Characterization of Influenza A(H1N1)pdm09 Viruses Isolated in the 2018-2019 and 2019-2020 Influenza Seasons in Japan.

The influenza A(H1N1)pdm09 virus that emerged in 2009 causes seasonal epidemic worldwide. The virus acquired several amino acid substitutions that were responsible for antigenic drift until the 2018-2019 influenza season. Viruses possessing mutations in the NA and PA proteins that cause reduced susceptibility to NA inhibitors and baloxavir marboxil, respectively, have been detected after antiviral treatment, albeit infrequently. Here, we analyzed HA, NA, and PA sequences derived from A(H1N1)pdm09 viruses that were isolated during the 2018-2019 and 2019-2020 influenza seasons in Japan. We found that A(H1N1)pdm09 viruses possessing the D187A and Q189E substitutions in HA emerged and dominated during the 2019-2020 season; these substitutions in the antigenic site Sb, a high potency neutralizing antibody-eliciting site for humans, changed the antigenicity of A(H1N1)pdm09 viruses. Furthermore, we found that isolates possessing the N156K substitution, which was predicted to affect the antigenicity of A(H1N1)pdm09 virus at the laboratory level, were detected at a frequency of 1.0% in the 2018-2019 season but 10.1% in the 2019-2020 season. These findings indicate that two kinds of antigenically drifted viruses-N156K and D187A/Q189E viruses-co-circulated during the 2019-2020 influenza season in Japan.

Electrocardiographic Diagnosis of Hypertrophic Cardiomyopathy in the Pre- and Post-Diagnostic Phases in Children and Adolescents.

BACKGROUND: The usefulness of electrocardiographic (ECG) voltage criteria for diagnosing hypertrophic cardiomyopathy (HCM) in pediatric patients is poorly defined.Methods and Results:ECGs at the 1st grade (mean [±SD] age 6.6±0.3 years) were available for 11 patients diagnosed with HCM at around the 7th grade (13.2±0.3 years). ECGs were available for another 64 patients diagnosed with HCM in the 1st (n=15), 7th (n=32), and 10th (n=17) grades. Fifty-one voltage criteria were developed by grade and sex using 62,841 ECGs from the general population. Voltage criteria were set at the 99.95th percentile (1/2,000) point based on the estimated prevalence of childhood HCM (2.9 per 100,000 [1/34,483]) to decrease false negatives. Conventional criteria were from guidelines for school-aged children in Japan. Of 11 patients before diagnosis, 2 satisfied conventional criteria in 1st grade; 5 (56%) of the remaining 9 patients fulfilled 2 voltage criteria (R wave in limb-lead I [RI]+S wave in lead V3 [SV3] and R wave in lead V3 [RV3]+SV3). Robustness analysis for sensitivity showed RV3+SV3 was superior to RI+SV3. For all patients after diagnosis, RI+SV4 was the main candidate. However, conventional criteria were more useful than voltage criteria. CONCLUSIONS: Early HCM prediction was possible using RV3+SV3 in >50% of patients in 1st grade. Voltage criteria may help diagnose prediagnostic or early HCM, and prevent tragic accidents, although further prospective studies are required.

A significance of school screening electrocardiogram in the patients with ventricular noncompaction.

Left ventricular noncompaction (LVNC) is a hereditary cardiomyopathy and is associated with high morbidity and mortality. However, the role and significance of school screening for LVNC have not been fully elucidated. In this multicenter, retrospective cohort study, a total of 105 children with LVNC were included from 2000 to 2017. At the initial presentation, 44 patients (41.9%) were diagnosed by school screening. One (1.0%) patient underwent heart transplantation and four (3.8%) patients died during the study. Electrocardiogram data showed a high prevalence of fragmented QRS (33.4%) and J wave (15.7%). Treatments were needed in eight (18.2%) patients who were detected by school screening. The multivariable proportional hazards model showed T-wave abnormality on electrocardiogram in first graders was independent risk factors for major adverse cardiac events (odds ratio 4.94, p value = 0.0007). Moreover, dilation of the left atrium on chest X-ray and low ejection fraction on echocardiogram at the initial treatment were independent risk factors for treatment (odds ratio 1.7 × 107 and 22.3, p = 0.0362 and 0.0028, respectively). This study is the first report focusing on school screening in a large pediatric cohort with LVNC. With the use of abnormalities in electrocardiogram, school screening may be a good detector of and predictor for LVNC.

Antigenic variants of influenza B viruses isolated in Japan during the 2017-2018 and 2018-2019 influenza seasons.

