Expert consensus document on automated diagnosis of the electrocardiogram: The task force on automated diagnosis of the electrocardiogram in Japan part 3: Inappropriate internal processing in the automatic diagnosis of electrocardiograms and its problems.

Computer diagnosis of electrocardiograms is widely used to provide useful information in clinical practice and medical checkups. However, it is common for users to be confused by the inappropriate diagnosis. We illustrate some examples of inappropriate automatic diagnoses and discuss the actual situation of inappropriate automatic processing and its problems.

Brentuximab vedotin plus AVD followed by involved-node radiotherapy in a patient with classic Hodgkin lymphoma following gray zone lymphoma after autologous stem-cell transplantation failure.

BACKGROUND: No consensus has been reached yet concerning treatment strategies for a sequential classic Hodgkin lymphoma (CHL) following gray zone lymphoma (GZL). Prognosis of GZL after a failed autologous hematopoietic stem-cell transplantation (auto-HCT) is poor and treatment strategy is very limited. As yet there are limited data showing clinical outcomes of brentuximab vedotin (BV) for GZL, especially for sequential CHL after GZL. CASE PRESENTATION: We report a case of CHL following primary refractory GZL after a failed auto-HCT and showed favorable response to first-line CHL-directed chemoradiotherapy consisting of BV plus doxorubicin, vinblastine, and dacarbazin (AVD) followed by irradiation. The sequential cases with an early evolution, whose diagnosis of second lymphoma was made within a year, have been recently reported very poor survival shorter than a year. Whether a sequential CHL following GZL should be treated as a primary or relapsed disease has not been clearly elucidated. Our patient showed favorable response to first-line CHL-directed chemoradiotherapy without allogenic hematopoietic stem-cell transplantation and has in continuous remission for 2 years. CONCLUSIONS: The management of our case could help for physicians to make better treatment decisions and provide insights for further exploration in future studies.

Expert consensus document on automated diagnosis of the electrocardiogram: The task force on automated diagnosis of the electrocardiogram in Japan: Part 2: Current status of inappropriate automated diagnosis is widely used electrocardiographs in Japan.

It is important to objectively grasp the current status of automated electrocardiogram (ECG) diagnosis. This report aimed to analyze and evaluate ECG records that our members have encountered as an inappropriate diagnosis in real-world clinical practices.

Ambient-task combined lighting to regulate autonomic and psychomotor arousal levels without compromising subjective comfort to lighting.

BACKGROUND: Although evidence of both beneficial and adverse biological effects of lighting has accumulated, biologically favorable lighting often does not match subjectively comfortable lighting. By controlling the correlated color temperature (CCT) of ambient lights, we investigated the feasibility of combined lighting that meets both biological requirements and subjective comfort. METHODS: Two types of combined lightings were compared; one consisted of a high-CCT (12000 K) light-emitting diode (LED) panel as the ambient light and a low-CCT (5000 K) LED stand light as the task light (high-low combined lighting), and the other consisted of a low-CCT (4500 K) LED panel as the ambient light and the same low-CCT (5000 K) stand light as the task light (low-low combined lighting) as control. Ten healthy subjects (5 young and 5 elderly) were exposed to the two types of lighting on separate days. Autonomic function by heart rate variability, psychomotor performances, and subjective comfort were compared. RESULTS: Both at sitting rest and during psychomotor workload, heart rate was higher and the parasympathetic index of heart rate variability was lower under the high-low combined lighting than the low-low combined lighting in both young and elderly subject groups. Increased psychomotor alertness in the elderly and improved sustainability of concentration work performance in both age groups were also observed under the high-low combined lighting. However, no significant difference was observed in the visual-analog-scale assessment of subjective comfort between the two types of lightings. CONCLUSIONS: High-CCT ambient lighting, even when used in combination with low-CCT task lighting, could increase autonomic and psychomotor arousal levels without compromising subjective comfort. This finding suggests the feasibility of independent control of ambient and task lighting as a way to achieve both biological function regulation and subjective comfort.

Expert consensus document on automated diagnosis of the electrocardiogram: The task force on automated diagnosis of the electrocardiogram in Japan. Part 1: Nomenclature for diagnosis and abnormal findings.

