Diabetes Primes Neutrophils for Neutrophil Extracellular Trap Formation through Trained Immunity.

Neutrophils are primed for neutrophil extracellular trap (NET) formation during diabetes, and excessive NET formation from primed neutrophils compromises wound healing in patients with diabetes. Here, we demonstrate that trained immunity mediates diabetes-induced NET priming in neutrophils. Under diabetic conditions, neutrophils exhibit robust metabolic reprogramming comprising enhanced glycolysis via the pentose phosphate pathway and fatty acid oxidation, which result in the accumulation of acetyl-coenzyme A. Adenosine 5'-triphosphate-citrate lyase-mediated accumulation of acetyl-coenzyme A and histone acetyltransferases further induce the acetylation of lysine residues on histone 3 (AcH3K9, AcH3K14, and AcH3K27) and histone 4 (AcH4K8). The pharmacological inhibition of adenosine 5'-triphosphate-citrate lyase and histone acetyltransferases completely inhibited high-glucose-induced NET priming. The trained immunity of neutrophils was further confirmed in neutrophils isolated from patients with diabetes. Our findings suggest that trained immunity mediates functional changes in neutrophils in diabetic environments, and targeting neutrophil-trained immunity may be a potential therapeutic target for controlling inflammatory complications of diabetes.

Design of PD-L1-Targeted Lipid Nanoparticles to Turn on PTEN for Efficient Cancer Therapy.

Lipid nanoparticles (LNPs) exhibit remarkable mRNA delivery efficiency, yet their majority accumulate in the liver or spleen after injection. Tissue-specific mRNA delivery can be achieved through modulating LNP properties, such as tuning PEGylation or varying lipid components systematically. In this paper, a streamlined method is used for incorporating tumor-targeting peptides into the LNPs; the programmed death ligand 1 (PD-L1) binding peptides are conjugated to PEGylated lipids via a copper-free click reaction, and directly incorporated into the LNP composition (Pep LNPs). Notably, Pep LNPs display robust interaction with PD-L1 proteins, which leads to the uptake of LNPs into PD-L1 overexpressing cancer cells both in vitro and in vivo. To evaluate anticancer immunotherapy mediated by restoring tumor suppressor, mRNA encoding phosphatase and tensin homolog (PTEN) is delivered via Pep LNPs to PTEN-deficient triple-negative breast cancers (TNBCs). Pep LNPs loaded with PTEN mRNA specifically promotes autophagy-mediated immunogenic cell death in 4T1 tumors, resulting in effective anticancer immune responses. This study highlights the potential of tumor-targeted LNPs for mRNA-based cancer therapy.

Association between toothbrushing and cardiovascular risk factors: a cross-sectional study using Korean National Health and Nutrition Examination Survey 2015-2017.

BACKGROUND: Previous studies have suggested that frequent toothbrushing is associated with a lower risk of future cardiovascular events. We sought to investigate further the relationship between toothbrushing, cardiovascular risk factors, and lifestyle behaviours. METHODS: We analysed a cross-sectional survey including 13,761 adults aged 30 years or older without a history of cardiovascular diseases from the Korean National Health and Nutritional Examination Survey. Conventional cardiovascular risk factors (blood pressure, lipid profiles, and fasting glucose), and inflammatory markers (high-sensitivity C-reactive protein [hsCRP], and white blood cell counts [WBC]) were investigated in relation to the frequency of toothbrushing. RESULTS: The estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk, calculated using the pooled cohort equations was 13.7%, 9.1%, and 7.3% for participants who reported toothbrushing 0-1, 2, and ≥ 3 times a day, respectively. Both conventional risk factors and inflammatory markers were significantly associated with frequent toothbrushing. However, after adjusting potential confounding factors such as age, sex, comorbidities, and lifestyle behaviours, only inflammatory markers were remained as significant factors. CONCLUSIONS: Oral hygiene behaviours are closely linked to cardiovascular risk factors. This study suggests that reduced systemic inflammatory burden may explain the benefit of improved oral hygiene in terms of cardiovascular risk.

Oral TNF-α siRNA delivery via milk-derived exosomes for effective treatment of inflammatory bowel disease.