BACKGROUND: Here, we genetically and antigenically analyzed influenza B viruses (IBVs) isolated in Japan during the 2017-2018 and 2018-2019 influenza seasons. METHODS: A total of 68 IBVs (61 B/Yamagata/16/88-like [B/Yamagata]-lineage and 7 B/Victoria/2/87-like [B/Victoria]-lineage) were antigenically and genetically characterized by using hemagglutination inhibition (HI) assays and phylogenetic analysis, respectively. The susceptibility of IBVs to neuraminidase (NA) inhibitors was assessed by using a fluorescence-based NA inhibition assay. RESULTS: All 61 B/Yamagata-lineage isolates were genetically closely related to B/Phuket/3073/2013, the vaccine strain for these two seasons. Eleven B/Yamagata-lineage isolates tested were antigenically similar to B/Phuket/3073/2013 by the HI test. Seven B/Victoria-lineage isolates were genetically closely related to B/Texas/02/2013, the WHO-recommended vaccine strain for the 2017-2018 season; however, they were antigenically distinct from B/Texas/02/2013 with an eightfold or 16-fold difference in HI titer. Of these 7 isolates, 4 possessed a two-amino-acid deletion at positions 162 and 163 in hemagglutinin (HA) and the other 3 had a three-amino-acid deletion at positions 162-164 in HA. Importantly, the variants with the three-amino-acid deletion appeared to be antigenically different from the B/Colorado/06/2017 virus with the two-amino-acid deletion, the vaccine strain for the 2018-2019 season with a fourfold or eightfold difference in HI titer. One B/Yamagata-lineage isolate carrying a G407S mutation in its NA showed a marked reduction in susceptibility to zanamivir, peramivir, and laninamivir. CONCLUSIONS: These results highlight the need for continued monitoring for the prevalence of the antigenic variant with the three-amino-acid deletion and the variant with reduced NA inhibitor susceptibility.

Influenza A variants with reduced susceptibility to baloxavir isolated from Japanese patients are fit and transmit through respiratory droplets.

Here we report the isolation of the influenza A/H1N1 2009 pandemic (A/H1N1pdm) and A/H3N2 viruses carrying an I38T mutation in the polymerase acidic protein-a mutation that confers reduced susceptibility to baloxavir marboxil-from patients before and after treatment with baloxavir marboxil in Japan. These variants showed replicative abilities and pathogenicity that is similar to those of wild-type isolates in hamsters; they also transmitted efficiently between ferrets by respiratory droplets.

Standard Values and Characteristics of Electrocardiographic Findings in Children and Adolescents.

BACKGROUND: Reference values and the characteristics of the electrocardiographic (ECG) findings using a large number of subjects are lacking for children and adolescents.Methods and Results:A total of 56,753 digitally stored ECGs of participants in a school-based ECG screening system were obtained between 2006 and 2009 in Kagoshima, Japan. Each ECG was manually reviewed by 2 pediatric cardiologists and only ECGs with sinus rhythm were included. A final total of 48,401 ECGs from 16,773 1st (6 years old, 50% girls), 18,126 7th (12 years old, 51% girls), and 13,502 10th graders (15 years old, 52% girls) were selected. ECG variables showed differences in age and sex. However, the effects of age and sex on ECG variables such as the PQ interval, QRS voltage, and STJ segment were also different. The 98th percentile values of well-known surrogate parameters for ventricular hypertrophy in the present study were much higher than the conventional criteria. CONCLUSIONS: The present study of a large number of pediatric subjects showed that the effects of age and sex on ECG parameters are different, and that criteria for ventricular hypertrophy should be newly determined by age and sex. We have developed reference data for STJ segment elevation for children and adolescents. These findings are useful for creating guidelines and recommendations for interpretation of pediatric ECG.

Classification and assessment of computerized diagnostic criteria for Brugada-type electrocardiograms.

BACKGROUND: Although a Brugada-type electrocardiogram (ECG) is occasionally detected in mass health screening examinations in apparently healthy individuals, the automatic computerized diagnostic criteria for Brugada-type ECGs have not been established. OBJECTIVE: This study was performed to establish the criteria for the computerized diagnosis of Brugada-type ECGs and to evaluate their diagnostic accuracy. METHODS: We examined the ECG parameters in leads V1 to V3 in patients with Brugada syndrome and cases with right bundle branch block. Based on the above parameters, we classified the ECGs into 3 types of Brugada-type ECGs, and the conditions for defining each type were explored as the diagnostic criteria. The diagnostic effectiveness of the proposed criteria was assessed using 548 ECGs from 49 cases with Brugada-type ECGs and the recordings from 192,673 cases (36,674 adults and 155,999 school children) obtained from their annual health examinations. RESULTS: The Brugada-type ST-segment elevation in V1 to V3 was classified into 3 types, types 1, 2/3, and a suggestive Brugada ECG (type S). The automatic diagnostic criteria for each type were established by the J-point amplitude, ST-segment elevation with its amplitude and configuration, as well as the T-wave morphology in leads V1 to V3. CONCLUSION: The proposed criteria demonstrated a reasonable accuracy (type 1: 91.9%, type 2/3: 86.2%, type S: 76.2%) for diagnosing Brugada-type ECG in comparison to the macroscopic diagnosis by experienced observers. Moreover, the automatic criteria had a comparable detection rate (0.6% in adults, 0.16% in children) of Brugada-type ECGs to the macroscopic inspection in the health screening examinations.

