Device Integrity of Drug-eluting Depot Stent for Smart Drug Delivery

Atherosclerosis, or hardening of the arteries, is a condition in which plaque, made of cholesterol, fatty substances, cellular waste products, calcium, and fibrin, builds up inside the arteries. A metallic stent is a small mesh tube that is used to treat these narrowed arteries such as coronary artery diseases. The drug-eluting stent has a metallic stent platform coated with drug-polymer mix and has been shown to be superior to its metallic stent counterpart in reducing restenosis. In the past few years, a novel variation of the drug-eluting stent with micro-sized drug reservoirs (depot stent) has been introduced to the market. It allows smart programmable drug delivery with spatial/temporal control and has potential advantages over conventional stents. The drug-polymer mix compound can be altered from one reservoir to the next, allowing a highly-controlled release of different medications. For example, this depot stent concept can be applied in the renal indication for potential treatment of both renal artery stenosis (upstream) and its associated kidney diseases (downstream) simultaneously. However, the creation of such drug reservoirs on the stent struts inevitably compromises its mechanical integrity. In this study, the effects of these drug reservoirs on stent key clinical attributes were systematically investigated. We developed finite element models to predict the mechanical integrity of a balloon-expandable stent at various stages of its function life such as manufacturing and acute deployment, as well as the stent radial strength and chronic fatigue life. Simulation results show that (1) creating drug reservoirs on a stent strut could impact the stent fatigue resistance to certain degrees; (2) drug reservoirs on the high stress concentration regions led to much greater loss in all key clinical attributes than reservoirs on other locations; (3) reservoir shape change resulted in little differences in all key clinical attributes; and (4) for the same drug loading capacity, larger and fewer reservoirs yielded higher fatigue safety factor. These results can help future stent designers to achieve the optimal balance of stent mechanical integrity and smart drug delivery, thereby opening up a wide variety of new opportunities for disease treatments. We also proposed an optimized depot stent with tripled drug capacity and acceptable marginal trade-off in key clinical attributes when compared to the current drug-eluting stents. This depot stent prototype was manufactured for the demonstration of our design concept

Serologic Status for Pandemic (H1N1) 2009 Virus, Taiwan

We studied preexisting immunity to pandemic (H1N1) 2009 virus in persons in Taiwan. A total of 18 (36%) of 50 elderly adults in Taiwan born before 1935 had protective antibodies against currently circulating pandemic (H1N1) 2009 virus. Seasonal influenza vaccines induced antibodies that did not protect against pandemic (H1N1) 2009 virus

Development of Interstitial Lung Disease Among Patients With Atrial Fibrillation Receiving Oral Anticoagulants in Taiwan.

ImportanceThere are emerging concerns from case reports and pharmacovigilance analyses of a possible risk of interstitial lung disease (ILD) associated with the use of factor Xa (FXa) inhibitors.ObjectiveTo evaluate the risk of incident ILD associated with the use of oral anticoagulants (OACs) in patients with nonvalvular atrial fibrillation (NVAF).Design, setting, and participantsThis nationwide retrospective cohort study used data from the Taiwan National Health Insurance Research Database. Patients with NVAF without preexisting lung disease who received OACs from June 1, 2012, to December 31, 2017, were included. Propensity score stabilized weighting (PSSW) was used to balance covariates across the medication groups (FXa inhibitors, dabigatran, and warfarin, with warfarin as the reference). Patients were followed up from the drug index date until the onset of ILD, death, or end of the study (December 31, 2019), whichever occurred first. Data were analyzed from September 11, 2021, to August 3, 2022.ExposuresPatients with NVAF were treated with FXa inhibitors, dabigatran, or warfarin.Main outcomes and measuresNew-onset idiopathic ILD.ResultsAmong the 106 044 patients (mean [SD] age, 73.4 [11.9] years; 59 995 men [56.6%]) included in the study, 64 555 (60.9%) received FXa inhibitors (apixban [n = 15 386], edoxaban [n = 12 413], and rivaroxaban [n = 36 756]), 22 501 (21.2%) received dabigatran, and 18 988 (17.9%) received warfarin at baseline. The FXa inhibitors were associated with a higher risk of incident ILD (0.29 vs 0.17 per 100 patient-years; hazard ratio, 1.54 [95% CI, 1.22-1.94]; P Conclusions and relevanceResults of this study suggest that FXa inhibitors were associated with lung injury among patients with NVAF who were treated with OACs. Physicians should be vigilant in monitoring for any potential adverse lung outcomes associated with the use of these 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.

BackgroundAlthough 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.MethodsIn 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.ResultsAfter 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).ConclusionsCompared with DPP4i, SGLT2i but not GLP-1RA was associated with a lower risk of incident AF in patients with type 2 diabetes

Prefrontal activity and heart rate variability during cognitive tasks may show different changes in young and older adults with and without mild cognitive impairment