Oral administration facilitates the direct delivery of drugs to lesions within the small intestine and colon, making it an ideal approach for treating patients with inflammatory bowel disease. However, multiple physical barriers impede the delivery of oral RNA drugs through the gastrointestinal tract. Herein, we developed a novel oral siRNA delivery system that protects nucleic acids in extreme environments by employing exosomes derived from milk to encapsulate tumor necrosis factor-alpha (TNF-α) siRNA completely. The remarkable structural stability of milk-derived exosomes (M-Exos), as opposed to those from HEK293T cells, makes them exceptional siRNA carriers. Results demonstrate that milk exosomes loaded with TNF-α siRNA (M-Exo/siR) can effectively inhibit the expression of TNF-α-related inflammatory cytokines. Moreover, given that milk exosomes are composed of unique lipids with high bioavailability, orally administered M-Exo/siR effectively reach colonic tissues, leading to decreased TNF-α expression and successful alleviation of colitis symptoms in a dextran sulfate sodium-induced inflammatory bowel disease murine model. Hence, milk-derived exosomes carrying TNF-α siRNA can be effectively employed to treat inflammatory bowel disease. Indeed, using exosomes naturally derived from milk may shift the current paradigm of oral gene delivery, including siRNA.

Prognostic Implication of Platelet Reactivity According to Left Ventricular Systolic Dysfunction Status in Patients Treated With Drug-Eluting Stent Implantation: Analysis of the PTRG-DES Consortium.

BACKGROUND: Coronary artery disease patients undergoing percutaneous coronary intervention (PCI) often exhibit reduced left ventricular ejection fraction (LVEF). However, the impact of LV dysfunction status in conjunction with platelet reactivity on clinical outcomes has not been previously investigated. METHODS: From the multicenter PTRG-DES (Platelet function and genoType-Related long-term prognosis in DES-treated patients) consortium, the patients were classified as preserved-EF (PEF: LVEF ≥ 50%) and reduced-EF (REF: LVEF< 5 0%) group by echocardiography. Platelet reactivity was measured using VerifyNow P2Y12 assay and high platelet reactivity (HPR) was defined as PRU ≥ 252. The major adverse cardiac and cerebrovascular events (MACCEs) were a composite of death, myocardial infarction, stent thrombosis and stroke at 5 years after PCI. Major bleeding was defined as Bleeding Academic Research Consortium bleeding types 3-5. RESULTS: A total of 13,160 patients from PTRG-DES, 9,319 (79.6%) patients with the results of both PRU and LVEF were analyzed. The incidence of MACCE and major bleeding was higher in REF group as compared with PEF group (MACCEs: hazard ratio [HR] 2.17, P < 0.001, 95% confidence interval [CI] 1.85-2.55; major bleeding: HR 1.78, P < 0.001, 95% CI 1.39-2.78). The highest rate of MACCEs was found in patients with REF and HPR, and the difference between the groups was statistically significant (HR 3.14 in REF(+)/HPR(+) vs. PEF(+)/HPR(-) group, P < 0.01, 95% CI 2.51-3.91). The frequency of major bleeding was not associated with the HPR in either group. CONCLUSION: LV dysfunction was associated with an increased incidence of MACCEs and major bleeding in patients who underwent PCI. The HPR status further exhibited significant increase of MACCEs in patients with LV dysfunction in a large, real-world registry. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04734028.

Psychometric Properties of the Advance Care Planning Engagement Survey-9 in Cardiovascular and Metabolic Diseases.

The purpose of this study was to test the reliability and validity of the Advance Care Planning Engagement Survey-9 Korean version in patients with cardiovascular diseases or metabolic syndrome. In this cross-sectional study, data on advance care planning engagement, registration of advance directives and the intention, and sociodemographic characteristics were collected from 105 patients (mean age, 66.3 years) at 4 medical institutions. Cronbach α was used to test the reliability. Confirmatory factor analysis and independent t tests were used to test the validity. Cronbach α s for the total scale and the self-efficacy and readiness dimensions were .93, .82, and .97, respectively. In confirmatory factor analysis with 2 factors, all indices of model fit were acceptable: comparative fit index, 0.995; Tucker-Lewis index, 0.989; standardized root-mean-square residual, 0.024; root-mean-square error of approximation, 0.059; and factor loadings > 0.65. Patients who registered advance directives ( P < .001) or had the intention ( P < .001) had higher scores of the Advance Care Planning Engagement Survey-9 Korean version than their counterparts. The findings demonstrate that the Advance Care Planning Engagement Survey-9 Korean version was a reliable and valid instrument. Health care providers, including nurses, can use this instrument to assess and manage advance care planning engagement in Korean patients with cardiovascular diseases or metabolic syndrome.

