Associations between type 2 diabetes mellitus and chronic liver diseases: evidence from a Mendelian randomization study in Europeans and East Asians.

Objective: Multiple observational studies have demonstrated an association between type 2 diabetes mellitus (T2DM) and chronic liver diseases (CLDs). However, the causality of T2DM on CLDs remained unknown in various ethnic groups. Methods: We obtained instrumental variables for T2DM and conducted a two-sample mendelian randomization (MR) study to examine the causal effect on nonalcoholic fatty liver disease (NAFLD), hepatocellular carcinoma (HCC), viral hepatitis, hepatitis B virus (HBV) infection, and hepatitis C virus (HCV) infection risk in Europeans and East Asians. The primary analysis utilized the inverse variance weighting (IVW) technique to evaluate the causal relationship between T2DM and CLDs. In addition, we conducted a series of rigorous analyses to bolster the reliability of our MR results. Results: In Europeans, we found that genetic liability to T2DM has been linked with increased risk of NAFLD (IVW : OR =1.3654, 95% confidence interval [CI], 1.2250-1.5219, p=1.85e-8), viral hepatitis (IVW : OR =1.1173, 95%CI, 1.0271-1.2154, p=0.0098), and a suggestive positive association between T2DM and HCC (IVW : OR=1.2671, 95%CI, 1.0471-1.5333, p=0.0150), HBV (IVW : OR=1.1908, 95% CI, 1.0368-1.3677, p=0.0134). No causal association between T2DM and HCV was discovered. Among East Asians, however, there was a significant inverse association between T2DM and the proxies of NAFLD (ALT: IVW OR=0.9752, 95%CI 0.9597-0.9909, p=0.0021; AST: IVW OR=0.9673, 95%CI, 0.9528-0.9821, p=1.67e-5), and HCV (IVW: OR=0.9289, 95%CI, 0.8852-0.9747, p=0.0027). Notably, no causal association was found between T2DM and HCC, viral hepatitis, or HBV. Conclusion: Our MR analysis revealed varying causal associations between T2DM and CLDs in East Asians and Europeans. Further research is required to investigate the potential mechanisms in various ethnic groups, which could yield new insights into early screening and prevention strategies for CLDs in T2DM patients.

Prevalence and clinical implications of polypharmacy and potentially inappropriate medication in elderly patients with heart failure: results of six months' follow-up.

OBJECTIVES: To investigate the prevalence of polypharmacy and potentially inappropriate medication (PIM) in elderly patients with heart failure (HF) and their impact on readmission and mortality. METHODS: We conducted a study of 274 participants aged 60 years or older with HF. The prevalence of polypharmacy (defined as the use of five or more medications) was calculated, and the 2019 American Geriatrics Society Beers criteria were applied to access PIMs. Medications and PIMs were characterized at admission and discharge, and changes in prescriptions during hospitalization were compared. The impact of polypharmacy and PIM on readmission and mortality were investigated. RESULTS: The median age of this study population was 68 years old. The median number of prescribed drugs was 7 at admission and 10 at discharge. At discharge, 99.27% of all patients were taking five or more drugs. The incidence of composite endpoint and cardiovascular readmission increased with the number of polypharmacy within 6 months. The use of guideline-directed medical therapy reduced the incidence of composite endpoint events and cardiovascular readmission, while the use of non-cardiovascular medications increased the composite endpoint events. The frequency of PIMs was 93.79% at discharge. The incidence of composite endpoint events increased with the number of PIMs. "PIMs in older adults with caution" increased cardiovascular readmission and "PIMs based on kidney function" increased cardiovascular mortality. Several comorbidities were associated with cardiovascular mortality or non-cardiovascular readmission. CONCLUSIONS: Polypharmacy and PIM were highly prevalent in elderly patients with HF, and their use was associated with an increased risk of composite endpoint events, readmission and mortality. Non-cardiovascular medications, "PIMs in older adults with caution", "PIMs based on kidney function" and several comorbidities were important factors associated with hospital readmission and mortality. Our findings highlight the importance of medication optimization in the management of HF in elderly patients.

Comprehensive analysis of the basement membrane in lung adenocarcinoma by bulk and single-cell sequencing analysis.

