Association between genetically proxied PCSK9 inhibition and systemic lupus erythematosus risk: A mendelian randomization study.

BACKGROUND: Preclinical and epidemiological studies suggest that proprotein convertase subtilisin/kexin type 9 (PCSK9) had a potential effect on the development of SLE, but it was unclear whether a causal relationship exists. We aimed to investigate the association between genetically proxied inhibition of PCSK9 and the risk of SLE using a two-sample Mendelian randomization (MR) approach. METHODS: Single nucleotide polymorphisms (SNPs) associated with PCSK9 were extracted from pooled data obtained from the Global Lipid Genetics Consortium (GLGC) Genome-wide Association Study (GWAS) related to LDL-c levels, which was used as a proxy for PCSK9 inhibition. Pooled statistics for SLE were obtained from an independent GWAS dataset including 5201 SLE patients and 9066 controls. Inverse variance-weighted random-effects models were used to examine the association between genetically proxied inhibition of PCSK9 and the risk of SLE. MR-Egger, weighted median, weighted mode, Simple mode, and co-location analyses were used as sensitivity analyses to test the robustness of the analyses. RESULTS: Genetically proxied inhibition of PCSK9 was associated with a reduced risk of SLE (OR = 0.51, 95% CI = 0.34 to 0.77, p = .001). This finding was replicated in an earlier GLGC GWAS analysis (OR = 0.59, 95% CI = 0.40 to 0.87, p = .007). Sensitivity analysis ensured that the results were robust. Co-localization analysis did not find evidence of shared causal variation between PCSK9 and SLE. CONCLUSIONS: This Mendelian randomization study showed that PCSK9 was associated with SLE pathogenesis, and its inhibition was associated with a reduced risk of SLE. This study has offered a prospective therapeutic avenue for intervening in the progression of SLE by inhibiting PCSK9 levels.

Long-term trends in Alzheimer's disease and other dementias deaths with high body mass index in China from 1990 to 2019, and projections up to 2042.

BACKGROUND: In China, the rising prevalence of high Body Mass Index (BMI) is linked to increasing health issues, including Alzheimer's disease (AD). This study analyzes mortality trends related to AD and other dementias associated with high BMI from 1990 to 2019, considering age, period, and birth cohort effects, and forecasts future trends. METHODS: We analyzed mortality data for AD and other dementias linked to high BMI in Chinese residents from the Global Burden of Disease 2019 database. Using Joinpoint regression, we examined age-standardized mortality rate (ASMR) trends and calculated annual and average annual percentage changes (APC and AAPC). Age-period-cohort models provided deeper insights, with Bayesian models used to project future ASMR trends to 2042. RESULTS: From 1990 to 2019, the ASMR for AD and other dementias associated with high BMI in China showed an overall increasing trend. Females had a lower increase rate than males, yet their overall levels remained higher. Specifically, the ASMR for males increased by an average of 2.70% per year, peaking between 2006 and 2010, while for females, it increased by an average of 2.29% per year, also peaking in the same period. Age-period-cohort analysis revealed increasing mortality relative risk with age and period, but a decrease with birth cohort. Projections suggest a continued rise in ASMR by 2042, with rates for males and females expected to be 2.48/100,000 and 2.94/100,000, respectively. CONCLUSION: The increasing mortality trend from AD and other dementias associated with high BMI highlights the urgent need for policy interventions focused on overweight prevention, particularly vital for addressing the health challenges in China's aging population.

Architecture and potential roles of a delta-class glutathione S-transferase in protecting honey bee from agrochemicals.

The European honey bee, Apis mellifera, serves as the principle managed pollinator species globally. In recent decades, honey bee populations have been facing serious health threats from combined biotic and abiotic stressors, including diseases, limited nutrition, and agrochemical exposure. Understanding the molecular mechanisms underlying xenobiotic adaptation of A. mellifera is critical, considering its extensive exposure to phytochemicals and agrochemicals present in the environment. In this study, we conducted a comprehensive structural and functional characterization of AmGSTD1, a delta class glutathione S-transferase (GST), to unravel its roles in agrochemical detoxification and antioxidative stress responses. We determined the 3-dimensional (3D) structure of a honey bee GST using protein crystallography for the first time, providing new insights into its molecular structure. Our investigations revealed that AmGSTD1 metabolizes model substrates, including 1-chloro-2,4-dinitrobenzene (CDNB), p-nitrophenyl acetate (PNA), phenylethyl isothiocyanate (PEITC), propyl isothiocyanate (PITC), and the oxidation byproduct 4-hydroxynonenal (HNE). Moreover, we discovered that AmGSTD1 exhibits binding affinity with the fluorophore 8-Anilinonaphthalene-1-sulfonic acid (ANS), which can be inhibited with various herbicides, fungicides, insecticides, and their metabolites. These findings highlight the potential contribution of AmGSTD1 in safeguarding honey bee health against various agrochemicals, while also mitigating oxidative stress resulting from exposure to these substances.