Machine learning for predicting hepatitis B or C virus infection in diabetic patients.

Highly prevalent hepatitis B and hepatitis C virus (HBV and HCV) infections have been reported among individuals with diabetes. Given the frequently asymptomatic nature of hepatitis and the challenges associated with screening in some vulnerable populations such as diabetes patients, we conducted an investigation into the performance of various machine learning models for the identification of hepatitis in diabetic patients while also evaluating the significance of features. Analyzing NHANES data from 2013 to 2018, machine learning models were evaluated; random forest (RF), support vector machine (SVM), eXtreme Gradient Boosting (XGBoost), and least absolute shrinkage and selection operator (LASSO) along with stacked ensemble model. We performed hyperparameter tuning to improve the performance of the model, and selected important predictors using the best performance model. LASSO showed the highest predictive performance (AUC-ROC = 0.810) rather than other models. Illicit drug use, poverty, and race were highly ranked as predictive factors for developing hepatitis in diabetes patients. Our study demonstrated that a machine-learning-based model performed optimally in the detection of hepatitis among diabetes patients, achieving high performance. Furthermore, models and predictors evaluated from the current study, we expect, could be supportive information for developing screening or treatment methods for hepatitis care in diabetes patients.

Post-insertion technique to introduce targeting moieties in milk exosomes for targeted drug delivery.

BACKGROUND: Recently, increased attention has been given on exosomes as ideal nanocarriers of drugs owing to their intrinsic properties that facilitate the transport of biomolecular cargos. However, large-scale exosome production remains a major challenge in the clinical application of exosome-based drug delivery systems. Considering its biocompatibility and stability, bovine milk is a suitable natural source for large-scale and stable exosome production. Because the active-targeting ability of drug carriers is essential to maximize therapeutic efficacy and minimize side effects, precise membrane functionalization strategies are required to enable tissue-specific delivery of milk exosomes with difficulty in post-isolation modification. METHODS: In this study, the membrane functionalization of a milk exosome platform modified using a simple post-insertion method was examined comprehensively. Exosomes were engineered from bovine milk (mExo) with surface-tunable modifications for the delivery of tumor-targeting doxorubicin (Dox). The surface modification of mExo was achieved through the hydrophobic insertion of folate (FA)-conjugated lipids. RESULTS: We have confirmed the stable integration of functionalized PE-lipid chains into the mExo membrane through an optimized post-insertion technique, thereby effectively enhancing the surface functionality of mExo. Indeed, the results revealed that FA-modified mExo (mExo-FA) improved cellular uptake in cancer cells via FA receptor (FR)-mediated endocytosis. The designed mExo-FA selectively delivered Dox to FR-positive tumor cells and triggered notable tumor cell death, as confirmed by in vitro and in vivo analyses. CONCLUSIONS: This simple and easy method for post-isolation modification of the exosomal surface may be used to develop milk-exosome-based drug delivery systems.

Design of siRNA Bioconjugates for Efficient Control of Cancer-Associated Membrane Receptors.

Research on siRNA delivery has seen tremendous growth over the past few decades. As one of the major delivery strategies, siRNA bioconjugates offer the potential to enhance and extend the pharmacological properties of siRNAs while minimizing toxicity. In this paper, we suggest the development of a siRNA conjugate platform with peptides and proteins that are ligands of target receptors for cancer treatment. The siRNA bioconjugates target and block the receptor membrane proteins, enter the cells through receptor-mediated endocytosis, and inhibit the expression of that same target membrane receptor, thereby doubly controlling the function of the membrane proteins. The three kinds of bioconjugates targeting CD47, PD-L1, and EGFR were synthesized via two different copper-free click chemistry reactions. Results showed the cellular uptake of each conjugate, reduction of target gene expression, and efficient functional control of receptor proteins. This platform provides an effective approach for regulating membrane proteins in various diseases beyond cancer.

Structural Relationships Between Cognitive Function, Depressive Symptoms, Self-Care Confidence, and Maintenance in Patients With Heart Failure.