Background: The basement membrane (BM), as a critical component of the extracellular matrix, plays a role in cancer progression. However, the role of the BM in lung adenocarcinoma (LUAD) remains unclear. Methods: A total of 1383 patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) cohorts were enrolled in the study, and BM-related differentially expressed genes (BM-DEGs) were screened using weighted gene coexpression network analysis (WGCNA) and differential expression analysis. We next built a prognostic model using Cox regression analysis and separated patients into two groups based on the median risk score. This signature was validated with in vitro experiments, and its mechanism was investigated by enrichment and tumour microenvironment analyses. We also evaluated whether this signature could predict sensitivity to chemotherapy and immunotherapy. Finally, single-cell RNA sequencing analysis was utilized to analyse the expression of signature genes in different cells. Results: Thirsty-seven BM-DEGs were discovered, and a prognostic signature based on 4 BM-DEGs (HMCN2, FBLN5, ADAMTS15 and LAD1) was obtained in the TCGA cohort and validated in GEO cohorts. Survival curves and ROC curve analysis demonstrated that the risk score was a significant predictor of survival in all cohorts even when considering the effect of other clinical indexes. Low-risk patients had longer survival times, higher immune cell infiltration levels and better immunotherapeutic responses. Single-cell analysis showed that FBLN5 and LAD1 were overexpressed in fibroblasts and cancer cells, respectively, compared to normal cells. Conclusion: This study evaluated the clinical role of the BM in LUAD and primarily explored its mechanism.

The associations between gut microbiota and chronic respiratory diseases: a Mendelian randomization study.

Introduction: Growing evidence indicates that variations in the composition of the gut microbiota are linked to the onset and progression of chronic respiratory diseases (CRDs), albeit the causal relationship between the two remains unclear. Methods: We conducted a comprehensive two-sample Mendelian randomization (MR) analysis to investigate the relationship between gut microbiota and five main CRDs, including chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), sarcoidosis, and pneumoconiosis. For MR analysis, the inverse variance weighted (IVW) method was utilized as the primary method. The MR-Egger, weighted median, and MR-PRESSO statistical methods were used as a supplement. To detect heterogeneity and pleiotropy, the Cochrane and Rucker Q test, MR-Egger intercept test, and MR-PRESSO global test were then implemented. The leave-one-out strategy was also applied to assess the consistency of the MR results. Results: Based on substantial genetic data obtained from genome-wide association studies (GWAS) comprising 3,504,473 European participants, our study offers evidence that several gut microbial taxa, including 14 probable microbial taxa (specifically, 5, 3, 2, 3 and 1 for COPD, asthma, IPF, sarcoidosis, and pneumoconiosis, respectively) and 33 possible microbial taxa (specifically, 6, 7, 8, 7 and 5 for COPD, asthma, IPF, sarcoidosis, and pneumoconiosis, respectively) play significant roles in the formation of CRDs. Discussion: This work implies causal relationships between the gut microbiota and CRDs, thereby shedding new light on the gut microbiota-mediated prevention of CRDs.

Benzo(α)pyrene induces oxidative stress and inflammation in human vascular endothelial cells through AhR and NF-κB pathways.

Exposure to polycyclic aromatic hydrocarbons (PAHs) contributes to development and exacerbation of atherosclerosis and cardiovascular disease. However, the underlying molecular mechanisms remain elusive. In the current study, the effect of benzo(α)pyrene (BaP) in human umbilical vein endothelial cells (HUVECs) was investigated, including its impact on apoptosis, cell viability, oxidative stress and inflammatory cytokine release. The role of aryl hydrocarbon receptor (AhR) and NF-κB signaling pathways involved in BaP-induced oxidative stress and inflammation was further investigated. Exposure to BaP induced cell apoptosis and terminal oxidative stress and inflammation responses in HUVECs. BaP also increased the expression of ICAM-1 and VCAM-1. Furthermore, BaP treatment of HUVECs activated AhR and NF-κB signaling pathways, and promoted reactive oxygen species generation and inflammatory cytokine release. The current findings suggest that BaP induced inflammatory cytokine release from HUVECs through oxidative stress accompanied with AhR and NF-κB pathway activation.

Efficacy, safety, and tolerability of combined pirfenidone and N-acetylcysteine therapy: a systematic review and meta-analysis.