Distribution characteristics of circulating B cell subpopulations in patients with chronic kidney disease.

This study compared the levels of circulating B cell subpopulations in patients with different stages of chronic kidney disease (CKD), investigated the effects of haemodialysis (HD) on the B cell-related immune spectrum in patients with end-stage renal disease, and evaluated the link between renal function and immune homeostasis. Overall, 197 patients with CKD (158 non-dialysis patients with CKD stages I-V and 39 end-stage patients undergoing maintenance HD) and 77 healthy controls were included. Compared to healthy controls, patients with CKD stages I-II showed no significant differences except for the proportion of transitional B cells; patients with CKD stage V showed a significant decrease in the proportions of transitional B cells and CD5+ B cells and a significant increase in double-negative (DN) B cells. Compared with early-stage patients with CKD, the absolute count of various B cell subpopulations in advanced-stage patients with CKD showed a significant decrease. The distribution of circulating B cell subpopulations in patients with CKD was significantly altered and was associated with CKD progression. Furthermore, the proportion of DN B cells and CD5+ B cells was inconsistent pre- and post-HD. This in-depth study of the immune status of patients with CKD may have important clinical value.

Development and validation of a web-based predictive model for preoperative diagnosis of localized colorectal cancer and colorectal adenoma.

Background: Localized colorectal cancer (LCC) has obscure clinical signs, which are difficult to distinguish from colorectal adenoma (CA). This study aimed to develop and validate a web-based predictive model for preoperative diagnosis of LCC and CA. Methods: We conducted a retrospective study that included data from 500 patients with LCC and 980 patients with CA who were admitted to Dongyang People's Hospital between November 2012 and June 2022. Patients were randomly divided into the training (n=1036) and validation (n=444) cohorts. Univariate logistic regression, least absolute shrinkage and selection operator regression, and multivariate logistic regression were used to select the variables for predictive models. The area under the curve (AUC), calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) were used to evaluate the performance of the model. Results: The web-based predictive model was developed, including nine independent risk factors: age, sex, drinking history, white blood cell count, lymphocyte count, red blood cell distribution width, albumin, carcinoembryonic antigen, and fecal occult blood test. The AUC of the prediction model in the training and validation cohorts was 0.910 (0.892-0.929) and 0.894 (0.862-0.925), respectively. The calibration curve showed good consistency between the outcome predicted by the model and the actual diagnosis. DCA and CIC showed that the predictive model had a good clinical application value. Conclusion: This study first developed a web-based preoperative prediction model, which can discriminate LCC from CA and can be used to quantitatively assess the risks and benefits in clinical practice.

Asymmetric C3-Allylation of Pyridines.

Asymmetric intermolecular C-H functionalization of pyridines at C3 is unprecedented. Herein, we report the first examples of such transformations: specifically, C3-allylation of pyridines via tandem borane and iridium catalysis. First, borane-catalyzed pyridine hydroboration generates nucleophilic dihydropyridines; then, the dihydropyridine undergoes enantioselective iridium-catalyzed allylation; and finally, oxidative aromatization with air as the oxidant gives the C3-allylated pyridine. This protocol provides direct access to C3-allylated pyridines with excellent enantioselectivity (up to >99% ee) and is suitable for late-stage functionalization of pyridine-containing drugs.

GBNF-VAE: A Pathological Voice Enhancement Model Based on Gold Section for Bottleneck Feature With Variational Autoencoder.