Introduction: In order to promote self-care maintenance behavior in patients with heart failure (HF), it is necessary to identify the direct and indirect effects of major latent variables. Objective: This study aimed to identify structural relationships between different domains of cognitive function, depression and self-care confidence, and self-care maintenance. Methods: This descriptive study involved a secondary analysis using data of 201 patients with HF from two observational studies in three hospitals in Korea. The structural equation model using AMOS version 24.0 was constructed to assess the relationships among the variables. The Seoul Neuropsychological Screening Battery was used to assess global cognition, immediate/delayed memory, and executive function, and the Self-Care of HF Index v.6.2. was used for self-care confidence and maintenance. Results: Self-care maintenance was affected by memory function with a significant direct effect (ß=.43, p = .006), as well as self-care confidence (ß=.70, p < .001). Memory function and global function indirectly affected self-care maintenance through self-care confidence (ß = -.37, p = .002; ß = .14, p = .030). Depressive symptoms also had an indirect effect through self-care confidence on self-care maintenance (ß = -.21, p = .005). Conclusion: This study confirmed that it is important to increase self-care confidence through supportive care and to maintain memory function for maintaining self-care in the chronic course of HF patients. In particular, this study suggests that it is necessary to perform periodic memory check-ups for chronic HF patients on an outpatient basis, and counseling and education are needed to improve memory and increase confidence in self-care.

Diagnostic Value of a Wearable Continuous Electrocardiogram Monitoring Device (AT-Patch) for New-Onset Atrial Fibrillation in High-Risk Patients: Prospective Cohort Study.

BACKGROUND: While conventional electrocardiogram monitoring devices are useful for detecting atrial fibrillation, they have considerable drawbacks, including a short monitoring duration and invasive device implantation. The use of patch-type devices circumvents these drawbacks and has shown comparable diagnostic capability for the early detection of atrial fibrillation. OBJECTIVE: We aimed to determine whether a patch-type device (AT-Patch) applied to patients with a high risk of new-onset atrial fibrillation defined by the congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke, vascular disease, age 65-74 years, sex scale (CHA2DS2-VASc) score had increased detection rates. METHODS: In this nonrandomized multicenter prospective cohort study, we enrolled 320 adults aged ≥19 years who had never experienced atrial fibrillation and whose CHA2DS2-VASc score was ≥2. The AT-Patch was attached to each individual for 11 days, and the data were analyzed for arrhythmic events by 2 independent cardiologists. RESULTS: Atrial fibrillation was detected by the AT-Patch in 3.4% (11/320) of patients, as diagnosed by both cardiologists. Interestingly, when participants with or without atrial fibrillation were compared, a previous history of heart failure was significantly more common in the atrial fibrillation group (n=4/11, 36.4% vs n=16/309, 5.2%, respectively; P=.003). When a CHA2DS2-VASc score ≥4 was combined with previous heart failure, the detection rate was significantly increased to 24.4%. Comparison of the recorded electrocardiogram data revealed that supraventricular and ventricular ectopic rhythms were significantly more frequent in the new-onset atrial fibrillation group compared with nonatrial fibrillation group (3.4% vs 0.4%; P=.001 and 5.2% vs 1.2%; P<.001), respectively. CONCLUSIONS: This study detected a moderate number of new-onset atrial fibrillations in high-risk patients using the AT-Patch device. Further studies will aim to investigate the value of early detection of atrial fibrillation, particularly in patients with heart failure as a means of reducing adverse clinical outcomes of atrial fibrillation. TRIAL REGISTRATION: ClinicalTrials.gov NCT04857268; https://classic.clinicaltrials.gov/ct2/show/NCT04857268.

Performance of a Novel CT-Derived Fractional Flow Reserve Measurement to Detect Hemodynamically Significant Coronary Stenosis.