As these terms should accurately represent the abnormal findings and conditions as much as possible, we propose to unify these terms into terminologies that are not confusing and easy to understand for everyone.

Generation of hypoimmunogenic T cells from genetically engineered allogeneic human induced pluripotent stem cells.

Avoiding the immune rejection of transplanted T cells is central to the success of allogeneic cancer immunotherapies. One solution to protecting T-cell grafts from immune rejection involves the deletion of allogeneic factors and of factors that activate cytotoxic immune cells. Here we report the generation of hypoimmunogenic cancer-antigen-specific T cells derived from induced pluripotent stem cells (iPSCs) lacking ß2-microglobulin, the class-II major histocompatibility complex (MHC) transactivator and the natural killer (NK) cell-ligand poliovirus receptor CD155, and expressing single-chain MHC class-I antigen E. In mouse models of CD20-expressing leukaemia or lymphoma, differentiated T cells expressing a CD20 chimeric antigen receptor largely escaped recognition by NKG2A+ and DNAM-1+ NK cells and by CD8 and CD4 T cells in the allogeneic recipients while maintaining anti-tumour potency. Hypoimmunogenic iPSC-derived T cells may contribute to the creation of off-the-shelf T cell immunotherapies.

Prognostic Impact of the Fractionation of Total Body Irradiation for Patients with Acute Myeloid Leukemia Undergoing Myeloablative Allogeneic Hematopoietic Cell Transplantation.

Fractionated total body irradiation (TBI) at a total dose of 12 Gy is widely used for patients with acute myeloid leukemia (AML) undergoing allogeneic hematopoietic cell transplantation (HCT); however, there is limited information regarding the optimal number of fractions. To address this issue, Japanese nationwide transplantation registry data were analyzed. Because it was found that TBI was delivered almost exclusively in 4 (n = 1215, 30%) or 6 fractions (n = 2697, 67%), we focused on comparing 4- versus 6-fraction TBI. Compared to 6-fraction TBI, the 4-fraction version was associated with reduced risk of overall mortality (P = .002) and relapse (P = .018), while there was no difference in the risk of nonrelapse mortality (P = .422). The 4-fraction version did not aggravate acute graft-versus-host disease (GVHD), interstitial pneumonia, or sinusoidal obstruction syndrome of the liver. Chronic GVHD developed more frequently with the use of 4-fraction TBI, although the incidence of extensive chronic GVHD was similar. Subgroup analyses revealed that the 4-fraction version provided benefits for patients in non-complete remission (non-CR) but not for those in CR at transplantation. These findings suggest the advantage of 4-fraction over 6-fraction TBI for patients with AML undergoing allogeneic HCT in non-CR.

Survival Predictors of Heart Rate Variability After Myocardial Infarction With and Without Low Left Ventricular Ejection Fraction.

BACKGROUND: Heart rate variability (HRV) and heart rate (HR) dynamics are used to predict the survival probability of patients after acute myocardial infarction (AMI), but the association has been established in patients with mixed levels of left ventricular ejection fraction (LVEF). OBJECTIVE: We investigated whether the survival predictors of HRV and HR dynamics depend on LVEF after AMI. METHODS: We studied 687 post-AMI patients including 147 with LVEF ≤35% and 540 with LVEF >35%, of which 23 (16%) and 22 (4%) died during the 25 month follow-up period, respectively. None had an implanted cardioverter-defibrillator. From baseline 24 h ECG, the standard deviation (SDNN), root mean square of successive difference (rMSSD), percentage of successive difference >50 ms (pNN50) of normal-to-normal R-R interval, ultra-low (ULF), very-low (VLF), low (LF), and high (HF) frequency power, deceleration capacity (DC), short-term scaling exponent (α1), non-Gaussianity index (λ25 s), and the amplitude of cyclic variation of HR (Acv) were calculated. RESULTS: The predictors were categorized into three clusters; DC, SDNN, α1, ULF, VLF, LF, and Acv as Cluster 1, λ25 s independently as Cluster 2, and rMSSD, pNN50, and HF as Cluster 3. In univariate analyses, mortality was best predicted by indices belonging to Cluster 1 regardless of LVEF. In multivariate analyses, however, mortality in patients with low LVEF was best predicted by the combinations of Cluster 1 predictors or Cluster 1 and 3 predictors, whereas in patients without low LVEF, it was best predicted by the combinations of Cluster 1 and 2 predictors. CONCLUSION: The mortality risk in post-AMI patients with low LVEF is predicted by indices reflecting decreased HRV or HR responsiveness and cardiac parasympathetic dysfunction, whereas in patients without low LVEF, the risk is predicted by a combination of indices that reflect decreased HRV or HR responsiveness and indicator that reflects abrupt large HR changes suggesting sympathetic involvement.

