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Abstract: Background: Recent evidence suggests that atrial fibrillation (AF) adversely affects endothelial function. The goal of this study was to assess endothelial function in patients with AF before and after restoration of sinus rhythm by catheter ablation (ABL). Methods: Reactive hyperemia peripheral arterial tonometry (RH-PAT) measurements reflecting endothelial function were conducted with Endo-PAT2000 (Itamar Medical, Caesarea, Israel) in 27 patients with persistent AF before ABL and in 21 control subjects with sinus rhythm (SR). According to cardiac rhythm on the morning after ABL, patients were divided into two groups: day 1-restored SR group (n=19) and day 1-recurred AF group (n=8). Based on the cardiac rhythm at 6months after ABL, the restored SR group was further subdivided into the month 6-maintained SR group (n=11) and the month 6-recurred AF group (n=6). Results: Loge RH-PAT index (RHI) was significantly lower in the persistent AF group than in the control (SR) group (0.52±0.20; 0.69±0.24, p<0.01). Multivariate logistic regression analysis revealed that persistent AF was the only independent predictor of impaired endothelial function defined as loge RHI<0.6 (odds ratio, 4.96; 95% CI, 1.2 to 21.3; p<0.05). Loge RHI was significantly higher after ABL than before ABL (0.53±0.20; 0.73±0.25; p<0.01) in the day 1-restored SR group. Loge RHI of the month 6-maintained SR group was comparable to that of the day 1-restored SR group. Conclusions: These results suggest that AF is associated with impairment of endothelial dysfunction and that this impairment is reversed by restoration of sinus rhythm. [Copyright &y& Elsevier]

Objective: Some of the most common causes of chronic cough include cough variant asthma (CVA), bronchial asthma (BA), and asthma–COPD overlap (ACO). Although there is some overlap in the etiology of these diseases, it is clinically important to attempt an early differential diagnosis due to treatment strategies and prognoses. Methods: Spirometry and impulse oscillometry (IOS) before and after bronchodilator inhalation were analyzed for clinically diagnosed CVA (cCVA, n = 203), BA (cBA, n = 222), and ACO (cACO, n = 61). Results: A significant difference in ΔFEV1 was observed between cBA and cCVA (ΔFEV1 improvement of 122.5 mL/5.4% and 65.7 mL/2.2%, respectively), but no difference was observed in ΔPEF, ΔV50, or ΔV25. Except for R20 (resistance at 20 Hz), significant differences between the three groups were observed in IOS. In IOS, cCVA and cBA showed comparable peripheral airway response to bronchodilator which was thought to be commensurate with changes in V50 and V25. cACO improved ΔFEV1 improvement of 81.0 mL/6.2% and was distinguished by a downward respiratory system reactance (Xrs) waveform with a limited bronchodilator response. FEV1/FVC, %FEV1, and %V25 had relatively strong correlations with the three IOS parameters, X5 (reactance at 5 Hz), resonant frequency (Fres), and low-frequency reactance area (ALX), in the correlation between IOS and spirometers. Conclusion: Changes in IOS parameters were more sensitive in this study than changes in FEV1 or the flow-volume curve. Considering the benefits and relevance of the two different tests, simultaneous IOS and spirometry testing were useful in the diagnosis of asthmatic cough. [ABSTRACT FROM AUTHOR]

Background: Osimertinib is a third‐generation epidermal growth factor receptor‐tyrosine kinase inhibitor (EGFR‐TKI) approved for the treatment of patients with EGFR‐mutant non‐small cell lung cancer (NSCLC). However, the mechanisms of acquired drug resistance to osimertinib have not as yet been clarified. Exosomes and microRNAs (miRNAs) are involved in carcinogenesis and drug resistance in human cancers. Methods: We used previously established osimertinib‐resistant HCC827 (HCC827‐OR) and PC‐9 (PC‐9‐OR) cells. We evaluated the profiles of exosomal miRNA associated with resistance to osimertinib in EGFR‐mutant NSCLC cells. Results: Epithelial–mesenchymal transition (EMT) phenomenon was observed in HCC827‐OR and PC‐9‐OR cells. Microarray and quantitative reverse transcription‐polymerase chain reaction analysis revealed that miR‐210‐3p was co‐upregulated in exosomes isolated from HCC827‐OR and PC‐9‐OR cells compared with those isolated from parental HCC827 and PC‐9 cells. HCC827‐OR cell‐derived exosomes induced EMT changes and resistance to osimertinib in HCC827 cells. Subsequently, the induction of miR‐210‐3p directly promoted the EMT phenomenon and resistance to osimertinib in HCC827 cells. Conclusions: Exosomal miR‐210‐3p may play a crucial role in resistance to osimertinib in the tumor microenvironment of EGFR‐mutant NSCLC. [ABSTRACT FROM AUTHOR]