OBJECTIVE: Speech enhancement has become a promising technique to accommodate demands of the improvement in quality of a degraded speech signal. The main works now focus on separating normal speech from noise, but have neglected the low quality of impaired speech influenced by anomalous glottis flow. In order to effectively enhance the pathological speech, it is essential to design a separation mechanism for extracting high-dimensional timbre features and speech features separately to suppress low-dimensional noises. METHODS: In this paper, we propose an enhancement model GBNF-VAE to extract timbre efficiently by reducing anomalous airflow noise interference, and by combining the semantic features with timbre features to synthesize the enhanced speech. In particular, the bottleneck feature can characterize the timbre by the controlled number of nodes through the Golden Section method, which effectively improves computational efficiency. In addition, variational autoencoder is adopted to extract semantic features which are combined with the previous timbre features to synthesize the enhanced speech. RESULTS: Finally, spectrum observation, objective indicators and subjective evaluation all show the outstanding performance of GBNF-VAE in pathological speech quality enhancement.

Investigation on sleep-related cognition of Chinese health care workers during the first wave of COVID-19 pandemic.

Background: The COVID pandemic has brought tremendous negative effects on the mental health of health care workers, such as anxiety, depression, and sleep disorders. We conducted this study to evaluate the sleep-related cognition of Chinese health care workers (HCWs) during the first wave of COVID-19 pandemic and analyze its association with sleep quality, so as to provide scientific reference for improving sleep of HCWs. Patients and methods: A total of 404 HCWs from Yijishan Hospital of Wuhu City, China were enrolled in the study, selected by randomized cluster sampling in May 2020. We made a questionnaire to collect the general demographic information of the participants. The Pittsburgh Sleep Quality Index (PSQI) and a brief version of Dysfunctional Beliefs and Attitudes about Sleep Scale (DBAS-16) were used to measure sleep quality and sleep-related cognition, respectively. Results: The results showed that 312 HCWs (77.2%) had false beliefs and attitudes about sleep, while only 92 HCWs (22.8%) had correct beliefs about sleep. In addition, we found that those HCWs who were older, married, with a bachelor's degree or higher, nurses, more daily working hours (> 8 h) and monthly night shifts (≥ 5 times), had higher DBAS-16 scores (all p < 0.05). However, we did not find significant differences between men and women in DBAS-16 scores. According to the definition of PSQI, a total of 1/4 of the HCWs are poor sleepers and their DBAS-16 score was higher than good sleepers (t = 7.622, p < 0.001). In the end, we confirmed a positive correlation between sleep cognition and sleep quality (r = 0.392, p < 0.01). Conclusion: Our study revealed false beliefs and attitudes about sleep were prevalent among HCWs during the first wave of COVID-19 pandemic, and these false beliefs about sleep were closely correlated to sleep quality. We recommend fighting against these false beliefs about sleep.

Redox Modulatory Cu(II)-Baicalein Microflowers Prepared in One Step Effectively Promote Therapeutic Angiogenesis in Diabetic Mice.

Reactive oxygen species (ROS) have been implicated in multiple cellular processes, and an imbalance in redox homeostasis gives rise to diseases, therefore, reestablishing redox homeostasis is a way to cure. Here, copper-based metal-organic networks (Cu-MON) are generated by one-step reaction using anti-inflammatory and antioxidant baicalein as organic ligand and pro-angiogenic copper as metal ions. Phosphate buffered saline is required for triggering Cu-MON formation, and baicalein regulates the morphology and particle size of Cu-MON. Cu-MON are composed of Cu-baicalein complexes (82.08 wt%) and Cu3 (PO4 )2 ·3H2 O (17.92 wt%), thus exhibit a variable catalase-like activity against different H2 O2 levels due to the reversible change between Cu2+ /Cu1+ /Cu0 species. Intramuscular injection of Cu-MON significantly increases blood flow of ischemic limb in diabetic mice, enhances the relative activities of redox-related enzymes in ischemic muscle, thus effectively ameliorating the oxidative damage. Taken together, through moderate and dynamic "precise homeostasis regulation of cells," Cu-MON can be an efficient therapeutic strategy for peripheral arterial disease with diabetic complications.

Bidirectional two-sample Mendelian randomization study of causality between rheumatoid arthritis and myocardial infarction.