Risk stratification after acute myocardial infarction by amplitude-frequency mapping of cyclic variation of heart rate.

BACKGROUND: Blunted cyclic variation of heart rate (CVHR), measured as a decrease in CVHR amplitude (Acv), predicts mortality risk after acute myocardial infarction (AMI). However, Acv also can be reduced in mild sleep apnea with mild O2 desaturation. We investigated whether Acv's predictive power for post-AMI mortality could be improved by considering the effect of sleep apnea severity. METHODS: In 24-hr ECG in 265,291 participants of the Allostatic State Mapping by Ambulatory ECG Repository project, sleep apnea severity was estimated by the frequency of CVHR (Fcv) measured by an automated algorithm for auto-correlated wave detection by adaptive threshold (ACAT). The distribution of Acv on the Acv-Fcv relation map was modeled by percentile regression, and a function converting Acv into percentile value was developed. In the retrospective cohort of the Enhancing Recovery in Coronary Heart Disease (ENRICHD) study, consisting of 673 survivors and 44 non-survivors after AMI, the mortality predictive power of percentile Acv calculated by the function was compared with that of unadjusted Acv. RESULTS: Among the ALLSTAR ECG data, low Acv values appeared more likely when Fcv was low. The logistic regression analysis for mortality in the ENRICHD cohort showed c-statistics of 0.667 (SE, 0.041), 0.817 (0.035), and 0.843 (0.030) for Fcv, unadjusted Acv, and the percentile Acv, respectively. Compared with unadjusted Acv, the percentile Acv showed a significant net reclassification improvement of 0.90 (95% CI, 0.51-1.42). CONCLUSIONS: The predictive power of Acv for post-AMI mortality is improved by considering its relation to sleep apnea severity estimated by Fcv.

Redundancy among risk predictors derived from heart rate variability and dynamics: ALLSTAR big data analysis.

BACKGROUND: Many indices of heart rate variability (HRV) and heart rate dynamics have been proposed as cardiovascular mortality risk predictors, but the redundancy between their predictive powers is unknown. METHODS: From the Allostatic State Mapping by Ambulatory ECG Repository project database, 24-hr ECG data showing continuous sinus rhythm were extracted and SD of normal-to-normal R-R interval (SDNN), very-low-frequency power (VLF), scaling exponent α1 , deceleration capacity (DC), and non-Gaussianity λ25s were calculated. The values were dichotomized into high-risk and low-risk values using the cutoffs reported in previous studies to predict mortality after acute myocardial infarction. The rate of multiple high-risk predictors accumulating in the same person was examined and was compared with the rate expected under the assumption that these predictors are independent of each other. RESULTS: Among 265,291 ECG data from the ALLSTAR database, the rates of subjects with high-risk SDNN, DC, VLF, α1 , and λ25s values were 2.95, 2.75, 5.89, 15.75, and 18.82%, respectively. The observed rate of subjects without any high-risk value was 66.68%, which was 1.10 times the expected rate (60.74%). The ratios of observed rate to the expected rate at which one, two, three, four, and five high-risk values accumulate in the same person were 0.73 times (24.10 and 32.82%), 1.10 times (6.56 and 5.99%), 4.26 times (1.87 and 0.44%), 47.66 times (0.63 and 0.013%), and 1,140.66 times (0.16 and 0.00014%), respectively. CONCLUSIONS: High-risk predictors of HRV and heart rate dynamics tend to cluster in the same person, indicating a high degree of redundancy between them.

Quantitative detection of sleep apnea with wearable watch device.