BACKGROUND: While antifibrotic drugs significantly decrease lung function decline in idiopathic pulmonary fibrosis (IPF), there is still an unmet need to halt disease progression. Antioxidative therapy with N-acetylcysteine (NAC) is considered a potential additional therapy that can be combined with antifibrotics in some patients in clinical practice. However, data on the efficacy, tolerability, and safety of this combination are scarce. We performed a systematic review and meta-analysis to appraise the safety, tolerability, and efficacy of the combination compared to treatment with pirfenidone alone. METHODS: We systematically reviewed all the published studies with combined pirfenidone (PFD) and NAC (PFD + NAC) treatment in IPF patients. The primary outcomes referred to decline in pulmonary function tests (PFTs) and the rates of IPF patients with side effects. RESULTS: In the meta-analysis, 6 studies with 319 total IPF patients were included. The PFD + NAC group was comparable to the PFD alone group in terms of the predicted forced vital capacity (FVC%) and predicted diffusion capacity for carbon monoxide (DLco%) from treatment start to week 24. Side effects and treatment discontinuation rates were also comparable in both groups. CONCLUSION: This systematic review and meta-analysis suggests that combination with NAC does not alter the efficacy, safety, or tolerability of PFD in comparison to PFD alone in IPF patients.

Solar-induced chlorophyll fluorescence and short-term photosynthetic response to drought.

Drought is among the most damaging climate extremes, potentially causing significant decline in ecosystem functioning and services at the regional to global scale, thus monitoring of drought events is critically important. Solar-induced chlorophyll fluorescence (SIF) has been found to strongly correlate with gross primary production on the global scale. Recent advances in the remote sensing of SIF allow for large-scale, real-time estimation of photosynthesis using this relationship. However, several studies have used SIF to quantify the impact of drought with mixed results, and the leaf-level mechanisms linking SIF and photosynthesis are unclear, particularly how the relationship may change under drought. We conducted a drought experiment with 2-yr old Populus deltoides. We measured leaf-level gas exchange, SIF, and pulse amplitude modulated (PAM) fluorescence before and during the 1-month drought. We found clear responses of net photosynthesis and stomatal conductance to water stress, however, SIF showed a smaller response to drought. Net photosynthesis (Anet ) and conductance dropped 94% and 95% on average over the drought, while SIF values only decreased slightly (21%). Electron transport rate dropped 64% when compared to the control over the last week of drought, but the electron transport chain did not completely shut down as Anet approached zero. Additionally, SIF yield (SIFy ) was positively correlated with steady-state fluorescence (Fs ) and negatively correlated with non-photochemical quenching (NPQ; R2  = 0.77). Both Fs and SIFy , after normalization by the minimum fluorescence from a dark-adapted sample (Fo ), showed a more pronounced drought response, although the results suggest the response is complicated by several factors. Leaf-level experiments can elucidate mechanisms behind large-scale remote sensing observations of ecosystem functioning. The value of SIF as an accurate estimator of photosynthesis may decrease during mild stress events of short duration, especially when the response is primarily stomatal and not fully coupled with the light reactions of photosynthesis. We discuss potential factors affecting the weak SIF response to drought, including upregulation of NPQ, change in internal leaf structure and chlorophyll concentration, and photorespiration. The results suggest that SIF is mainly controlled by the light reactions of photosynthesis, which operate on different timescales than the stomatal response.

A quantitative approach for the analysis of clinician recognition of acute respiratory distress syndrome using electronic health record data.

IMPORTANCE: Despite its efficacy, low tidal volume ventilation (LTVV) remains severely underutilized for patients with acute respiratory distress syndrome (ARDS). Physician under-recognition of ARDS is a significant barrier to LTVV use. We propose a computational method that addresses some of the limitations of the current approaches to automated measurement of whether ARDS is recognized by physicians. OBJECTIVE: To quantify patient and physician factors affecting physicians' tidal volume selection and to build a computational model of physician recognition of ARDS that accounts for these factors. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, electronic health record data were collected for 361 ARDS patients and 388 non-ARDS hypoxemic (control) patients in nine adult intensive care units at four hospitals between June 24 and December 31, 2013. METHODS: Standardized tidal volumes (mL/kg predicted body weight) were chosen as a proxy for physician decision-making behavior. Using data-science approaches, we quantified the effect of eight factors (six severity of illness, two physician behaviors) on selected standardized tidal volumes in ARDS and control patients. Significant factors were incorporated in computational behavioral models of physician recognition of ARDS. RESULTS: Hypoxemia severity and ARDS documentation in physicians' notes were associated with lower standardized tidal volumes in the ARDS cohort. Greater patient height was associated with lower standardized tidal volumes (which is already normalized for height) in both ARDS and control patients. The recognition model yielded a mean (99% confidence interval) physician recognition of ARDS of 22% (9%-42%) for mild, 34% (19%-49%) for moderate, and 67% (41%-100%) for severe ARDS. CONCLUSIONS AND RELEVANCE: In this study, patient characteristics and physician behaviors were demonstrated to be associated with differences in ventilator management in both ARDS and control patients. Our model of physician ARDS recognition measurement accounts for these clinical variables, providing an electronic approach that moves beyond relying on chart documentation or resource intensive approaches.