Background: Epidemiological evidence suggests an association between rheumatoid arthritis (RA) and myocardial infarction (MI). However, causality remains uncertain. Therefore, this study aimed to explore the causal association between RA and MI. Methods: Using publicly available genome-wide association study summary datasets, bidirectional two-sample Mendelian randomization (TSMR) was performed using inverse-variance weighted (IVW), weighted median, MR-Egger regression, simple mode, and weighted mode methods. Results: The MR results for the causal effect of RA on MI (IVW, odds ratio [OR] = 1.041, 95% confidence interval [CI]: 1.007-1.076, P = 0.017; weighted median, OR = 1.027, 95% CI: 1.006-1.049, P = 0.012) supported a causal association between genetic susceptibility to RA and an increased risk of MI. MR results for the causal effect of MI on RA (IVW, OR = 1.012, 95% CI: 0.807-1.268, P = 0.921; weighted median, OR = 1.069, 95% CI: 0.855-1.338, P = 0.556) indicated that there was no causal association between genetic susceptibility to MI and an increased risk of RA. Conclusion: Bidirectional TSMR analysis supports a causal association between genetic susceptibility to RA and an increased risk of MI but does not support a causal association between genetic susceptibility to MI and an increased risk of RA.

Association of early severe thrombocytopenia and platelet course with in-hospital mortality in critically ill children.

This study aimed to assess the association of early severe thrombocytopenia and platelet course with in-hospital mortality in critically ill children. Data of critically ill children in this study were obtained from the Pediatric Intensive Care Database. Patients with and without severe thrombocytopenia were adjusted for covariates using propensity score matching (PSM) to ensure the robustness of the results. Univariate and multivariate logistic regression analyses were performed on the original and PSM cohorts, respectively. Results are presented as odds ratios (ORs) with 95% confidence intervals (95% CI). In studies of the platelet course, logistic regression analysis was used to assess the effect of different degrees of recovery on in-hospital mortality in critically ill children with early severe thrombocytopenia. The study included 4,848 critically ill children, of whom 450 with early severe thrombocytopenia were matched to 450 without early severe thrombocytopenia. Univariate and multivariate logistic regression results showed that early severe thrombocytopenia was an independent risk factor for in-hospital mortality in critically ill children in both the original and PSM groups. In addition, the study results of platelet course showed that the recovery of platelet count to ≥150 × 109/L in the short term was a protective factor for the prognosis of patients (OR, 0.301; 95% CI, 0.139-0.648, P = 0.002). Our study revealed that early severe thrombocytopenia is an independent risk factor for in-hospital mortality in critically ill children. In addition, in-hospital mortality was significantly reduced in children with early severe thrombocytopenia, whose platelet count returned to normal levels in the short term.

Red blood cell biomimetic nanoparticle with anti-inflammatory, anti-oxidative and hypolipidemia effect ameliorated atherosclerosis therapy.

A main pathogenic factor of atherosclerosis is the local oxidative stress microenvironment. Probucol (PU) has anti-inflammatory, antioxidative and hypolipidemic effects, showing great potential to treat atherosclerosis. However, its low bioavailability limits its development. Herein, PU was encapsulated to form RP-PU with star-shaped polymers and red blood cell membranes. Star-shaped polymers show lower solution viscosity, a smaller hydrodynamic radius and a higher drug loading content than linear polymers. RP-PU had a good sustained-release effect and excellent biocompatibility. RP-PU can be efficiently internalized by cells to improve biodistribution. ApoE-/- mice were treated with RP-PU, and the contents of lipids and related metabolic enzymes were effectively reduced. The collagen fibers in the aortic root sections were reduced by RP-PU compared with control and PU. Moreover, RP-PU inhibited foam cell formation, decreased ICAM-1 and MCP-1 expression and delayed lesion formation. Consequently, RP-PU biomimetic nanoparticles can be developed as an anti-atherosclerotic nanotherapeutic.

Association between lactate/albumin ratio and all-cause mortality in patients with acute respiratory failure: A retrospective analysis.

Previous studies have shown that lactate/albumin ratio (LAR) can be used as a prognostic biomarker to independently predict the mortality of sepsis and severe heart failure. However, the role of LAR as an independent prognostic factor in all-cause mortality in patients with acute respiratory failure (ARF) remains to be clarified. Therefore, we retrospectively analyzed 2170 patients with ARF in Medical Information Mart for Intensive Care Database III from 2001 to 2012. By drawing the receiver operating characteristic curve, LAR shows a better predictive value in predicting the 30-day mortality of ARF patients (AUC: 0.646), which is higher than that of albumin (AUC: 0.631) or lactate (AUC: 0.616) alone, and even higher than SOFA score(AUC: 0.642). COX regression analysis and Kaplan-Meier curve objectively and intuitively show that high LAR is a risk factor for patients with ARF, which is positively correlated with all-cause mortality. As an easy-to-obtain and objective biomarker, LAR deserves further verification by multi-center prospective studies.