BACKGROUND: Fractional flow reserve (FFR) based on computed tomography (CT) has been shown to better identify ischemia-causing coronary stenosis. However, this current technology requires high computational power, which inhibits its widespread implementation in clinical practice. This prospective, multicenter study aimed at validating the diagnostic performance of a novel simple CT based fractional flow reserve (CT-FFR) calculation method in patients with coronary artery disease. METHODS: Patients who underwent coronary CT angiography (CCTA) within 90 days and invasive coronary angiography (ICA) were prospectively enrolled. A hemodynamically significant lesion was defined as an FFR ≤ 0.80, and the area under the receiver operating characteristic curve (AUC) was the primary measure. After the planned analysis for the initial algorithm A, we performed another set of exploratory analyses for an improved algorithm B. RESULTS: Of 184 patients who agreed to participate in the study, 151 were finally analyzed. Hemodynamically significant lesions were observed in 79 patients (52.3%). The AUC was 0.71 (95% confidence interval [CI], 0.63-0.80) for CCTA, 0.65 (95% CI, 0.56-0.74) for CT-FFR algorithm A (P = 0.866), and 0.78 (95% CI, 0.70-0.86) for algorithm B (P = 0.112). Diagnostic accuracy was 0.63 (0.55-0.71) for CCTA alone, 0.66 (0.58-0.74) for algorithm A, and 0.76 (0.68-0.82) for algorithm B. CONCLUSION: This study suggests the feasibility of automated CT-FFR, which can be performed on-site within several hours. However, the diagnostic performance of the current algorithm does not meet the a priori criteria for superiority. Future research is required to improve the accuracy.

Impact of dementia and drug compliance on patients with acute myocardial infarction.

BACKGROUND: In South Korea, the number of people with dementia is rising at a worrisome rate, and many of them also have acute myocardial infarction (AMI), a disease with a high mortality rate. HYPOTHESIS: We speculated that dementia and drug compliance have significant impact on the mortality of patients with AMI. METHODS: The study derived data from the National Health Insurance Service-Senior for a retrospective cohort study. The total number of patients diagnosed with AMI for the first time between 2007 and 2013 was 16 835, among whom 2021 had dementia. Medication possession ratio (MPR) was used to assess medication adherence. RESULTS: AMI patients with dementia had unfavorable baseline characteristics; they had significantly higher risk of all-cause mortality (hazard ratio [HR]: 2.49; 95% confidence interval [CI]: 2.34-2.66; p < .001) and lower MPR (aspirin: 21.9% vs. 42.8%; p < .001). AMI patients were stratified by presence of dementia and medication adherence, and the survival rate was the highest among those with no dementia and good adherence, followed by those with no dementia and poor adherence, those with dementia and good adherence, and those with dementia and poor adherence. The multivariable analysis revealed that dementia (HR: 1.64; 95% CI: 1.53-1.75; p < .001) and poor adherence to medication (HR: 1.60; 95% CI: 1.49-1.71; p < .001) had a significant association with all-cause mortality in AMI patients. CONCLUSIONS: AMI patients with dementia have a higher mortality rate. Their prognosis is negatively affected by their poorer medication adherence than patients without dementia.

Immune checkpoint-targeted drug conjugates: A promising tool for remodeling tumor immune microenvironment.

Immune checkpoint blockade (ICB) therapy has shown remarkable outcomes along with multiple cases of complete regression in clinical practice. But unfortunately, most patients who have an immunosuppressive tumor immune microenvironment (TIME) respond poorly to these therapies. To improve the response rate of the patients, various treatment modalities that can boost cancer immunogenicity and remove immune tolerance have been combined with ICB therapies. However, the systemic administration of multiple immunotherapeutic agents can potentially cause severe off-target toxicities and immune-related adverse events, diminishing antitumor immunity and increasing the risk of additional complications. To address these problems, Immune Checkpoint-Targeted Drug Conjugates (IDCs) have been widely investigated for their ability to offer distinct advantages in remodeling the TIME for cancer immunotherapy. IDCs, consisting of immune checkpoint-targeting moieties, cleavable linkers, and payloads of immunotherapeutic agents, have a similar structure to conventional antibody-drug conjugates (ADCs) but target and block the immune checkpoint receptors, and then release the payloads conjugated through cleavable linkers. These unique mechanisms of IDCs prompt an immune-responsive TIME by modulating the multiple steps related to the cancer-immunity cycle, ultimately leading to tumor eradication. This review outlines the mode of action and advantages of IDCs. In addition, various IDCs for combinational immunotherapy are reviewed. Finally, the potential and challenges of IDCs for clinical translation are discussed.

Accuracy of Artificial Intelligence-Based Automated Quantitative Coronary Angiography Compared to Intravascular Ultrasound: Retrospective Cohort Study.