The spread of wearable watch devices with photoplethysmography (PPG) sensors has made it possible to use continuous pulse wave data during daily life. We examined if PPG pulse wave data can be used to detect sleep apnea, a common but underdiagnosed health problem associated with impaired quality of life and increased cardiovascular risk. In 41 patients undergoing diagnostic polysomnography (PSG) for sleep apnea, PPG was recorded simultaneously with a wearable watch device. The pulse interval data were analyzed by an automated algorithm called auto-correlated wave detection with adaptive threshold (ACAT) which was developed for electrocardiogram (ECG) to detect the cyclic variation of heart rate (CVHR), a characteristic heart rate pattern accompanying sleep apnea episodes. The median (IQR) apnea-hypopnea index (AHI) was 17.2 (4.4-28.4) and 22 (54%) subjects had AHI ≥15. The hourly frequency of CVHR (Fcv) detected by the ACAT algorithm closely correlated with AHI (r = 0.81), while none of the time-domain, frequency-domain, or non-linear indices of pulse interval variability showed significant correlation. The Fcv was greater in subjects with AHI ≥15 (19.6 ± 12.3 /h) than in those with AHI <15 (6.4 ± 4.6 /h), and was able to discriminate them with 82% sensitivity, 89% specificity, and 85% accuracy. The classification performance was comparable to that obtained when the ACAT algorithm was applied to ECG R-R intervals during the PSG. The analysis of wearable watch PPG by the ACAT algorithm could be used for the quantitative screening of sleep apnea.

Pulse rate variability: a new biomarker, not a surrogate for heart rate variability.

With the popularization of pulse wave signals by the spread of wearable watch devices incorporating photoplethysmography (PPG) sensors, many studies are reporting the accuracy of pulse rate variability (PRV) as a surrogate of heart rate variability (HRV). However, the authors are concerned about their research paradigm based on the assumption that PRV is a biomarker that reflects the same biological properties as HRV. Because PPG pulse wave and ECG R wave both reflect the periodic beating of the heart, pulse rate and heart rate should be equal, but it does not guarantee that the respective variabilities are also the same. The process from ECG R wave to PPG pulse wave involves several transformation steps of physical properties, such as those of electromechanical coupling and conversions from force to volume, volume to pressure, pressure impulse to wave, pressure wave to volume, and volume to light intensity. In fact, there is concreate evidence that shows discrepancy between PRV and HRV, such as that demonstrating the presence of PRV in the absence of HRV, differences in PRV with measurement sites, and differing effects of body posture and exercise between them. Our observations in adult patients with an implanted cardiac pacemaker also indicate that fluctuations in R-R intervals, pulse transit time, and pulse intervals are modulated differently by autonomic functions, respiration, and other factors. The authors suggest that it is more appropriate to recognize PRV as a different biomarker than HRV. Although HRV is a major determinant of PRV, PRV is caused by many other sources of variability, which could contain useful biomedical information that is neither error nor noise.

Optimal length of R-R interval segment window for Lorenz plot detection of paroxysmal atrial fibrillation by machine learning.

BACKGROUND: Heartbeat interval Lorenz plot (LP) imaging is a promising method for detecting atrial fibrillation (AF) in long-term monitoring, but the optimal segment window length for the LP images is unknown. We examined the performance of AF detection by LP images with different segment window lengths by machine learning with convolutional neural network (CNN). LP images with a 32 × 32-pixel resolution of non-overlapping segments with lengths between 10 and 500 beats were created from R-R intervals of 24-h ECG in 52 patients with chronic AF and 58 non-AF controls as training data and in 53 patients with paroxysmal AF and 52 non-AF controls as test data. For each segment window length, discriminant models were made by fivefold cross-validation subsets of the training data and its classification performance was examined with the test data. RESULTS: In machine learning with the training data, the averages of cross-validation scores were 0.995 and 0.999 for 10 and 20-beat LP images, respectively, and > 0.999 for 50 to 500-beat images. The classification of test data showed good performance for all segment window lengths with an accuracy from 0.970 to 0.988. Positive likelihood ratio for detecting AF segments, however, showed a convex parabolic curve linear relationship to log segment window length and peaked at 85 beats, while negative likelihood ratio showed monotonous increase with increasing segment window length. CONCLUSIONS: This study suggests that the optimal segment window length that maximizes the positive likelihood ratio for detecting paroxysmal AF with 32 × 32-pixel LP image is 85 beats.

