Adhesion-based high-throughput label-free cell sorting using ridged microfluidic channels.

Numerous applications in medical diagnostics, cell engineering therapy, and biotechnology require the identification and sorting of cells that express desired molecular surface markers. We developed a microfluidic method for high-throughput and label-free sorting of biological cells by their affinity of molecular surface markers to target ligands. Our approach consists of a microfluidic channel decorated with periodic skewed ridges and coated with adhesive molecules. The periodic ridges form gaps with the opposing channel wall that are smaller than the cell diameter, thereby ensuring cell contact with the adhesive surfaces. Using three-dimensional computer simulations, we examine trajectories of adhesive cells in the ridged microchannels. The simulations reveal that cell trajectories are sensitive to the cell adhesion strength. Thus, the differential cell trajectories can be leveraged for adhesion-based cell separation. We probe the effect of cell elasticity on the adhesion-based sorting and show that cell elasticity can be utilized to enhance the resolution of the sorting. Furthermore, we investigate how the microchannel ridge angle can be tuned to achieve an efficient adhesion-based sorting of cells with different compliance.

Identification of vilazodone as a novel plasminogen activator inhibitor to overcome Alzheimer's disease through virtual screening, molecular dynamics simulation, and biological evaluation.

Urokinase-type plasminogen activator (PLAU), a member of the S1 serine peptidase family in Clan PA, plays a crucial role in the conversion of plasminogen into active plasmin. However, the precise role of PLAU in the central nervous system remains incompletely elucidated, particularly, in relation to Alzheimer's disease (AD). In this study, we successfully identified that PLAU could promote cell senescence in neurons, indicating it as a potential target for AD treatment through a systematic approach, which included both bioinformatics analysis and experimental verification. Subsequently, a structure-based virtual screening approach was employed to identify a potential PLAU inhibitor from the Food and Drug Administration-approved drug database. After analyzing docking scores and thoroughly examining the receptor-ligand complex interaction modes, vilazodone emerges as a highly promising PLAU inhibitor. Additionally, molecular docking and molecular dynamics simulations were performed to generate a complex structure between the relatively stable inhibitor vilazodone and PLAU. Of note, vilazodone exhibited superior cytotoxicity against senescent cells, showing a senolytic activity through targeting PLAU and ultimately producing an anti-AD effect. These findings suggest that targeting PLAU could represent a promising therapeutic strategy for AD. Furthermore, investigating the inhibitory potential and structural modifications based on vilazodone may provide valuable insights for future drug development targeting PLAU in AD disorders.

Learning Multi-Types of Neighbor Node Attributes and Semantics by Heterogeneous Graph Transformer and Multi-View Attention for Drug-Related Side-Effect Prediction.

Since side-effects of drugs are one of the primary reasons for their failure in clinical trials, predicting their side-effects can help reduce drug development costs. We proposed a method based on heterogeneous graph transformer and capsule networks for side-effect-drug-association prediction (TCSD). The method encodes and integrates attributes from multiple types of neighbor nodes, connection semantics, and multi-view pairwise information. In each drug-side-effect heterogeneous graph, a target node has two types of neighbor nodes, the drug nodes and the side-effect ones. We proposed a new heterogeneous graph transformer-based context representation learning module. The module is able to encode specific topology and the contextual relations among multiple kinds of nodes. There are similarity and association connections between the target node and its various types of neighbor nodes, and these connections imply semantic diversity. Therefore, we designed a new strategy to measure the importance of a neighboring node to the target node and incorporate different semantics of the connections between the target node and its multi-type neighbors. Furthermore, we designed attentions at the neighbor node type level and at the graph level, respectively, to obtain enhanced informative neighbor node features and multi-graph features. Finally, a pairwise multi-view feature learning module based on capsule networks was built to learn the pairwise attributes from the heterogeneous graphs. Our prediction model was evaluated using a public dataset, and the cross-validation results showed it achieved superior performance to several state-of-the-art methods. Ablation experiments undertaken demonstrated the effectiveness of heterogeneous graph transformer-based context encoding, the position enhanced pairwise attribute learning, and the neighborhood node category-level attention. Case studies on five drugs further showed TCSD's ability in retrieving potential drug-related side-effect candidates, and TCSD inferred the candidate side-effects for 708 drugs.

The risk of incident atrial fibrillation in patients with type 2 diabetes treated with sodium glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors: a nationwide cohort study.