BACKGROUND: An accurate quantitative analysis of coronary artery stenotic lesions is essential to make optimal clinical decisions. Recent advances in computer vision and machine learning technology have enabled the automated analysis of coronary angiography. OBJECTIVE: The aim of this paper is to validate the performance of artificial intelligence-based quantitative coronary angiography (AI-QCA) in comparison with that of intravascular ultrasound (IVUS). METHODS: This retrospective study included patients who underwent IVUS-guided coronary intervention at a single tertiary center in Korea. Proximal and distal reference areas, minimal luminal area, percent plaque burden, and lesion length were measured by AI-QCA and human experts using IVUS. First, fully automated QCA analysis was compared with IVUS analysis. Next, we adjusted the proximal and distal margins of AI-QCA to avoid geographic mismatch. Scatter plots, Pearson correlation coefficients, and Bland-Altman were used to analyze the data. RESULTS: A total of 54 significant lesions were analyzed in 47 patients. The proximal and distal reference areas, as well as the minimal luminal area, showed moderate to strong correlation between the 2 modalities (correlation coefficients of 0.57, 0.80, and 0.52, respectively; P<.001). The correlation was weaker for percent area stenosis and lesion length, although statistically significant (correlation coefficients of 0.29 and 0.33, respectively). AI-QCA tended to measure reference vessel areas smaller and lesion lengths shorter than IVUS did. Systemic proportional bias was not observed in Bland-Altman plots. The biggest cause of bias originated from the geographic mismatch of AI-QCA with IVUS. Discrepancies in the proximal or distal lesion margins were observed between the 2 modalities, which were more frequent at the distal margins. After the adjustment of proximal or distal margins, there was a stronger correlation of proximal and distal reference areas between AI-QCA and IVUS (correlation coefficients of 0.70 and 0.83, respectively). CONCLUSIONS: AI-QCA showed a moderate to strong correlation compared with IVUS in analyzing coronary lesions with significant stenosis. The main discrepancy was in the perception of the distal margins by AI-QCA, and the correction of margins improved the correlation coefficients. We believe that this novel tool could provide confidence to treating physicians and help in making optimal clinical decisions.

Exosome-guided direct reprogramming of tumor-associated macrophages from protumorigenic to antitumorigenic to fight cancer.

Highly immunosuppressive tumor microenvironment containing various protumoral immune cells accelerates malignant transformation and treatment resistance. In particular, tumor-associated macrophages (TAMs), as the predominant infiltrated immune cells in a tumor, play a pivotal role in regulating the immunosuppressive tumor microenvironment. As a potential therapeutic strategy to counteract TAMs, here we explore an exosome-guided in situ direct reprogramming of tumor-supportive M2-polarized TAMs into tumor-attacking M1-type macrophages. Exosomes derived from M1-type macrophages (M1-Exo) promote a phenotypic switch from anti-inflammatory M2-like TAMs toward pro-inflammatory M1-type macrophages with high conversion efficiency. Reprogrammed M1 macrophages possessing protein-expression profiles similar to those of classically activated M1 macrophages display significantly increased phagocytic function and robust cross-presentation ability, potentiating antitumor immunity surrounding the tumor. Strikingly, these M1-Exo also lead to the conversion of human patient-derived TAMs into M1-like macrophages that highly express MHC class II, offering the clinical potential of autologous and allogeneic exosome-guided direct TAM reprogramming for arming macrophages to join the fight against cancer.

Hepatitis Risk in Diabetes Compared to Non-Diabetes and Relevant Factors: A Cross-Sectional Study with National Health and Nutrition Examination Survey (NHANES), 2013-2018.

This study aimed to identify the development of hepatitis B or C infection in diabetes patients compared to those without and to elucidate factors associated with the prevalence of hepatitis B or C infection in diabetes. We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES) 2013-2018. As evaluation factors, we included variables such as age, race, illicit drug use, and poverty. The diabetic group had a significantly higher prevalence of hepatitis B or C infection than the non-diabetic group (odds ratio (OR) = 1.73; 95% confidence interval (CI), 1.36-2.21, p < 0.01). In multivariate Cox regression, non-poverty and non-illicit drug use were lower risk factors contributing to hepatitis development in diabetes (hazard ratio (HR) = 0.50; 95% CI, 0.32-0.79, p < 0.01, and HR = 0.05; 95% CI, 0.03-0.08, p < 0.01, respectively). Logistic regression also showed that these factors were significant contributors to hepatitis development in the diabetic group (p < 0.01). In patients with diabetes, the development of hepatitis was higher than that in those without, and hepatitis development was influenced by poverty and illicit drug use. This may provide supporting evidence of response strategies for diabetes to care for hepatitis development in advance.

