Erythropoietin therapy improves endothelial function in patients with non-dialysis chronic kidney disease and anemia (EARNEST-CKD): A clinical study

Background:This study investigated whether administering erythropoiesis-stimulating agents (ESAs) improves endothelial function in patients with non-dialysis chronic kidney disease (CKD) and anemia.Methods:This single-center, prospective, single-arm comparison study enrolled patients with non-dialysis CKD (stages 4-5) and hemoglobin levels <10 g/dL. ESA administration followed the Kidney Disease: Improving Global Outcomes guideline. The primary endpoint was the change in flow-mediated dilatation after ESA administration in individual patients. The secondary endpoints were changes in 6-minute walk test results, blood pressure, New York Heart Association class, and echocardiographic parameters. The echocardiographic parameters examined included chamber quantification, Doppler parameters, and systolic and diastolic function parameters.Results:Initially, 13 patients were screened, but 2 discontinued due to either heart failure or voluntary withdrawal. The mean flow-mediated dilatation values significantly increased by 10.59% (from 1.36% ± 1.91% to 11.95% ± 8.11%, P = .001). Echocardiographic findings showed that the left ventricular mass index decreased by 11.9 g/m² (from 105.8 ± 16.3 to 93.9 ± 19.5 g/m², P = .006), and the left atrial volume index decreased by 10.8 mL/m² (from 50.1 ± 11.3 to 39.3 ± 11.3 mL/m², P = .004) after 12 weeks of ESA administration. There were no significant differences between pre- and post-ESA treatment 6-minute walk test results. No significant side effects were observed during the study period.Conclusions:This is the first clinical study to demonstrate that an ESA improves endothelial dysfunction, left ventricular hypertrophy, and left atrial volume in patients with non-dialysis CKD. Thus, ESAs may be considered as adjunctive therapy for reducing cardiovascular risk in these patients.     

Change in the Recurrence Pattern and Predictors over Time after Complete Cure of Hepatocellular Carcinoma

Background/AimsWe investigated changes in recurrence rates and significant recurrence predictors over time after complete cure of hepatocellular carcinoma (HCC).MethodsA total of 1,491 patients with first-time diagnosis of Barcelona Clinic Liver Cancer stage A HCC, completely cured by treatment between 2007 and 2016, were recruited from two Korean tertiary institutes.ResultsThe mean age of the population (1,144 men and 347 women) was 58.6 years. Of the total population, 914 patients (61.3%) had liver cirrhosis. Nine-hundred and forty-one (63.1%) and 550 (36.9%) patients were treated with surgical resection and radiofrequency ablation (RFA), respectively. One-year cumulative incidences of HCC recurrence were 14.3%, 9.9%, and 5.1% from the time of treatment, 3 years after treatment, and 5 years after treatment, respectively. Upon multivariate analysis, multiple tumors, maximal tumor size ≥3 cm, and high Model for End-Stage Liver Disease scores were independently associated with increased HCC recurrence risk from the time of treatment and 1 and 2 years after curative treatment (all p<0.05, except for maximal tumor size ≥3 cm for recurrence 2 years after treatment). Meanwhile, liver cirrhosis and RFA were independently associated with the increased HCC recurrence risk for almost all time points (liver cirrhosis all p<0.05; RFA all p<0.005 except for recurrence from 5 years after treatment).ConclusionsThe recurrence rate of HCC after curative treatment gradually decreased over time. Two years after treatment, when tumor-related factors lose their prognostic implications, may be used as a cutoff to define the boundary between early and late recurrence of HCC. (Gut Liver 2021;15-429)     

Development of a clinical risk score for incident diabetes: A 10-year prospective cohort study

Aims/IntroductionWe developed a self‐assessable Korean Diabetes Risk score using the data of the Korean Genome and Epidemiology Study.Materials and MethodsA total of 8,740 participants without diabetes at baseline were followed up biannually over a period of 10 years. We included variables that were significantly different between participants who developed diabetes mellitus and those who did not in the development cohort at baseline. We assigned a maximum score of 100 to the selected variable in each gender group. Next, the 10‐year probability of incident diabetes was calculated and validated in the validation cohort. Finally, we compared the predictive power of Korean Diabetes Risk score with models including fasting plasma glucose or glycated hemoglobin and other cohort models of Atherosclerosis Risk in Communities and Korea National Health and Nutrition Examination Survey.ResultsDuring a median follow‐up period of 9.7 years, 22.7% of the participants progressed to diabetes. The Korean Diabetes Risk score included age, living location (urban or rural area), waist circumference, hypertension, family history of diabetes and smoking history. The developed risk score yielded acceptable discrimination for incident diabetes (area under the curve 0.657) and the predictive power was improved when the model included fasting plasma glucose (area under the curve 0.690) or glycated hemoglobin (area under the curve 0.746). In addition, our model predicted incident diabetes more accurately than previous Western or Korean models.ConclusionsThis newly developed self‐assessable diabetes risk score is easily applicable to predict the future risk of diabetes even without the necessity for laboratory tests. This score is useful for the Korean diabetes prevention program, because high‐risk individuals can be easily screened.     