BACKGROUND: Although a few meta-analyses were conducted to compare the risk of incident atrial fibrillation (AF) between sodium-glucose cotransporter-2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and other anti-hyperglycemic agents using indirect or direct comparison, the above analyses showed conflicting results with each other. We aimed to evaluate the risk of new-onset AF associated with the use of SGLT2i, GLP-1RA, and dipeptidyl peptidase-4 inhibitor (DPP4i) among a large longitudinal cohort of diabetic patients. METHODS: In this nationwide retrospective cohort study based on the Taiwan National Health Insurance Research Database, a total of 344,893, 44,370, and 393,100 consecutive patients with type 2 diabetes without preexisting AF receiving GLP-1RA, SGLT2i, and DPP4i, respectively, were enrolled from May 1, 2016, to December 31, 2019. We used 1:1 propensity score matching (PSM) to balance covariates across paired study groups. Patients were followed from the drug index date until the occurrence of AF, death, discontinuation of the index drug, or the end of the study period (December 31, 2020), whichever occurred first. RESULTS: After PSM, there were 245,442, 43,682, and 39,190 paired cohorts of SGLT2i-DPP4i, SGLT2i-GLP-1RA, and GLP-1RA-DPP4i, respectively. SGLT2i treatment was associated with lower risk of new-onset AF in participants with type 2 diabetes compared with either DPP4i [hazard ratio (HR):0.90; 95% confidential interval (CI) 0.84-0.96; P = 0.0028] or GLP-1RA [HR 0.74; 95% CI 0.63-0.88; P = 0.0007] treatment after PSM. There was no difference in the risk of incident AF between GLP-1RA and DPP4i users [HR 1.01; 95% CI 0.86-1.19; P = 0.8980]. The above findings persisted among several important subgroups. Dapagliflozin was specifically associated with a lower risk of new-onset AF compared with DPP4i (P interaction = 0.02). CONCLUSIONS: Compared with DPP4i, SGLT2i but not GLP-1RA was associated with a lower risk of incident AF in patients with type 2 diabetes.

Chinese Version of the Vision-Related Quality of Life (NEI-VFQ-25) among Patients with Various Ocular Disorders: A Pilot Study.

Background and Objectives: Subjective visual function is currently becoming an increasing appreciation in assessing the health-related quality of life. This study aimed to assess the vision-related quality of life (VRQOL) among patients with refractive errors, keratoconus, senile cataract, and age-related macular degeneration (AMD) using the Chinese version of the National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ-25). Materials and Methods: The questionnaire of NEI-VFQ-25 was filled out in a clinical setting or by telephone/mail. Univariate and multivariate analyses were used to determine which factors are associated with the NEI-VFQ-25. Results: From June 2018 to January 2019, 28 patients with refractive error, 20 patients with keratoconus, 61 with senile cataracts, and 17 with AMD completed the questionnaire NEI-VFQ-25. There were significant differences in the NEI-VFQ-25 subscale of general vision (p = 0.0017), ocular pain (p = 0.0156), near activities (p = 0.0002), vision-specific social functioning (p = 0.007), vision-specific mental health (p = 0.0083), vision-specific dependency (p = 0.0049), color vision (p < 0.0001), peripheral vision (p = 0.0065), and total score (p < 0.0001) among four disease groups, respectively. The multiple linear regression revealed that the best-corrected visual acuity (BCVA) and disease group were important factors of the total NEI-VFQ-25. After adjusting for BCVA, patients with AMD had a worse total NEI-VFQ-25 score than patients with refractive error, keratoconus, or senile cataracts. Conclusions: Among the patients with four ocular disorders and a broad vision spectrum from normal, partial sight, low vision to legal blindness, the BCVA of their better eye was the most important factor in the VRQOL.

Clinical Outcomes in Atrial Fibrillation Patients With a History of Cancer Treated With Non-Vitamin K Antagonist Oral Anticoagulants: A Nationwide Cohort Study.