LncRNA TUG1 protects against cardiomyocyte ischaemia reperfusion injury by inhibiting HMGB1.

The aim of this study was to investigate whether lncRNA TUG1 could mediate the progression of ischemia-reperfusion injury following acute myocardial infraction. Mouse cardiomyocytes HL-1 cells were subjected to oxygen glucose deprivation followed by reperfusion (OGD/R) to induce myocardial I/R injury. The expression of TUG1 was detected by real-time PCR. Overexpression or down expression of TUG1 was performed in mouse HL-1 cardiomyocytes. The myocardial cell viability and apoptosis were respectively detected. In addition, the expression levels of inflammatory factors, apoptosis-related proteins and HMGB1 proteins were detected. Besides, an inhibitor of HMGB1 was used to treat cells to verify the relationship between TUG1 and HMGB1 protein. The expression of TUG1 was significantly up-regulated in OGD/R-induced myocardial HL-1 cells. The overexpression of TUG1-induced inflammation and apoptosis in OGD-R-induced myocardial HL-1 cells. Knock down of TUG1 protected OGD/R-induced myocardial I/R injury by inhibiting HMGB1 expression. Suppression of lncRNA TUG1 may prevent myocardial I/R injury following acute myocardial infarction via inhibiting HMGB1 expression.

Blood purification in two patients with clinically amyopathic dermatomyositis associated with interstitial lung disease with anti-melanoma differentiation-associated gene-5 antibody (MDA-5).

Patients of clinically amyopathic dermatomyositis associated with rapidly progressive interstitial pneumonia (CADM-RFIP) with positive anti-MDA5 antibody usually presents rapid deterioration and traditional therapy such as cyclophosphamide combined with high-dose prednisone pulse therapy shows no clear benefit at whiles. However, blood purification combined with traditional therapy works according to the literature. We herein report two CADM-RFIP patients administered with DNA immunoadsorption combined with traditional therapy and then reviewed the literature of blood purification in CADM-RFIP patients at home and abroad to date. We emphasize blood purification such as DNA immunoadsorption could apply in the early stage of CADM-RFIP, which can decrease inflammation and allow us more time to control the condition better.

Goos-Hänchen and Imbert-Fedorov shifts at gradient metasurfaces.

Motivated by recent experimental observation of photonic spin Hall effect at metasurfaces, we study lateral Goos-Hänchen (GH) and transverse Imbert-Fedorov (IF) shifts of an arbitrarily polarized light beam totally reflected from metasurfaces, in terms of stationary phase method and energy flux method. The intriguing phenomenon is that the gradient in phase discontinuity results in anomalous reflection and refraction, and the GH and IF shifts can be thus controlled from negative to positive values by changing the sign of phase discontinuity. The tunable GH and IF shifts have potential applications in nano-optics, with the development of novel functionalities and performances of metasurfaces.

FluoSpec 2-An Automated Field Spectroscopy System to Monitor Canopy Solar-Induced Fluorescence.

Accurate estimation of terrestrial photosynthesis has broad scientific and societal impacts. Measurements of photosynthesis can be used to assess plant health, quantify crop yield, and determine the largest CO2 flux in the carbon cycle. Long-term and continuous monitoring of vegetation optical properties can provide valuable information about plant physiology. Recent developments of the remote sensing of solar-induced chlorophyll fluorescence (SIF) and vegetation spectroscopy have shown promising results in using this information to quantify plant photosynthetic activities and stresses at the ecosystem scale. However, there are few automated systems that allow for unattended observations over months to years. Here we present FluoSpec 2, an automated system for collecting irradiance and canopy radiance that has been deployed in various ecosystems in the past years. The instrument design, calibration, and tests are recorded in detail. We discuss the future directions of this field spectroscopy system. A network of SIF sensors, FluoNet, is established to measure the diurnal and seasonal variations of SIF in several ecosystems. Automated systems such as FluoSpec 2 can provide unique information on ecosystem functioning and provide important support to the satellite remote sensing of canopy photosynthesis.