases for original articles published before April 2020. Random effect models were used to obtain pooled estimates of the associations between VI and cognitive outcomes (cognitive impairment and dementia) with subgroup analyses of VI measures, cross-sectional associations of VI with cognitive impairment, and longitudinal associations of baseline VI with incident cognitive impairment and dementia. Potential sources of heterogeneity were explored by meta-regression. Publication bias was evaluated with Egger's test. RESULTS: Sixteen studies including 76,373 participants were included in this meta-analysis, with five cross-sectional studies and eleven longitudinal studies. There was a significantly increased risk of cognitive outcomes with VI identified by subjective measures (odds ratio (OR)=1.63; 95% confidence interval (CI): 1.26-1.99) and objective measures (OR = 1.59; 95% CI: 1.40-1.78). The odds of baseline cognitive impairment were 137% higher in older adults with VI compared with those without VI (OR = 2.37, 95% CI: 1.84-3.03) at baseline. Compared with older adults without VI at baseline, those with baseline VI had a higher relative risk (RR) of incident cognitive impairment (RR = 1.41; 95% CI: 1.31-1.51) and dementia (RR = 1.44, 95% CI: 1.19-1.75). CONCLUSIONS: VI was associated with increased risks of cognitive impairment and dementia across cross-sectional and longitudinal studies. Additional research and randomized clinical trials are warranted to examine the implications of treatment for VI, such as wearing glasses and cataract surgery, to avoid cognitive impairment and dementia.

Air pollutants, genetic susceptibility and risk of incident idiopathic pulmonary fibrosis.

BACKGROUND: Air pollutants are considered as non-negligible risk factors of idiopathic pulmonary fibrosis (IPF). However, the relationship between long-term air pollution and the incidence of IPF is unknown. Our objective was to explore the associations of air pollutants with IPF risk and further assess the modification effect of genetic susceptibility. METHODS: We used land-use regression model estimated concentrations of nitrogen dioxide (NO2), nitrogen oxides (NO x ) and particulate matter (fine particulate matter with diameter <2.5 µm (PM2.5) and particulate matter with diameter <10 µm (PM10)). The polygenic risk score (PRS) was constructed using 13 independent single nucleotide polymorphisms. Cox proportional hazard models were used to evaluate the associations of air pollutants with IPF risk and further investigate the modification effect of genetic susceptibility. Additionally, absolute risk was calculated. RESULTS: Among 433 738 participants from the UK Biobank, the incidence of IPF was 27.45 per 100 000 person-years during a median follow-up of 11.78 years. The adjusted hazard ratios of IPF for each interquartile range increase in NO2, NO x and PM2.5 were 1.11 (95% CI 1.03-1.19), 1.07 (95% CI 1.01-1.13) and 1.09 (95% CI 1.02-1.17), respectively. PM2.5 had the highest population attribution risk, followed by NO x and NO2. There were additive interactions between NO2, NO x and PM2.5 and genetic susceptibility. Participants with a high PRS and high air pollution had the highest risk of incident IPF compared with those with a low PRS and low air pollution (adjusted hazard ratio: NO2 3.94 (95% CI 2.77-5.60), NO x 3.08 (95% CI 2.21-4.27), PM2.5 3.65 (95% CI 2.60-5.13) and PM10 3.23 (95% CI 2.32-4.50)). CONCLUSION: Long-term exposures to air pollutants may elevate the risk of incident IPF. There are additive effects of air pollutants and genetic susceptibility on IPF risk.

Overexpression of MiR-633 Suppresses the Tumorigenicity of Gastric Cancer Cells and Induces Apoptosis by Targeting MAPK1.

OBJECTIVE: MicroRNA (miRNA/miR)-633 is dysregulated in several types of cancers and is involved in tumorigenesis. However, the function and role of this miRNA in gastric cancer (GC) are not fully understood. The aim of the present study was to evaluate miR-633 expression in GC cell lines and in GC tissue vs. adjacent normal tissue, and to determine its association with clinicopathological data. This work was extended to investigate the effects of miR-633 overexpression on tumor cells in vitro. METHODS: Reverse transcription-quantitative PCR (RT-qPCR) was used to detect and compare the expression level of miR-633 in GC cells, as well as in GC and normal adjacent tissue samples. The clinical significance of miR-633 was also analyzed. MiR-633 lentivirus (LV-miR-633) and negative control lentivirus (LV-NC) were generated and used to transduce SGC-7901 and HGC-27 GC cells in order to analyze the effect of miR-633 on their phenotype. The effects of miR-633 overexpression on GC cell proliferation, apoptosis, migration and invasion were investigated. The target gene of miR-633 was predicted, then confirmed using a dual luciferase reporter gene assay, RT-qPCR and Western blotting. RESULTS: MiR-633 was significantly downregulated in GC cell lines, as well as in GC tissue compared with adjacent normal tissue. Moreover, miR-633 expression was associated with the tumor/node/metastasis (TNM) stage, invasion depth, Borrmann classification and lymph node metastasis (P<0.05). Compared with the LV-NC group, transduction with LV-miR-633 reduced the proliferation, the number of clones, the wound healing rate, the number of invading cells and the number of cells in the G1 phase of the cell cycle (P<0.01). LV-miR-633 also increased the apoptosis rate (P<0.01). The expression level of mitogen-activated protein kinase (MAPK) 1, high-mobility group box 3 (HMGB3), claudin 1 (CLDN1) and MAPK13 were downregulated in LV-miR-633-transduced cells (P<0.01). The dual luciferase reporter assay confirmed that the 3'-untranslated region of MAPK1 was the target site of miR-633 (P<0.01). CONCLUSION: MiR-633 acts as a tumor suppressor in GC, and its expression level is associated with TNM stage, invasion depth, Borrmann type and lymph node metastasis. Overexpression of miR-633 inhibits the proliferation and migration of GC cells and induces apoptosis and cell cycle arrest at the in G1 phase. In addition, miR-633 negatively regulates the expression of MAPK1, HMGB3, CLDN1 and MAPK13 and directly targets MAPK1.