Background and Purpose: Data on clinical outcomes for nonvitamin K antagonist oral anticoagulant (NOACs) and warfarin in patients with atrial fibrillation and cancer are limited, and patients with active cancer were excluded from randomized trials. We investigated the effectiveness and safety for NOACs versus warfarin among patients with atrial fibrillation with cancer. Methods: In this nationwide retrospective cohort study from Taiwan National Health Insurance Research Database, we identified a total of 6274 and 1681 consecutive patients with atrial fibrillation with cancer taking NOACs and warfarin from June 1, 2012, to December 31, 2017, respectively. Propensity score stabilized weighting was used to balance covariates across study groups. Results: There were 1031, 1758, 411, and 3074 patients treated with apixaban, dabigatran, edoxaban, and rivaroxaban, respectively. After propensity score stabilized weighting, NOAC was associated with a lower risk of major adverse cardiovascular events (hazard ratio, 0.63 [95% CI, 0.50­0.80]; P=0.0001), major adverse limb events (hazard ratio, 0.41 [95% CI, 0.24­0.70]; P=0.0010), venous thrombosis (hazard ratio, 0.37 [95% CI, 0.23­0.61]; P<0.0001), and major bleeding (hazard ratio, 0.73 [95% CI, 0.56­0.94]; P=0.0171) compared with warfarin. The outcomes were consistent with either direct thrombin inhibitor (dabigatran) or factor Xa inhibitor (apixaban, edoxaban, and rivaroxaban) use, among patients with stroke history, and among patients with different type of cancer and local, regional, or metastatic stage of cancer (P interaction >0.05). When compared with warfarin, NOAC was associated with lower risk of major adverse cardiovascular event, and venous thrombosis in patients aged <75 but not in those aged ≥75 years (P interaction <0.05). Conclusions: Thromboprophylaxis with NOACs rather than warfarin should be considered for the majority of the atrial fibrillation population with cancer.

Effectiveness and Safety of Direct Oral Anticoagulants in an Asian Population with Atrial Fibrillation Undergoing Dialysis: A Population-Based Cohort Study and Meta-Analysis.

PURPOSE: Whether direct oral anticoagulants (DOACs) are more effective and safer than warfarin among Asian patients with non-valvular atrial fibrillation (NVAF) undergoing dialysis remains unclear. METHODS: We first compared the risks of ischemic stroke/systemic embolism (IS/SE) and major bleeding associated with DOACs compared with warfarin, in NVAF Asians undergoing dialysis using the Taiwan National Health Insurance Research Database (NHIRD) (Aim 1). Next, we searched PubMed and Medline from January 1, 2010 until January 31, 2020, to perform a systematic review and meta-analysis of all observational real-world studies comparing DOACs with warfarin specifically focused on NVAF patients with stage 4 or 5 chronic kidney disease undergoing dialysis (Aim 2). Finally, we tested the hypothesis whether AF patients undergoing dialysis treated with OACs (warfarin and DOACs) would be associated with lower risk of adverse clinical outcomes as compared to those without OACs using the Taiwan NHIRD (Aim 3). RESULTS: From June 1, 2012, to December 31, 2017, a total of 3237 and 9263 NVAF patients comorbid with ESRD receiving oral anticoagulant (OACs) (490 on DOAC, 2747 on warfarin) or no OACs, respectively, were enrolled. Propensity score matching was used to balance covariates across the study groups. For the comparison of DOAC vs. warfarin (Aim 1), DOACs had comparable risks of IS/SE and major bleeding to warfarin in our present cohort. From the original 85 results retrieved, nine studies (including our study) with a total of 6490 and 22,494 patients treated with DOACs and warfarin were included in the meta-analysis, respectively. There were 5343 (82%) and 20,337 (90%) patients treated with DOACs and warfarin undergoing dialysis, respectively. The pooled meta-analysis also indicated no difference of the effectiveness (HR:0.90; [95%CI:0.74-1.10]; P = 0.32) and safety outcomes (HR:0.75; [95%CI:0.54-1.05]; P = 0.09) between DOACs and warfarin (Aim 2). For the comparison of OAC (+) vs. OAC (-) (Aim 3), OAC-treatment was associated with a higher risk of IS/SE (hazard ratio (HR):1.54; [95% confidential interval (CI):1.29-1.84];P < 0.0001) and comparable risk of major bleeding compared to those without OAC treatment. CONCLUSIONS: DOACs did not provide benefit over warfarin regarding effectiveness and safety in AF patients undergoing dialysis. The use of OAC was not associated with a lower risk of IS/SE in ESRD AF patients when compared to those without OAC use.

Major adverse cardiovascular and limb events in patients with diabetes and concomitant peripheral artery disease treated with sodium glucose cotransporter 2 inhibitor versus dipeptidyl peptidase-4 inhibitor.