Market potential and value-added opportunities of cold-hardy berries and small fruits in the Intermountain West, USA.

Novel cold-hardy berries and small fruits represent an opportunity for growers in the Intermountain West, USA, as the harsh environment is not suited for other common berries and small fruits. This study analyzed the fresh market and value-added potential of haskap berries (Lonicera caerulea), saskatoon berries (Amelenchier alnifolia), and dwarf sour cherry (DSC) fruit (Prunus x kerrasis) by instrumental and consumer studies. Fresh and 2-week stored haskap (cv. Aurora), saskatoon (Lee 3), and DSC (Romeo) were measured for fruit weight, flesh firmness, bulk titratable acidity, pH, and soluble solid content. Participants (n = 115) in at-home sensory tests scored these fruits for overall liking (OL, 9-point hedonic scale), purchase intent (PI, 5-point scale), and willingness-to-pay (WTP, 5-point scale). Ten participants further shared insight on these fruits in focus groups. Instrumental testing found a significant decrease in flesh firmness for 2-week stored haskap, but the consumers' OL was still comparable to fresh haskap. The fresh and 2-week stored haskap received significantly higher OL, PI, and WTP scores (7.7 ± 1.0, 3.8 ± 1.0, and $3.7 ± 1.0; 7.7 ± 1.2, 3.8 ± 1.1, and $3.7 ± 1.0, respectively) compared to saskatoon (6.1 ± 1.8, 2.8 ± 1.1, and $3.0 ± 0.9, respectively) and DSC (5.6 ± 2.2, 2.5 ± 1.2, and $3.1 ± 1.0, respectively) (α = 0.05). The focus groups indicated that participants want to support local produce. The participants expressed interest in fresh unprocessed haskap berries, but preferred saskatoon and DSC in different value-added formats. Hence, this study concluded that there is an untapped fresh-market potential for haskap berries and there are value-added opportunities to extend the sale season and improve the palatability of saskatoon and DSC. PRACTICAL APPLICATION: This research has examined consumer perception of three species of novel small fruits by determining fresh-market potential and linking this to the opportunity for value-added product development. For haskap berries, the study not only indicated fresh market potential, but for the cultivar Aurora, consumer liking was not meaningfully altered by 2 weeks of cold storage. These results are meaningful because they will assist growers in the Intermountain West with market planning, including the possibility of formulating products that utilize these novel crops. This study provides growers the opportunity to diversify their income stream by utilizing local produce.

BioMatrix Versus Orsiro Stents for Coronary Artery Disease: A Multicenter, Randomized, Open-Label Study.

BACKGROUND: Comparative studies of ultrathin-strut biodegradable polymer sirolimus-eluting stent (BP-SES) have reported promising results and validated its excellent outcomes in terms of safety and efficacy. However, there are limited studies comparing BP drug-eluting stents with struts of different thicknesses. We compared the long-term clinical outcomes of patients treated with an ultrathin-strut BP-SES or a thick-strut biodegradable polymer biolimus-eluting stent (BP-BES). METHODS: The BIODEGRADE trial (Biomatrix and Orsiro Drug-Eluting Stents in Angiographic Result in Patients With Coronary Artery Disease) is a multicenter prospective randomized study comparing coronary revascularization in patients with ultrathin-strut BP-SES and thick-strut BP-BES with the primary end point of target lesion failure at 18 months posttreatment. We performed the prespecified analysis of 3-year clinical outcomes. RESULTS: In total, 2341 patients were randomized to receive treatment with ultrathin-strut BP-SES (N=1175) or thick-strut BP-BES (N=1166). The 3-year incidence rate of target lesion failure was 3.2% for BP-SES and 5.1% for BP-BES (P=0.023). The difference was primarily due to differences in ischemia-driven target lesion revascularization (BP-SES, 1.5%; BP-BES, 2.8%; P=0.035) between groups. A landmark analysis of the late follow-up period showed significant differences in target lesion failure, with outcomes being better in BP-SES. Cardiac death and target lesion revascularization were significantly lower in the BP-SES group. CONCLUSIONS: In a large, randomized trial, the long-term clinical outcome of target lesion failure at 3 years was significantly better among patients treated with the ultrathin-strut BP-SES. The results indicate the superiority of the ultrathin-strut BP-SES compared with the thick-strut BP-BES. REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT02299011.