Difference in autonomic nervous effect of blue light depending on the angle of incidence on the eye.

OBJECTIVE: Blue light has been attributed to the adverse biological effects caused by the use of smartphones and tablet devices at night. However, it is not realistic to immediately avoid nighttime exposure to blue light in the lifestyle of modern society, so other effective methods should be investigated. Earlier studies reported that inferior retinal light exposure causes greater melatonin suppression than superior retinal exposure. We examined whether the autonomic responses to blue light depends on the angle of incidence to the eye. RESULTS: In eight healthy subjects, blue light from organic electroluminescent lighting device (15.4 lx at subjects' eye) was exposed from 6 angles (0º, 30º, 45º, 135º, 150º, and 180º) for 5 min each with a 10-min interval of darkness. After adjusting the order effect of angles, however, no significant difference in heart rate or autonomic indices of heart rate variability with the angle of incidence was detected in this study.

[Classic Hodgkin lymphoma developing early after treatment of follicular lymphoma].

There are few reports of a patient presenting with combined follicular lymphoma (FL) and classical Hodgkin lymphoma (cHL). A 37-year-old Japanese man was diagnosed with FL with generalized lymphadenopathy and treated with R-CHOP. Four months later, he presented with fever, elevated lactic acid dehydrogenase (LDH), and pancytopenia. Consequently, he was diagnosed with cHL in the bone marrow. Identical clonality of FL and cHL tumor cells suggested identical immunoglobulin heavy chain gene rearrangements. He was treated with salvage chemotherapy and high-dose chemotherapy with autologous hematopoietic stem cell transformation (HDT-ASCT), which has led to complete remission and no recurrence for more than two years after transplantation. Our case suggests that HDT-ASCT may be an effective treatment for this rare clinical condition.

Effects of aging on foot pedal responses to visual stimuli.

BACKGROUND: Car accidents due to unexpected forward or backward runaway by older drivers are a serious social problem. Although the cause of these accidents is often attributed to stepping on the accelerator instead of the brake, it is difficult to induce such pedal application errors systematically with usual drive simulators. We developed a simple personal computer system that induces the pedal errors, and investigate the effects of age on the error behaviors. METHODS: The system consisted of a laptop computer and a three-pedal foot mouse. It measured response time, accuracy, and flexibility of pedal operation to visual stimuli. The system displayed two open circles on the computer display, lighting one of the circles in a random order and interval. Subjects were instructed to press the foot pedal with their right foot as quickly as possible when the circle was lit; the ipsilateral pedal to the lit circle in a parallel mode and the contralateral pedal in a cross mode. When the correct pedal was pressed, the light went off immediately, but when the wrong pedal was pressed, the buzzer sounded and the light remained on until the correct pedal was pressed. During a 6-min trial, the mode was switched between parallel and cross every 2 min. During the cross mode, a cross mark appears on the display. The pedal responses were evaluated in 52 subjects divided into young (20-29 years), middle-aged (30-64 years), and older (65-84 years) groups. Additionally, the repeatability of the pedal response characteristic indicators was examined in 14 subjects who performed this test twice. RESULTS: The mean response time was 95 ms (17%) longer in the older group than in the young group. More characteristically, however, the older group showed 2.1 times more frequent pedal errors, fell into long hesitations (response freezing > 3 s) 16 times more often, and took 1.8 times longer period to correct the wrong pedal than the young groups. The indicators of pedal response characteristics showed within-individual repeatability to the extent that can identify the age-dependent changes. CONCLUSIONS: Hesitations and extended error correction time can be associated with increased crash risk due to unexpected runaway by older drivers. The system we have developed may help to uncover and evaluate physiological characteristics related to crash risk in the elderly population.

Inter-arm difference of systolic blood pressure measured by automated double-cuff device is associated with arterial stiffness in patients with hypertension.