BACKGROUND: Whether sodium glucose co-transporter 2 inhibitors (SGLT2i) are associated with a lower risk of cardiovascular as well as adverse lower limb events in patients with type-2 diabetes mellitus (T2DM) and concomitant peripheral artery disease (PAD) is unclear. We aimed to evaluate the risk of cardiovascular and limb events, and death associated with the use of SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i) among a longitudinal and national cohort of patients with T2DM. METHODS: In this nationwide retrospective cohort study based on the Taiwan National Health Insurance Research Database, we identified a total of 11,431 and 93,972 consecutive T2DM patients with PAD taking SGLT2i and DPP4i, respectively, from May 1, 2016, to December 31, 2017. We used 1:1 propensity score matching (PSM) to balance covariates across study groups. Patients were followed from the drug index date until the occurrence of clinical outcomes, death, discontinuation of the index drug, or the end of the study period, whichever occurred first. RESULTS: Overall, 56% and 44% of the patients were treated with dapagliflozin and empagliflozin, respectively. The use of SGLT2i had comparable risks of ischemic stroke and acute myocardial infarction, and was associated with lower risks of congestive heart failure (CHF) [hazard ratio (HR): 0.66; 95% confidence interval (CI) 0.49-0.89; p = 0.0062], lower limb ischemia requiring revascularization (HR: 0.73; 95% CI 0.54-0.98; p = 0.0367) or amputation (HR: 0.43; 95% CI 0.30-0.62; p < 0.0001), and cardiovascular death (HR: 0.67; 95% CI 0.49-0.90; p = 0.0089) when compared with the DDP4i group after PSM. The subgroup analysis revealed consistent results for CHF and major adverse limb outcomes for SGLT2i versus DPP4i among patients aged ≥ 75 years, the presence of chronic kidney disease and established cardiovascular disease was consistent with the main analysis. CONCLUSIONS: SGLT2i were associated with lower risks of CHF and adverse lower limb events compared with DPP4i among patients with T2DM and PAD in real-world practice.

Effectiveness, safety, and major adverse limb events in atrial fibrillation patients with concomitant diabetes mellitus treated with non-vitamin K antagonist oral anticoagulants.

BACKGROUND: Evidence of adverse clinical outcomes for non-vitamin K antagonist oral anticoagulant (NOACs) and warfarin in patients with atrial fibrillation (AF) and diabetes mellitus are limited. We investigated the effectiveness, safety, and major adverse limb events for NOACs versus warfarin among diabetic AF patients. METHODS: In this nationwide retrospective cohort study collected from Taiwan National Health Insurance Research Database, we identified a total of 20,967 and 5812 consecutive AF patients with diabetes taking NOACs and warfarin from June 1, 2012, to December 31, 2017, respectively. We used propensity-score stabilized weighting to balance covariates across study groups. RESULTS: NOAC was associated with a lower risk of major adverse cardiovascular events (MACE) (adjusted hazard ratio (aHR):0.88; [95% confidential interval (CI) 0.78-0.99]; P = 0.0283), major adverse limb events (MALE) (aHR:0.72;[95% CI 0.57-0.92]; P = 0.0083), and major bleeding (aHR:0.67;[95% CI 0.59-0.76]; P < 0.0001) compared to warfarin. NOACs decreased MACE in patients of ≥ 75 but not in those aged < 75 years (P interaction = 0.01), and in patients with ischemic heart disease (IHD) compared to those without IHD (P interaction < 0.01). For major adverse limb events, the advantage of risk reduction for NOAC over warfarin persisted in high risk subgroups including age ≥ 75 years, chronic kidney disease, IHD, peripheral artery disease, or use of concomitant antiplatelet drugs. CONCLUSION: Among diabetic AF patients, NOACs were associated with a lower risk of thromboembolism, major bleeding, and major adverse limb events than warfarin. Thromboprophylaxis with NOACs should be considered in the diabetic AF population with a high atherosclerotic burden.

Mortality after major bleeding in Asian atrial fibrillation patients receiving different direct oral anticoagulants: a nationwide, propensity score study.

In this research, we assessed mortality after major bleeding events in atrial fibrillation (AF) patients taking four direct oral anticoagulants (DOACs). Drawing data from the Taiwan National Health Insurance Research Database between 2016 and 2019, we focused on AF patients on DOACs who had major bleeding episodes. Using propensity score stabilized weighting, we established four comparable pseudo-DOAC groups. Among 2770 patients (460 dabigatran, 1322 rivaroxaban, 548 apixaban, 440 edoxaban), 85.3% were prescribed low-dose regimens. The 7-day mortality rate was 9.0%, surging to 16.0% by the 30th day. Compared with dabigatran, there was a distinct divergence in 7-day mortality of factor Xa inhibitors (p = 0.012), with hazard ratios of 1.83 (95% CI 1.11-3.00, p = 0.017) for rivaroxaban, 2.13 (95% CI 1.23-3.66, p = 0.007) for apixaban, and 2.41 (95% CI 1.39-4.19, p = 0.002) for edoxaban. This pattern remained consistent when analyzing the subgroup that received lower dosages of DOACs. In conclusion, factor Xa inhibitors were associated with a significantly higher risk of 7-day mortality following major bleeding events than dabigatran among AF patients.