• Childhood varicella patients has declined after implementation of universal two-dose varicella vaccination in Japan. • Sporadic varicella outbreaks in Japan mainly occur in non–universal vaccination targets. • Catch-up immunization for non-universal vaccination targets is needed to control varicella in Japan. To elucidate the trend and clinical spectrum of virologically diagnosed varicella patients after implementation of universal vaccination as a national immunization program in Japan. Study subjects were patients suspected of varicella, less than 15 years of age, who visited 14 pediatric clinics in the Nagoya VZV Study Group from September 2015 to August 2019. Practitioners collected patient samples and information such as backgrounds, clinical symptoms, and previous immunization status. All patients were confirmed as having varicella based on molecular diagnostic assays. Varicella zoster virus (VZV) DNA was detected in swab samples from 506 (83.1%) of the 609 suspected patients. The 455 varicella patients for whom vaccination status was available were divided into two groups: 180 universal vaccination targets and 275 non-targets. Numbers of monthly varicella patients decreased gradually during the observation period. In the 2016/17 season, the seasonal epidemic of varicella became undetectable in the universal vaccination target group, and starting in the 2017/18 season, it was obscured even in the non-target group. The median age of patients was significantly lower in the universal vaccination target group (3 years) than the non-target group (7 years) (P < 0.001). Vaccination status differed significantly between the two groups (P < 0.001). Most varicella patients were in the non-target group, especially those who had been vaccinated once (60.4%). Frequency of fever (P < 0.001) and number of skin rashes at the time of the first hospital visit (P = 0.001) were significantly higher in the non-target group. Although the number of childhood varicella patients declined after implementation of national immunization with two doses of varicella vaccination, sporadic outbreaks still occurred, mainly in the non–universal vaccination target group. Insufficient vaccination of members of this group is likely to be a major reason for small local outbreaks. [ABSTRACT FROM AUTHOR]

• The use of PPIs increase cardiovascular events in patients with hemodialysis. • The use of PPIs link to QTc interval prolongation in patients with hemodialysis. • Bleeding events do not decrease with the use of PPIs in patients with hemodialysis. Proton pump inhibitors (PPIs) are known to increase the risk of mortality and cardiovascular events in the general population. However, in patients with maintenance hemodialysis, PPI effects are under investigated. We analyzed the risk of PPIs for cardiovascular events using the Kagoshima Dialysis (KIDS) registry, a prospective, multicenter, observational study in patients with maintenance hemodialysis in Japan. In all, 531 patients were enrolled from June 2015 to December 2018. One-year follow-up data were available for 376 patients (Use of PPIs at baseline (PPI group): 217 patients and without PPIs (No PPI group): 159 patients). The incidence of a composite outcome (all-cause mortality, non-fatal myocardial infarction, or non-fatal stroke) was higher in patients in the PPI group than the No PPI group (15.2% vs. 4.4%; hazard ratio (HR): 3.65, 95% confidence interval (CI): 1.61–8.23, P = 0.002). In the multivariate analysis, even after adjustment for covariates, the use of PPIs was an independent risk factor for a composite outcome (HR: 2.38, 95% CI: 1.02–5.54, P = 0.045). We performed propensity score matching analysis as a sensitivity analysis, showing a consistent result. The incidence of bleeding showed no difference between the two groups (15.7% vs. 11.3%; HR: 1.46, 95% CI: 0.83–2.59, P = 0.19). These results indicate that the use of PPIs in patients with maintenance hemodialysis might increase mortality and cardiovascular events without decreasing the risk of bleeding. Therefore, it should always be analyzed if a patient truly needs PPIs. [ABSTRACT FROM AUTHOR]