Antibacterial Activity of Propolis-Embedded Zeolite Nanocomposites for Implant Application

This study investigates the potential of propolis-embedded zeolite nanocomposites for dental implant application. Propolis-embedded zeolite nanocomposites were fabricated by complexation of propolis and zeolites. Then, they were pelleted with Poly(L-lactide) (PLA)/poly(ε-caprolactone) (PCL) polymer for the fabrication of a dental implant. The chemical properties of propolis were not changed during the fabrication of propolis-embedded zeolite nanocomposites in attenuated total reflection-fourier transform infra-red (ATR FT-IR) spectroscopy measurements. Propolis was continuously released from propolis-embedded zeolite nanocomposites over one month. PLA/PCL pellets containing propolis-embedded zeolite nanocomposites showed longer sustained release behavior compared to propolis-embedded zeolite nanocomposites. Propolis-embedded zeolite nanocomposite powder showed similar antibacterial activity against C. albicans in an agar plate and formed an inhibition zone as well as chlorohexidine (CHX) powder. Eluted propolis solution from PLA/PCL pellets also maintained antibacterial activity as well as CHX solution. Furthermore, eluted propolis solution from PLA/PCL pellets showed significant antibacterial efficacy against C. albicans, S. mutans and S. sobrinus. Dental implants fabricated from PLA/PCl polymer and propolis-embedded zeolite nanocomposites also have antibacterial efficacy and negligible cytotoxicity against normal cells. We suggest that PLA/PCl pellets containing propolis-embedded zeolite nanocomposites are promising candidates for dental implants.     

ST-segment elevation versus non-ST-segment elevation myocardial infarction in current smokers after newer-generation drug-eluting stent implantation

We compared the 2-year major clinical outcomes between ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) in patients who are current smokers who underwent successful percutaneous coronary intervention (PCI) with newer-generation drug-eluting stents (DESs). The availability of data in this regard is limited.A total of 8357 AMI patients were included and divided into 2 groups: the STEMI group (n = 5124) and NSTEMI group (n = 3233). The primary endpoint was the occurrence of major adverse cardiac events (MACE), defined as all-cause death, recurrent myocardial infarction (re-MI), or coronary repeat revascularization. The secondary endpoints were the cumulative incidences of the individual components of MACE and stent thrombosis (definite or probable).After propensity score-matched (PSM) analysis, 2 PSM groups (2250 pairs, C-statistics = 0.795) were generated. In the PSM patients, both for 1 month and at 2 years, the cumulative incidence of MACE (P = .183 and P = .655, respectively), all-cause death, cardiac death, re-MI, all-cause death or MI, any repeat revascularization, and stent thrombosis (P = .998 and P = .341, respectively) was not significantly different between the STEMI and NSTEMI groups. In addition, these results were confirmed using multivariate analysis.In the era of contemporary newer-generation DESs, both during 1 month and at 2 years after index PCI, the major clinical outcomes were not significantly different between the STEMI and NSTEMI groups confined to the patients who are current smokers. However, further research is needed to confirm these results.     

Effectiveness and safety of single transseptal ablation for atrial fibrillation in real‐word practice

BackgroundWe have previously reported that unilateral groin‐single transseptal (ST) ablation in patients with paroxysmal atrial fibrillation (AF) was safe and significantly reduced patient discomfort compared with bilateral groin‐double transseptal (DT) ablation.HypothesisIn the present study, we hypothesized that ST ablation would be as effective and safe as DT ablation in real‐world practice like previous study. Among the 1765 consecutive patients in the Yonsei AF ablation cohort from October 2015 to January 2020, 1144 patients who underwent radiofrequency ablation were included for the analysis. Among them, 450 underwent ST ablation and 694 underwent DT ablation.ResultsThe total procedure time, ablation time, and fluoroscopy time were longer in the ST group than in the DT group (p < .05 for all). The hospital stay after catheter ablation was 1.3 ± 1.1 days which was longer in DT group than ST group (p = .001). No significant difference was observed in the complication rate (p = .263) and AF‐free survival rate (log‐rank p = .19) between the groups. However, after excluding patients who used antiarrhythmic drugs when AF recurred, the AF‐free survival rates were lower in the DT group than in the ST group before and after propensity score matching (log‐rank p = .026 and .047, respectively).ConclusionAlthough the ST approach increases the procedure time compared with the DT approach owing to the need for more frequent catheter exchanges, the ST approach is a feasible and safe strategy for AF ablation in terms of rhythm outcomes and risk of complications.     