Clinical Outcomes in Type 2 Diabetes Patients After Acute Myocardial Infarction: A Comparison of Sodium-Glucose Cotransporter 2 Inhibitors vs. Non-Users.

To compare clinical outcomes in patients with type 2 diabetes (T2D) after acute myocardial infarction (AMI) using sodium-glucose cotransporter-2 inhibitors (SGLT2i) vs. non-use of SGLT2i. A national cohort study based on the Taiwan National Health Insurance Research Database enrolled 944 patients with T2D who had experienced AMI and were treated with SGLT2i and 8,941 patients who did not receive SGLT2i, respectively, from May 1, 2016, to December 31, 2019. We used propensity score matching to balance covariates across study groups. The follow-up period was from the index date to the independent occurrence of the study outcomes, discontinuation of the index drug, or the end of the study period (December 31, 2020), whichever occurred first. The SGLT2i group exhibited a significantly lower incidence of cardiovascular death (0.865% per year vs. 2.048% per year; hazard ratio (HR): 0.42; 95% confidence interval (CI): 0.24-0.76; P = 0.0042), heart failure hospitalization (1.987% per year vs. 3.395% per year; HR: 0.59; 95% CI: 0.39-0.89; P = 0.0126), and all-cause mortality (3.406% per year vs. 4.981% per year, HR: 0.69; 95% CI: 0.50-0.95; P = 0.0225) compared with the non-SGLT2i group. There were no significant differences between the two groups in the incidence of AMI, ischemic stroke, coronary revascularization, major adverse cardiovascular events, composite renal outcomes, or lower limb amputation. These findings suggest that the use of SGLT2i may have favorable effects on clinical outcomes in patients with T2D after AMI.

SGLT2 inhibitors vs. GLP-1 receptor agonists and clinical outcomes in patients with diabetes with/without atrial fibrillation.

CONTEXT: The coexistence of diabetes mellitus and atrial fibrillation (AF) is associated with substantial risks of adverse cardiovascular events. OBJECTIVE: The relevant outcomes associated with the use of sodium-glucose cotransporter-2 inhibitor (SGLT2i) versus glucagon-like peptide-1 receptor agonists (GLP-1RA) among patients with type 2 diabetes (T2D) with/without concomitant AF remained unknown. METHODS: In this nationwide retrospective cohort study from Taiwan National Health Insurance Research Database, there were 344,392 and 31,351 patients with T2D without AF, and 11,462 and 816 T2D patients with AF treated with SGLT2i and GLP-1RA from May 1, 2016, to December 31, 2019. Patients were followed from the drug-index date until the occurrence of study events, discontinuation of the index drug, or the end of the study period (December 31, 2020), whichever occurred first. We used propensity score stabilized weight to balance covariates across two medication groups. RESULTS: The incidence rate of all study outcomes in patients with concomitant AF was much higher than in those without concomitant AF. For the AF cohort, SGLT2i vs. GLP-1RA was associated with a lower risk of hospitalization for heart failure (2.32 vs. 4.74 events per 100 person-years; hazard ratio (HR):0.48 [95% confidential interval (CI):0.36-0.66]), with no benefit seen for the non-AF cohort (P for homogeneity < 0.01). SGLT2i vs. GLP-1RA was associated with a lower risk of composite kidney outcomes both in the AF (0.38 vs. 0.79 events per 100 person-years; HR:0.47; [95%CI:0.23-0.96]) and non-AF cohorts (0.09 vs. 0.18 events per 100 person-years; HR:0.53; [95%CI:0.43-0.64]). There were no significant differences in the risk of major adverse cardiovascular events and all-cause mortality in those who received SGLT2i compared to GLP-1RA for the AF or non-AF cohorts. CONCLUSION: Considering the high risk of developing HF and/or high prevalence of concomitant HF in patients with diabetes, whether SGLT2i should be the preferred treatment to GLP-1RA for such a high-risk population requires further investigation.

Effect of febuxostat on adverse events and mortality in gout in Taiwan: An interrupted time series analysis.