BackgroundAge-related decline in cognitive function is often linked to changed prefrontal cortex (PFC) activity and heart rate variability (HRV). Mild cognitive impairment (MCI), a transitional stage between normal aging and dementia, might have further degeneration beyond aging. This study aimed to investigate the differences between young and older adults with or without MCI in cognitive functions, task-induced PFC activation and HRV changes.MethodsThirty-one healthy young adults (YA), 44 older adults (OA), and 28 older adults with MCI (OA-MCI) were enrolled and compared in this cross-sectional study. Each participant received a one-time assessment including cognitive and executive functions, as well as the simultaneous recording of PFC activity and HRV during a cognitive task paradigm.ResultsWe observed age-related decrease in global cognitive functions, executive functions, HRV, and increase in PFC activity. The MCI further deteriorated the global cognitive and executive performances, but not the HRV or the prefrontal activation.ConclusionOlder people showed lower performances in general cognitive function and executive function, compensatory increase of PFC activity, and reduced HRV. Older people with MCI had further deterioration in cognitive performance, but not in PFC activation and HRV

Pyk2 activates the NLRP3 inflammasome by directly phosphorylating ASC and contributes to inflammasome-dependent peritonitis

The inflammasome adaptor protein, ASC, contributes to both innate immune responses and inflammatory diseases via self-oligomerization, which leads to the activation of the protease, caspase-1. Here, we report that the cytosolic tyrosine kinases, FAK and Pyk2, are differentially involved in NLRP3 and AIM2 inflammasome activation. The inhibition of FAK and Pyk2 with RNA interference or chemical inhibitors dramatically abolished ASC oligomerization, caspase-1 activation, and IL-1β secretion in response to NLRP3 or AIM2 stimulation. Pyk2 is phosphorylated by the kinase Syk and relocalizes to the ASC specks upon NLRP3 inflammasome activation. Pyk2, but not FAK, could directly phosphorylate ASC at Tyr146, and only the phosphorylated ASC could participate in speck formation and trigger IL-1β secretion. Moreover, the clinical-trial-tested Pyk2/FAK dual inhibitor PF-562271 reduced monosodium urate-mediated peritonitis, a disease model used for studying the consequences of NLRP3 activation. Our results suggest that although Pyk2 and FAK are involved in inflammasome activation, only Pyk2 directly phosphorylates ASC and brings ASC into an oligomerization-competent state by allowing Tyr146 phosphorylation to participate ASC speck formation and subsequent NLRP3 inflammation

Excavatoids O and P, New 12-Hydroxybriaranes from the Octocoral Briareum excavatum

Two new 12-hydroxybriarane diterpenoids, designated as excavatoids O (1) and P (2), were isolated from the octocoral Briareum excavatum. The structures of briaranes 1 and 2 were established on the basis of extensive spectral data analysis. Excavatoid P (2) is the first metabolite which possesses a 6β -chlorine atom in briarane analogues

Toona sinensis

Toona sinensis is one of the most popular vegetarian cuisines in Taiwan and it has been shown to possess antioxidant, antiangiogenic, and anticancer properties. In this study, we investigated the antiatherosclerotic potential of aqueous leaf extracts from Toona sinensis (TS; 25–100 μg/mL) and its major bioactive compound, gallic acid (GA; 5 μg/mL), in LPS-treated rat aortic smooth muscle (A7r5) cells. We found that pretreatment with noncytotoxic concentrations of TS and GA significantly inhibited inflammatory NO and PGE2 production by downregulating their precursors, iNOS and COX-2, respectively, in LPS-treated A7r5 cells. Furthermore, TS and GA inhibited LPS-induced intracellular ROS and their corresponding mediator, p47phox. Notably, TS and GA pretreatment significantly inhibited LPS-induced migration in transwell assays. Gelatin zymography and western blotting demonstrated that treatment with TS and GA suppressed the activity or expression of MMP-9, MMP-2, and t-PA. Additionally, TS and GA significantly inhibited LPS-induced VEGF, PDGF, and VCAM-1 expression. Further investigation revealed that the inhibition of iNOS/COX-2, MMPs, growth factors, and adhesion molecules was associated with the suppression of NF-κB activation and MAPK (ERK1/2, JNK1/2, and p38) phosphorylation. Thus, Toona sinensis may be useful for the prevention of atherosclerosis

Late initiation of renal replacement therapy is associated with worse outcomes in acute kidney injury after major abdominal surgery

Introduction Abdominal surgery is probably associated with more likelihood to cause acute kidney injury (AKI). The aim of this study was to evaluate whether early or late start of renal replacement therapy (RRT) defined by simplified RIFLE (sRIFLE) classification in AKI patients after major abdominal surgery will affect outcome. Methods A multicenter prospective observational study based on the NSARF ( National Taiwan University Surgical ICU Associated Renal Failure) Study Group database. 98 patients (41 female, mean age 66.4 +/- 13.9 years) who underwent acute RRT according to local indications for post-major abdominal surgery AKI between 1 January, 2002 and 31 December, 2005 were enrolled The demographic data, comorbid diseases, types of surgery and RRT, as well as the indications for RRT were documented. The patients were divided into early dialysis (sRIFLE-0 or Risk) and late dialysis (LD, sRIFLE -Injury or Failure) groups. Then we measured and recorded patients' outcome including in-hospital mortality and RRT wean-off until 30 June, 2006. Results The in-hospital mortality was compared as endpoint. Fifty-seven patients (58.2%) died during hospitalization. LD (hazard ratio (HR) 1.846; P = 0.027), old age (HR 2.090; P = 0.010), cardiac failure (HR 4.620; P < 0.001), pre-RRT SOFA score (HR 1.152; P < 0.001) were independent indicators for in-hospital mortality. Conclusions The findings of this study support earlier initiation of acute RRT, and also underscore the importance of predicting prognoses of major abdominal surgical patients with AKI by using RIFLE classification