Resolution of abnormal body surface maps in children with atrial septal defect after intracardiac repair.

INTRODUCTION: The genesis of repolarization abnormalities of ECG waveforms in atrial septal defect (ASD), which typically is characterized by right ventricular (RV) volume overload, has not been explored, particularly in association with postoperative hemodynamic improvement. The aim of this study was to evaluate the effects of reduced RV overload after ASD closure on depolarization and repolarization abnormalities on body surface maps (BSMs). METHODS AND RESULTS: BSMs of 14 children with ASD were recorded preoperatively and at early postoperative (1-6 months) and late postoperative (>9 months) stages. BSMs of 31 age-matched healthy children were studied as normal controls. Before intracardiac repair, QRS isopotential maps of children with ASD showed delayed RV breakthrough and subsequent rightward enlargement of the positive area with a maximum shifting to the right. Delayed conduction of the RV, particularly at the outflow tract area, was noted. The preoperative QRST isointegral maps exhibited the two-maximum pattern reflecting repolarization abnormality. The delayed appearance of breakthrough and delayed RV conduction on the QRS isopotential maps persisted from the preoperative to the late postoperative stage, whereas the two-maximum pattern on the QRST isointegral maps normalized to the one-dipole pattern at an early stage after repair. CONCLUSION: Abnormal repolarization parameters in ASD patients showed rapid improvement postoperatively, despite the persistence of depolarization abnormalities. Therefore, the two-maximum pattern on the QRST isointegral maps indicates a primary T wave change due to hemodynamic RV volume overload.

Changes in body surface potential distributions induced by isoproterenol and Na channel blockers in patients with the Brugada syndrome.

BACKGROUND: The characteristics of unique ECG findings in the Brugada syndrome have not been well explained. METHODS: To clarify their characteristics and mechanisms, body surface maps (BSM) were recorded from patients with the Brugada syndrome (13 cases; a mean age of 48 years) before and after administration of isoproterenol (ISP) or Na channel blockers (12 cases). RESULTS: ST elevation in V1-V3 was decreased by 0.1 mV or more after ISP infusion in 8 of 11 cases and elevated after Na channel blockers in 8 of 12. In ventricular activation time (VAT) isochronal map, delayed conduction was noted on upper anterior chest in 11 and on anterior left chest in two. Delayed conduction areas were decreased by ISP and expanded by Na channel blockers. QRST isointegral map showed normal findings in baseline with minimal changes after ISP or Na channel blockers. Activation recovery interval (ARI) isochronal map showed prolonged area on upper anterior chest in baseline, being reduced by ISP and expanded by Na channel blockers. ARI dispersion (ARI-d), defined as difference between the maximum and minimum value of ARI, was larger in Brugada patients than that of normal subjects in baseline, and decreased after ISP and increased after Na channel blockers. CONCLUSION: ST elevation in the Brugada syndrome is primarily caused by abnormality in depolarization rather than in repolarization. BSM can provide better information to clarify a mechanism of ECG changes adding its diagnostic value for this unique syndrome.

Who is at risk for cardiac events in young patients with long QT syndrome?

The objective of this study was to determine who is at risk for cardiac events among young patients with long QT syndrome (LQTS) with or without a past history of LQTS-related cardiac events. The subjects were young patients with LQTS who had visited one of 36 hospitals from January 1997 to August 2000 in Japan. To predict the risk factors for cardiac events, stepwise regression analyses were performed for a total of 197 cases. There were 7 of 129 cases (5%) without a past history and 32 of the 68 (47%) cases with a past history of LQTS-related cardiac events that experienced new events after diagnosis (p<0.0001). Patients with a family history showed a higher incidence of symptoms both before and after diagnosis than patients with sporadic occurrence. Analyses revealed that noncompliance with medication and a lower age at diagnosis were significant predictors for the group with a past history. A negative predictive value <4 points was 100% in the group without a past history. To prevent future cardiac events, compliance with medication must be improved in those with a past history. A total LQTS score <4 points was useful to predict the absence of cardiac events in the group without a past history.

Moving dipole analysis of normal and abnormal ventricular activation by magnetocardiography.

The current source during ventricular excitation of the in situ heart has not been well characterized. We analyzed current dipoles of ventricular excitation by magnetocardiography (MCG) in 16 healthy subjects and 10 patients with the Wolff-Parkinson-White syndrome or premature ventricular contraction. Single current dipoles were estimated by MCG with the spatial position, direction, and strength in the initial 40 ms of QRS (moving dipole analysis). In 12 of the 16 healthy subjects, the origin of current dipoles moved consecutively from the initial position with the increase in the peak strength at 30 ms of QRS. In the other 4 healthy subjects, dipoles moved discontinuously jumping to the right-anterior thorax at 17.8 ms (mean). In abnormal ventricular excitation, the dipoles remained in the initial position with little movement, smaller strength of dipole than that of normal with a delayed peak time. The moving dipole analysis can be applied to determine spatial distribution of normal and abnormal excitation sources at the initial phase of ventricular depolarization in the in situ heart.