OBJECTIVES: To evaluate the influence of febuxostat on adverse events and mortality in gout. METHODS: We retrospectively enrolled patients with newly diagnosed gout and prescribed urate-lowering therapy between 2006 and 2017 from the Taiwan National Health Insurance Database. These patients were divided into 2 groups: with and without comorbidities (n = 294 847 and 194 539). An interrupted time series analysis with adjustments for demographics, comorbidities, and comedication by propensity score-based stabilized weights was used to compare the trend of adverse events and mortality before vs after febuxostat was introduced in 2012. RESULTS: The proportion of febuxostat use gradually increased from 0% in 2012 to 30% in those with comorbidities and 10% in those without comorbidities in 2017. Allopurinol use decreased from 30% in 2012 to 10% in 2017. The slope of the 1-year incidence rate of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) (per 10 000 patients) significantly reduced after 2012 in those with and without comorbidities (-0.375 per quarter, P = .015 and -.253 per quarter, P = .049). The slope of the 3-year incidence rate of acute myocardial infarction (AMI) (per 1000 patients), percutaneous coronary intervention (PCI) (per 1000 patients), and all-cause mortality (per 100 patients) significantly increased after 2012 in those with comorbidities (+0.207 per quarter, P = .013; +.389 per quarter, P = .002; +.103 per quarter, P = .001). CONCLUSIONS: Febuxostat may reduce SJS and TEN in all gout patients but increase AMI, PCI, and all-cause mortality in gout patients with comorbidities.

Cardiovascular, renal, and lower limb outcomes in patients with type 2 diabetes after percutaneous coronary intervention and treated with sodium-glucose cotransporter 2 inhibitors vs. dipeptidyl peptidase-4 inhibitors.

AIMS: Patients with type 2 diabetes (T2D) who undergo percutaneous coronary intervention (PCI) are at higher risk of adverse cardiovascular and renal events than non-diabetic patients. However, limited evidence is available regarding the cardiovascular, renal, and limb outcomes of patients with T2D after PCI and who were treated with sodium-glucose cotransporter-2 inhibitors (SGLT2i). We compare the specified outcomes in patients with T2D after PCI who were treated with SGLT2i vs. dipeptidyl peptidase-4 inhibitors (DPP4i). METHODS AND RESULTS: In this nationwide retrospective cohort study, we identified 4248 and 37 037 consecutive patients with T2D who underwent PCI with SGLT2i and DPP4i, respectively, for 1 May 2016-31 December 2019. We used propensity score matching (PSM) to balance the covariates between study groups. After PSM, SGLT2i, and DPP4i were associated with comparable risks of ischaemic stroke, acute myocardial infarction, and lower limb amputation. However, SGLT2i was associated with significantly lower risks of heart failure hospitalization [HFH; 1.35% per year vs. 2.28% per year; hazard ratio (HR): 0.60; P = 0.0001], coronary revascularization (2.33% per year vs. 3.36% per year; HR: 0.69; P = 0.0003), composite renal outcomes (0.10% per year vs. 1.05% per year; HR: 0.17; P < 0.0001), and all-cause mortality (2.27% per year vs. 3.80% per year, HR: 0.60; P < 0.0001) than were DPP4i. CONCLUSION: Our data indicated that SGLT2i, compared with DPP4i, were associated with lower risks of HFH, coronary revascularization, composite renal outcomes, and all-cause mortality for patients with T2D after PCI. Further randomized or prospective studies can investigate the effects of SGLT2i in patients with T2D after PCI.

High-Intensity Ultraviolet-C Irradiation Efficiently Inactivates SARS-CoV-2 Under Typical Cold Chain Temperature.

SARS-CoV-2 contaminated items in the cold chain becomes a threat to public health, therefore the effective and safe sterilization method fit for the low temperature is needed. Ultraviolet is an effective sterilization method while its effect on SARS-CoV-2 under low-temperature environment is unclear. In this research, the sterilization effect of high-intensity ultraviolet-C (HIUVC) irradiation against SARS-CoV-2 and Staphylococcus aureus on different carriers at 4 °C and - 20 °C was investigated. The results showed that dose of 15.3 mJ/cm2 achieved more than 3 log reduction of SARS-CoV-2 on gauze at 4 °C and - 20 °C. The vulnerability of coronavirus to HIUVC under - 20 °C was not significantly different than those under 4 °C. Four models including Weibull, biphasic, log-linear tail and log linear were used to fit the survival curves of SARS-CoV-2 and Staphylococcus aureus. The biphasic model fitted best with R2 ranging from 0.9325 to 0.9878. Moreover, the HIUVC sterilization correlation between SARS-CoV-2 and Staphylococcus aureus was established. This paper provides data support for the employment of HIUVC under low-temperature environment. Also, it provides a method of using Staphylococcus aureus as a marker to evaluate the sterilization effect of cold chain sterilization equipment.