Correlation between real-time heart rate and fatigue in chest compression providers during cardiopulmonary resuscitation: A simulation-based interventional study

Background:The American Heart Association guidelines recommend switching chest compression providers at least every 2 min depending on their fatigue during cardiopulmonary resuscitation (CPR). Although the provider''s heart rate is widely used as an objective indicator for detecting fatigue, the accuracy of this measure is debatable.Objectives:This study was designed to determine whether real-time heart rate is a measure of fatigue in compression providers.Study design:A simulation-based prospective interventional study including 110 participants.Methods:Participants performed chest compressions in pairs for four cycles using advanced cardiovascular life support simulation. Each participant''s heart rate was measured using wearable healthcare devices, and qualitative variables regarding individual compressions were obtained from computerized devices. The primary outcome was correct depth of chest compressions. The main exposure was the change in heart rate, defined as the difference between the participant''s heart rate during individual compressions and that before the simulation was initiated.Results:With a constant compression duration for one cycle, the overall accuracy of compression depth significantly decreased with increasing heart rate. Female participants displayed significantly decreased accuracy of compression depth with increasing heart rate (odds ratio [OR]: 0.97; 95% confidence interval [CI]: 0.95–0.98; P < .001). Conversely, male participants displayed significantly improved accuracy with increasing heart rate (OR: 1.03; 95% CI: 1.02–1.04; P < .001).Conclusion:Increasing heart rate could reflect fatigue in providers performing chest compressions with a constant duration for one cycle. Thus, provider rotation should be considered according to objectively measured fatigue during CPR.     

Riboflavin instability is a key factor underlying the requirement of a gut microbiota for mosquito development

We previously determined that several diets used to rear Aedes aegypti and other mosquito species support the development of larvae with a gut microbiota but do not support the development of axenic larvae. In contrast, axenic larvae have been shown to develop when fed other diets. To understand the mechanisms underlying this dichotomy, we developed a defined diet that could be manipulated in concert with microbiota composition and environmental conditions. Initial studies showed that axenic larvae could not grow under standard rearing conditions (27 °C, 16-h light: 8-h dark photoperiod) when fed a defined diet but could develop when maintained in darkness. Downstream assays identified riboflavin decay to lumichrome as the key factor that prevented axenic larvae from growing under standard conditions, while gut community members like Escherichia coli rescued development by being able to synthesize riboflavin. Earlier results showed that conventional and gnotobiotic but not axenic larvae exhibit midgut hypoxia under standard rearing conditions, which correlated with activation of several pathways with essential growth functions. In this study, axenic larvae in darkness also exhibited midgut hypoxia and activation of growth signaling but rapidly shifted to midgut normoxia and arrested growth in light, which indicated that gut hypoxia was not due to aerobic respiration by the gut microbiota but did depend on riboflavin that only resident microbes could provide under standard conditions. Overall, our results identify riboflavin provisioning as an essential function for the gut microbiota under most conditions A. aegypti larvae experience in the laboratory and field.