PURPOSE: Inter-arm differences of SBP ≧5 mmHg have been associated with all-cause and cardiovascular mortalities in hypertensive subjects. Inter-arm differences of SBP appears to be mediated by arterial stiffness. We hypothesized inter-arm differences of SBP ≧5 mmHg may be related to higher pulse pressure/stroke volume index, a surrogate marker of arterial stiffness. MATERIALS AND METHODS: To obtain inter-arm differences of SBP (the absolute difference of right and left arm) and ankle-brachial index, bilateral blood pressures were measured simultaneously at the four limbs using an automated oscillometric device in patients with treated hypertension (n = 234) and in normotensive subjects (n = 40). Pulse pressure was calculated as SBP-DBP. Stroke volume was obtained by time-velocity integral method using echocardiography. Left ventricular mass and relative wall thickness were calculated by the conventional methods. RESULTS: All hypertensive patients were medically treated and had average blood pressure levels of 135/85 mmHg. Inter-arm differences of SBP ≧5 mmHg was detected in 26.5% of hypertensive patients. Hypertensive patients with inter-arm differences of SBP ≧5 mmHg had higher pulse pressure/stroke volume index, lower ankle-brachial index, higher BMI, and higher relative wall thickness, higher prevalence of female than those with inter-arm differences of SBP <5 mmHg. Multiple linear regression analysis confirmed inter-arm differences of SBP ≧5 mmHg was associated with higher pulse pressure/stroke volume index, higher relative wall thickness, and lower ankle-brachial index. CONCLUSION: Inter-arm difference of SBP measured by automated double-cuff device was related to large artery stiffness in patients with hypertension.

Type I Interferon Delivery by iPSC-Derived Myeloid Cells Elicits Antitumor Immunity via XCR1+ Dendritic Cells.

Type I interferons (IFNs) play important roles in antitumor immunity. We generated IFN-α-producing cells by genetically engineered induced pluripotent stem cell (iPSC)-derived proliferating myeloid cells (iPSC-pMCs). Local administration of IFN-α-producing iPSC-pMCs (IFN-α-iPSC-pMCs) alters the tumor microenvironment and propagates the molecular signature associated with type I IFN. The gene-modified cell actively influences host XCR1+ dendritic cells to enhance CD8+ T cell priming, resulting in CXCR3-dependent and STING-IRF3 pathway-independent systemic tumor control. Administration of IFN-α-iPSC-pMCs in combination with immune checkpoint blockade overcomes resistance to single-treatment modalities and generates long-lasting antitumor immunity. These preclinical data suggest that IFN-α-iPSC-pMCs might constitute effective immune-stimulating agents for cancer that are refractory to checkpoint blockade.

In Vitro Detection of Cellular Adjuvant Properties of Human Invariant Natural Killer T Cells.

Invariant natural killer T (iNKT) cells are a subset of T lymphocytes that play a crucial role in the tumor surveillance. The activation of iNKT cells by their specific ligand α-galactosylceramide (α-GalCer) induces the activation of dendritic cells (DCs) via reciprocal interaction, which results in the generation of cellular immunity against cancer. Here we describe a method to detect DC-mediated cellular adjuvant properties of human iNKT cells in vitro.

Generation of HIV-Resistant Macrophages from IPSCs by Using Transcriptional Gene Silencing and Promoter-Targeted RNA.

Highly active antiretroviral therapy (HAART) has markedly prolonged the prognosis of HIV-1 patients. However, lifelong dependency on HAART is a continuing challenge, and an effective therapeutic is much desired. Recently, introduction of short hairpin RNA (shRNA) targeting the HIV-1 promoter was found to suppress HIV-1 replication via transcriptional gene silencing (TGS). The technology is expected to be applied with hemato-lymphopoietic cell transplantation of HIV patients to suppress HIV transcription in transplanted hemato-lymphopoietic cells. Combination of the TGS technology with new cell transplantation strategy with induced pluripotent stem cell (iPSC)-derived hemato-lymphopoietic cells might contribute to new gene therapy in the HIV field. In this study, we evaluated iPSC-derived macrophage functions and feasibility of TGS technology in macrophages. Human iPSCs were transduced with shRNAs targeting the HIV-1 promoter region (shPromA) by using a lentiviral vector. The shPromA-transfected iPSCs were successfully differentiated into functional macrophages, and they exhibited strong protection against HIV-1 replication with alteration in the histone structure of the HIV-1 promoter region to induce heterochromatin formation. These results indicated that iPS-derived macrophage is a useful tool to investigate HIV infection and protection, and that the TGS technology targeting the HIV promoter is a potential candidate of new gene therapy.