Adverse cardiovascular, limb, and renal outcomes in patients with diabetes after peripheral artery disease revascularization treated with sodium glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors.

AIMS: The effectiveness and limb safety of sodium glucose co-transporter 2 inhibitors (SGLT2i) for patients with type-2 diabetes (T2D) who have received peripheral artery disease (PAD) revascularization are unknown. METHODS AND RESULTS: In this nationwide retrospective cohort study, we identified a total of 2,455 and 8,695 patients with T2D who had undergone PAD revascularization and received first prescriptions for SGLT2i and dipeptidyl peptidase-4 inhibitors (DPP4i), respectively, between May 1, 2016, and December 31, 2019. We used 1:1 propensity score matching (PSM) to balance covariates between the two study groups. Patients were followed up from the drug index date until the occurrence of specified outcomes, death, discontinuation of the index drug, or the end of the study period, whichever occurred first. After PSM, we observed that compared with DPP4i, SGLT2i were associated with comparable risks of ischemic stroke, acute myocardial infarction, and heart failure hospitalization but were associated with a lower risk of cardiac death (hazard ratio [HR]: 0.60; 95% confidence interval [CI]: 0.40-0.90]; p = 0.0126). Regarding major limb outcomes, SGLT2i were associated with comparable risks of repeated revascularization and lower limb amputation compared with DPP4i. SGLT2i were associated with a lower risk of composite renal outcomes (HR: 0.40; 95% CI: 0.27-0.59; p < 0.0001) compared with DPP4i. CONCLUSION: In a real-world study of patients with T2D who had undergone PAD revascularization, SGLT2i were associated with lower risks of cardiac death and composite renal outcomes but not associated with increased risks of adverse limb events compared with DPP4i.

Clinical outcomes in elderly atrial fibrillation patients at increased bleeding risk treated with very low dose vs. regular-dose non-vitamin K antagonist oral anticoagulants: a nationwide cohort study.

AIMS: The Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE-AF) trial showed that edoxaban at a very low dosage (VLD) of 15 mg/day was more effective than a placebo at preventing stroke/systemic embolism without significantly increasing the risk of serious bleeding. We aimed to compare the effectiveness and safety for VLD non-vitamin K antagonist oral anticoagulants (NOACs) [edoxaban 15 mg o.d., dabigatran 110 or 150 o.d., apixaban 2.5 mg o.d., or rivaroxaban 10 mg (without the diagnosis of chronic kidney disease) or <10 mg o.d.] vs. regular-dosage (RD) NOACs (edoxaban 60/30 mg o.d. or other labeling-dosage NOACs) among a real-world cohort of elderly atrial fibrillation (AF) population similar to the ELDERCARE-AF cohort. METHODS AND RESULTS: In this nationwide retrospective cohort study from Taiwan National Health Insurance Research Database (NHIRD), we identified a total of 7294 and 4151 consecutive AF patients aged 80 years or older with a CHADS2 (congestive heart failure, hypertension, age 75 years or older, diabetes mellitus, previous stroke/transient ischemic attack (2 points) score ≥2 who met the enrollment criteria (generally similar to ELDERCARE-AF) taking VLD and RD NOACs from 1 June 2012 to 31 December 2019, respectively. Propensity-score stabilized weighting (PSSW) was used to balance covariates across study groups. Patients were followed up from the first date of prescription for NOACs until the first occurrence of any study outcome, death, or until the end date of the study period (31 December 2020). After PSSW, VLD NOAC was associated with a comparable risk of ischemic stroke/systemic embolism and major bleeding but a higher risk of major adverse limb events (MALEs) requiring lower limb revascularization or amputation [hazard ratio (HR): 1.54, 95% confidential interval (CI): 1.09-2.18; P = 0.014), venous thrombosis (HR: 3.75, 95% CI: 1.56-8.97; P = 0.003), and all-cause mortality (HR: 1.21, 95% CI: 1.15-1.29; P <0.001) compared with RD NOACs. VLD NOACs showed worse outcomes in most net clinical outcome (NCO) benefits. The main result was consistent based on on-treatment analysis or accounting for death as a competing risk. In general, the advantage of NCOs for the RD NOACs over VLD NOACs persisted in most high-risk subgroups, consistent with the main analysis (P for interaction > 0.05). CONCLUSION: Use of VLD NOACs was associated with a greater risk of arterial and venous thrombosis, death as well as the composite outcomes, when compared with that of RD NOAC in high-risk elderly AF patients at increased bleeding risk. Thromboprophylaxis with RD NOAC is still preferable over VLD NOAC for the majority of elderly AF patients at increased bleeding risk.