Diet crucially affects the health of all animals (1). Most animals have a gut microbiota that can also affect host health both positively and negatively (2–6). However, understanding of the mechanisms underlying the effects of the gut microbiota remains a major challenge. This is because animals often consume complex or variable diets, and harbor large, multimember microbial communities that can result in many interactions that hinder identification of the factors responsible for particular host responses (2, 6–11). Metaanalyses and multiomic approaches can provide inferential insights on how diet–microbe or microbe–microbe interactions affect hosts (11–18), but functional support can be difficult to generate if proposed mechanisms cannot be studied experimentally (2, 14). Thus, study systems where hosts can be reared on defined diets with or without a microbiota of known composition can significantly advance mechanistic insights by providing the means to control and manipulate dietary, microbial, and environmental variables that potentially affect a given host response (19–21).Mosquitoes are best known as insects that blood feed on humans and other vertebrates. Only adult-stage female mosquitoes blood feed, which is required for egg formation by most species (22). Blood feeding has also led to several mosquitoes evolving into vectors that can transmit disease-causing microbes between hosts (22). In contrast, the juvenile stages of all mosquitoes are aquatic, with most species feeding on detritivorous diets (22–24). Larvae hatch from eggs with no gut microbiota but quickly acquire relatively low-diversity communities from the environment by feeding (25). Most gut community members are aerobic or facultatively anaerobic bacteria in four phyla (Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria), although other microbes, such as fungi and apicomplexans, have also been identified (25–39). Gut community composition also commonly varies within and between species as a function of where larvae develop, diet, and other variables (28–30, 32, 34, 40–42).Aedes aegypti has a worldwide distribution in tropical and subtropical regions, and is the primary vector of the agents that cause yellow fever, dengue fever, and lymphatic filariasis in humans (43). Preferentially living in urban habitats, females lay eggs in water-holding containers with microbial communities, and larvae molt through four instars before pupating and emerging as adults (30, 35, 41, 43). Conventionally reared cultures with a gut microbiota are usually maintained in the laboratory under conditions that mimic natural habitats with rearing temperatures of 25 to 28 °C and a 12- to 16-h light: 8- to 12-h dark photoperiod (44–46). Most insects that require microbial partners for survival live on nutrient-poor diets where microbes provision nutrients that cannot be synthesized or produced in sufficient abundance by the host (3). Mosquito larvae can experience resource limitations in the field (23–25), but in the laboratory are reared on undefined, nutrient-rich diets, such as rodent chow, fish food flakes, or mixtures of materials like liver powder, fish meal, and yeast extract (44–46). Nonetheless, our previous studies indicated that axenic A. aegypti as well as other species consume but fail to grow beyond the first instar when fed several diets that support the development of nonsterile, conventionally reared larvae (30, 47–49). Escherichia coli and several other bacteria identified as gut community members could colonize the gut (producing monoxenic, gnotobiotic larvae) and rescue development, but feeding axenic larvae dead bacteria could not (30, 35, 47). The presence of a gut microbiota in conventional and gnotobiotic but not axenic larvae was also associated with midgut hypoxia and activation of several signaling pathways with growth functions (50, 51). Finally, our own previous results using a strain of E. coli susceptible to ampicillin (50), and more recently a method for clearing an auxotrophic strain of E. coli from gnotobiotic larvae (52), both showed that the proportion of individuals that develop into adults correlates with the duration that larvae have living bacteria in their gut.Altogether, the preceding results suggested that A. aegypti and several other mosquitoes require a gut microbiota for development. In contrast, another recent study showed that axenic A. aegypti larvae develop into adults, albeit more slowly than larvae with a gut microbiota, when fed diets comprised of autoclaved bovine liver powder (LP) and brewer’s yeast (Saccharomyces cerevisiae) extract (YE) or autoclaved LP, YE, and E. coli (EC) embedded in agar (53). This latter finding suggests the undefined dietary components used provide factors larvae require for development into adults, whereas a gut microbiota was also required to provide these factors under the conditions in which our own previous studies were conducted. The goal of this study was to identify what these factors are. Toward this end, we first assessed the growth of axenic A. aegypti when fed diets containing autoclaved LP, YE, and EC under different conditions. We then used this information to develop a defined diet that allowed us to systematically manipulate nutrient, microbial, and environmental variables. We report that the instability of riboflavin is a key factor underlying why A. aegypti larvae require a gut microbiota under most conditions experienced in the laboratory and field.     

Validity of the telephone interview for cognitive status (TICS) and modified TICS (TICSm) for mild cognitive imparment (MCI) and dementia screening

This study aimed to validate the TICS and modified TICS (TICSm) in Korean elderly population and to compare MCI and dementia screening ability between TICS and TICSm. TICS and TICSm were administered to 70 cognitively normal (CN), 75 MCI, and 85 dementia subjects, with mini-mental state examination (MMSE) and other cognitive and functional measures. TICS and TICSm scores were highly correlated with other global cognitive and functional scores. The CN vs. dementia discrimination ability of both instruments was as excellent as that of MMSE (sensitivity/specificity at optimal cutoff: 87.1/90.1 for TICS; 88.2/90.0 for TICSm). Although their CN vs. MCI discrimination performances were comparable to that of MMSE, they were far from perfect (sensitivity/specificity: 69.3/68.6 for TICS; 73.3/67.1 for TICSm). There was no significant difference in dementia or MCI screening accuracy between TICS and TICSm. Both of them also showed high test-retest reliability. Our findings indicate that TICS and TICSm are reliable and as valid as MMSE in regard of screening cognitively impaired elderly. In terms of the comparison between TICSm and TICS, however, TICSm has little advantage over TICS for screening dementia and even MCI, in spite of longer administration time and more efforts required.