Objective Matched case control study was conducted to elucidate the effectiveness of the Oka/Biken vaccine immediately after implementation of the universal immunization program in Japan. Methods Cases were laboratory confirmed varicella patient under 15 years of age diagnosed at 14 designated pediatric clinics between September 2015 and September 2016. Controls were selected from patients who visited the same practice for different reasons as the varicella case within 2 weeks. Swab samples were collected from varicella suspected patients and molecular diagnostic assays were used to confirm varicella cases. Matched odds ratio were used to calculate vaccine effectiveness (VE). Results Varicella zoster virus DNA was detected in 183 (81.3%) of 225 suspected cases. One sample was excluded because it was positive for the Oka vaccine strain (182/225, 80.9%). Three hundred twenty-three control subjects were enrolled. The effectiveness of 1 dose of the Oka/Biken vaccine compared with no vaccine was 76.7% (95% confidence interval [CI]: 58.6–86.9%; P < 0.001). The effectiveness of 2 doses of the Oka/Biken vaccine was 94.2% (95% CI: 85.7–97.6%; P < 0.001). After adjusting for potential confounding effects, the adjusted VE of 1 and 2 doses of varicella vaccine were 76.9% (95% CI: 58.1–87.3%; P < 0.001) and 94.7% (95% CI: 86.0–98.0%; P < 0.001), respectively. Conclusions VE of one dose of Oka/Biken varicella vaccine was insufficient to control varicella. Therefore, two doses of Oka/Biken varicella vaccine is significant for controlling varicella in Japan. [ABSTRACT FROM AUTHOR]

Some healthy individuals carry human herpesvirus-6 (HHV-6) within a host chromosome, which is called inherited chromosomally integrated human herpesvirus-6 (iciHHV-6). Because iciHHV-6 is generally considered a non-pathogenic condition, it is important to distinguish iciHHV-6 from HHV-6 reactivation in immunocompromised hosts because both conditions manifest high copy numbers of the HHV-6 in peripheral blood mononuclear cells. Although fluorescent in situ hybridization (FISH) is a reliable method for the diagnosis of iciHHV-6, HHV-6-specific FISH probes are not commercially available. In our present study, we established a simple PCR-based method for producing FISH probes that can detect the chromosomal integration site of iciHHV-6 at high sensitivity. Using these probes, we confirmed that HHV-6 signals were consistently located at the telomeric region in all of the 13 iciHHV-6 individuals examined. Interestingly, in all seven Japanese iciHHV-6A patients, signals were detected exclusively on chromosome 22q. This method provides a simple and fast approach for iciHHV-6 diagnosis in the clinical laboratory. [ABSTRACT FROM AUTHOR]

Bilirubin can prevent oxidation of low-density lipoprotein (LDL) and may protect against atherosclerosis and coronary heart disease (CHD). The goal of this study was to characterize the relationship between bilirubin and CHD through measurements of bilirubin concentration, coronary endothelial function, and markers of oxidative stress, inflammation, and lipid/glucose metabolism. The study population consisted of 141 patients without CHD who underwent Doppler flow study. Vascular reactivity was examined by intracoronary administration of papaverine, acetylcholine (ACh) and nitroglycerin using a Doppler guide wire. Serum bilirubin, high-sensitivity C-reactive protein (hsCRP), malondialdehyde-modified LDL, LDL cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose (FPG), and immunoreactive insulin were also measured. Homeostasis model assessment insulin resistance index and estimated glomerular filtration rate (eGFR) were calculated. Univariate analysis revealed that both percent change in coronary blood flow (CBF) and coronary artery diameter induced by ACh correlated positively with log-transformed bilirubin ( r = 0.22, P < 0.05; r = 0.20, P < 0.05, respectively). Percent change in CBF in response to ACh correlated positively with eGFR ( r = 0.24, P < 0.05) and correlated inversely with age, LDL-C, and log-transformed FPG ( r = −0.24, P < 0.05; r = −0.17, P < 0.05, r = −0.22, P < 0.05, respectively). Multivariate analysis revealed that log-transformed bilirubin was the only independent predictor of percent change in CBF in response to ACh. Multivariate analysis revealed that log-transformed hsCRP and HDL-C were independent predictors of log-transformed bilirubin. These results suggest that a high level of bilirubin is associated with favorable coronary endothelial function, which may be mediated via the effect of bilirubin on inflammation and HDL-C. [ABSTRACT FROM AUTHOR]