Emergence of debubblers in microfluidics: A critical review.

Bubbles in microfluidics-even those that appear to be negligibly small-are pervasive and responsible for the failure of many biological and chemical experiments. For instance, they block current conduction, damage cell membranes, and interfere with detection results. To overcome this unavoidable and intractable problem, researchers have developed various methods for capturing and removing bubbles from microfluidics. Such methods are multifarious and their working principles are very different from each other. In this review, bubble-removing methods are divided into two broad categories: active debubblers (that require external auxiliary equipment) and passive debubblers (driven by natural processes). In each category, three main types of methods are discussed along with their advantages and disadvantages. Among the active debubblers, those assisted by lasers, acoustic generators, and negative pressure pumps are discussed. Among the passive debubblers, those driven by buoyancy, the characteristics of gas-liquid interfaces, and the hydrophilic and hydrophobic properties of materials are discussed. Finally, the challenges and prospects of the bubble-removal technologies are reviewed to refer researchers to microfluidics and inspire further investigations in this field.

Effect of Blue Light-Filtering Intraocular Lenses on Insomnia After Cataract Surgery: A Nationwide Cohort Study With 10-Year Follow-up.

PURPOSE: To compare the incidence of clinically diagnosed insomnia after cataract surgery in pseudophakic eyes with blue light-filtering intraocular lenses (BF-IOLs) and non-BF-IOLs. DESIGN: Nationwide cohort study using the Taiwan National Health Insurance Research Database. METHODS: We enrolled 171,415 patients who underwent cataract surgery in both eyes between 2008 and 2013 and followed them till 2018. Propensity score matching (PSM) was used to balance the baseline characteristics between the 2 IOL groups. The Cox model and cause-specific hazard model were used to estimate the hazard ratios (HRs) and subdistribution hazard ratio (SHR). RESULTS: Overall, 19,604 (11.4%) and 151,811 (88.6%) patients had BF-IOL and non-BF-IOL implants, respectively. The BF-IOL group tended to be younger and had fewer chronic diseases. Within a mean follow-up period of 6.2 years, the incidence rates of insomnia (per 100 person-years) in the BF-IOL and non-BF-IOL groups were 2.97 and 3.21, respectively. There was no significant difference in the incidence rate of insomnia between the 2 IOL groups after treating all-cause mortality as a competing risk (SHR 0.98, 95% CI 0.95-1.01) and after PSM (HR 0.97, 95% CI 0.92-1.01), respectively. Subgroup analysis revealed no significant difference in the insomnia rate between the 2 IOL groups for various age groups, 2 sex groups, and men with and without benign prostatic hyperplasia. CONCLUSION: In Taiwan, the use of a BF-IOL for up to 10 years had no apparent disadvantage over non-BF-IOLs with respect to insomnia.

CCK regulates osteogenic differentiation through TNFα/NF-κB in peri-implantitis.

OBJECTIVE: Peri-implantitis is characterized by peri-implant mucositis and alveolar bone resorption. This study investigated cholecystokinin (CCK) expression and the mechanism underlying its involvement in peri-implantitis. METHODS: mRNA sequencing was performed using the Gene Expression Omnibus database GSE106090. Human bone marrow mesenchymal stem cells (hBMSCs) were pretreated with various concentrations of CCK (0, 10, 30, or 100 nM) for 1 hour before induction in osteogenic differentiation medium for 2 weeks. Alkaline phosphatase (ALP) activity was determined, and the cells were stained with alizarin red. The expression levels of TNFα and the osteogenic markers ALP, RUNX2, and OCN were measured using quantitative real-time PCR. TNFα, phosphorylated P65, and total P65 levels were determined by western blot. RESULTS: Compared with healthy individuals, 262 and 215 genes were up- and down-regulated, respectively, in the periodontal tissues of patients with peri-implantitis. CCK expression was significantly upregulated in patients with peri-implantitis. CCK reduced ALP activity, osteogenic differentiation, and levels of the osteogenic markers ALP, RUNX2, and OCN. Moreover, CCK promoted levels of TNFα and phosphorylated P65, which is a marker of activation for the NF-κB inflammatory pathway. CONCLUSIONS: CCK regulates osteogenic differentiation through the TNFα/NF-κB axis in peri-implantitis.