Abstract: Background: Hyperglycemia upon hospital admission in patients with acute myocardial infarction is associated with the no-reflow phenomenon after successful reperfusion, and increased mortality. However, the mechanism underlying this phenomenon remains unclear. Therefore, the aim of this study was to characterize coronary hemodynamics in a homogenous group of non-diabetic patients without coronary artery disease. Methods and Results: A total of 104 consecutive non-diabetic patients (mean age, 62±14 years) without coronary artery disease underwent Doppler flow study of the left anterior descending coronary artery. Vascular reactivity was examined by intra-coronary administration of papaverine, acetylcholine (Ach), and nitroglycerin using a Doppler guidewire. Coronary vascular resistance (CVR) was calculated as the mean arterial pressure divided by coronary blood flow (CBF). Baseline CVR was shown as CVR at control and minimal CVR was shown as CVR with papaverine administration. Fasting plasma glucose (FPG) level had a significant, positive correlation with baseline CVR and minimal CVR (r =0.24, p <0.02 and r =0.21, p <0.05, respectively). Hemoglobin A1c (HbA1c) also had a significant, positive correlation with baseline CVR and minimal CVR (r =0.31, p <0.01 and r =0.32, p <0.01, respectively). The percent change in CBF induced by Ach was inversely correlated with HbA1c but not with FPG (r =0.22, p <0.05 and r =0.06, p =0.57, respectively). By contrast, neither FPG nor HbA1c had significant correlation with coronary flow reserve to papaverine. Conclusion: These data demonstrate that elevated glucose levels are associated with increases in baseline and minimal coronary vascular resistance. These changes may contribute to unfavorable coronary hemodynamics in non-diabetic patients without coronary heart disease. [Copyright &y& Elsevier]

An unhealthy lifestyle can increase the risk of cardiovascular disease. However, the mechanism by which lifestyle influences the development of cardiovascular disease remains unclear. Since coronary endothelial function is a predictor of cardiovascular prognosis, the goal of this study was to characterize the effect of enjoying hobbies on coronary endothelial function and cardiovascular outcomes. A total of 121 consecutive patients (76 men, 45 women) with almost normal coronary arteries underwent Doppler flow study of the left anterior descending coronary artery following sequential administration of papaverine, acetylcholine, and nitroglycerin. On the basis of responses to questionnaires, patients were divided into two groups; the Hobby group ( n = 71) who enjoyed hobbies, and the Non-hobby group ( n = 50) who had no hobbies. Cardiovascular outcomes were assessed at long-term follow-up using medical records or questionnaire surveys for major adverse cardiovascular events (MACE).The average follow-up period was 916 ± 515 days. There were no significant differences in demographics when comparing the two groups. The percent change in coronary blood flow and coronary artery diameter induced by acetylcholine was significantly greater in the Hobby group than in the Non-hobby group (49% ± 77% vs 25% ± 37%, P < 0.05, 4% ± 13% vs −3% ± 20%, P < 0.05, respectively). The MACE rate was significantly lower in the Hobby group than in the Non-hobby group ( P < 0.01). Enjoyment of hobbies was the only independent predictor of MACE (odds ratio 8.1 [95% confidence interval 1.60, 41.90], P = 0.01) among the variables tested. In the early stages of arteriosclerosis, enjoying hobbies may improve cardiovascular outcomes via its favorable effects on coronary endothelial function. [ABSTRACT FROM AUTHOR]

Background: Although reconduction after pulmonary vein (PV) isolation is considered to play a key role in the recurrence of paroxysmal atrial fibrillation (AF), there have been few reports regarding the precise time course of early reconduction. Several studies have suggested that transient PV reconduction facilitated by adenosine may predict long-term AF recurrence. This study was designed to clarify the incidence and time course of early reconduction after PVI during the procedure and to confirm whether the use of ATP after a certain observation period was useful to detect early reconduction after PVI. Methods: In 21 patients (18 males, 56 ± 11 years) with drug refractory AF, radiofrequency circumferential PV antrum ablation was performed in all 4 PVs. After the completion of isolation, electrograms in each PV were repeatedly recorded (1.98 ± 0.57 times per PV) using a circular mapping catheter for an observation period of 87 ± 29 minutes. After isolation of all 4 PVs, 30 mg of adenosine triphosphate (ATP) was administered during isoproterenol infusion. Results: PV electrical isolation was initially achieved in all 81 PVs. During the observation period, 12 (15%) PVs in 10 (48%) of 21 patients exhibited spontaneous reconduction. Among the remaining 69 PVs, 8 (12%) additional PVs had reconduction with the use of ATP. All PV reconduction was successfully eliminated by 4.5 ± 2.2 additional radiofrequency applications. Conclusion: A sufficient observation period and the use of ATP are useful to detect early reconduction after PV isolation. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: We introduced a harmonic-to-fundamental ratio (HFR) of the radiofrequency (RF) signals that reduces confounding effects of attenuation. We studied whether HFR analysis of RF signals received from contrast microbubbles allows accurate measurement of the left ventricular (LV) cavity area under varying levels of attenuation. Background: Attenuation is a fundamental problem in ultrasound imaging and limits the use of clinical echocardiography. Methods: RF data from short axis systolic and diastolic scans were obtained from 14 open-chest dogs following left-atrial bolus of Optison. Attenuation was induced by interposed silicone pads calibrated to induce 7dB or 14dB reductions of the backscattered RF signal. RF images were reconstructed from the RF signals, HFR values calculated for each image pixel for 0dB, 7dB and 14dB attenuation conditions, and LV area obtained by summation of “LV cavity pixels”. A reference LV cavity area was obtained from endocardial border tracings in enhanced scans by experts. Results: Correlation of the HFR-defined and reference areas at systole was R =0.95, R =0.94, and R =0.91 for 0dB, 7dB and 14dB levels of attenuation, respectively, and at diastole was R =0.95 for 0dB, 7dB and 14dB levels of attenuation. The mean difference from both systolic and diastolic values was <1.45cm2 (i.e. negligible) in all attenuation settings. Conclusion: Our novel HFR method supports precise measurement of the LV cavity area in contrast images with simulated high attenuation of ultrasound signals. [Copyright &y& Elsevier]

(1) Background: Acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is an intractable problem for many clinical oncologists. The mechanisms of resistance to EGFR-TKIs are complex. Long non-coding RNAs (lncRNAs) may play an important role in cancer development and metastasis. However, the biological process between lncRNAs and drug resistance to EGFR-mutated lung cancer remains largely unknown. (2) Methods: Osimertinib- and afatinib-resistant EGFR-mutated lung cancer cells were established using a stepwise method. A microarray analysis of non-coding and coding RNAs was performed using parental and resistant EGFR-mutant non-small cell lung cancer (NSCLC) cells and evaluated by bioinformatics analysis through medical-industrial collaboration. (3) Results: Colorectal neoplasia differentially expressed (CRNDE) and DiGeorge syndrome critical region gene 5 (DGCR5) lncRNAs were highly expressed in EGFR-TKI-resistant cells by microarray analysis. RNA-protein binding analysis revealed eukaryotic translation initiation factor 4A3 (eIF4A3) bound in an overlapping manner to CRNDE and DGCR5. The CRNDE downregulates the expression of eIF4A3, mucin 1 (MUC1), and phospho-EGFR. Inhibition of CRNDE activated the eIF4A3/MUC1/EGFR signaling pathway and apoptotic activity, and restored sensitivity to EGFR-TKIs. (4) Conclusions: The results showed that CRNDE is associated with the development of resistance to EGFR-TKIs. CRNDE may be a novel therapeutic target to conquer EGFR-mutant NSCLC. [ABSTRACT FROM AUTHOR]

• Human herpesvirus 6 (HHV-6) can be integrated into human chromosomes (ciHHV-6). • The pathological significance of ciHHV-6 remains unclear. • ciHHV-6 was screened by PCR of DNA from autoimmune disease patients. • ciHHV-6 prevalence was similar in autoimmune disease patients and healthy controls. • ciHHV-6 was not associated with autoimmune disease. Entire genome of human herpesvirus 6 (HHV-6) that integrates into human chromosomes is called chromosomally integrated HHV-6 (ciHHV-6). Several viral infections have been suggested to be involved in autoimmune connective tissue diseases (CTDs). Reactivated HHV-6 from the integrated viral genome can induce immune responses against the virus. Thus, it is plausible that ciHHV-6 is associated with autoimmune CTDs. We sought to determine whether the prevalence of ciHHV-6 was significantly higher in patients with autoimmune CTDs than in a healthy population. : A total of 846 peripheral blood samples collected from autoimmune CTD patients were analyzed. Since there was a large number of samples, they were pooled into 24 samples per group. Copy numbers of HHV-6 DNA were measured by real-time PCR. The threshold level for distinguishing between ciHHV-6 and active viral infection and the reliability of pooled DNA analysis were examined as initial validation experiments. : The threshold level was 1.6 × 10^6 copy/mL in whole blood. The reliability of pooled DNA analysis to identify one ciHHV-6 sample among 23 HHV-6 DNA-negative samples was high. No HHV-6 DNA was detected in any of the pooled DNA samples collected from the patients. The probability of the present study including the 846 autoimmune CTD patient's samples was statistically not different with a healthy Japanese population which was 0.2 % or 0.6 %. There was no significant difference in the prevalence of ciHHV-6 between a healthy population and patients with autoimmune CTDs. [ABSTRACT FROM AUTHOR]