A Brief Overview of the Molecular Landscape of Myelodysplastic Neoplasms.

Myelodysplastic neoplasm (MDS) is a heterogeneous group of clonal hematological disorders that originate from the hematopoietic and progenitor cells and present with cytopenias and morphologic dysplasia with a propensity to progress to bone marrow failure or acute myeloid leukemia (AML). Genetic evolution plays a critical role in the pathogenesis, progression, and clinical outcomes of MDS. This process involves the acquisition of genetic mutations in stem cells that confer a selective growth advantage, leading to clonal expansion and the eventual development of MDS. With the advent of next-generation sequencing (NGS) assays, an increasing number of molecular aberrations have been discovered in recent years. The knowledge of molecular events in MDS has led to an improved understanding of the disease process, including the evolution of the disease and prognosis, and has paved the way for targeted therapy. The 2022 World Health Organization (WHO) Classification and the International Consensus Classification (ICC) have incorporated the molecular signature into the classification system for MDS. In addition, specific germline mutations are associated with MDS development, especially in pediatrics and young adults. This article reviews the genetic abnormalities of MDS in adults with a brief review of germline predisposition syndromes.

Association between PTSD and Impedance Cardiogram-based contractility metrics during trauma recall: A controlled twin study.

Post-traumatic stress disorder (PTSD) is an independent risk factor for incident heart failure, but the underlying cardiac mechanisms remained elusive. Impedance cardiography (ICG), especially when measured during stress, can help understand the underlying psychophysiological pathways linking PTSD with heart failure. We investigated the association between PTSD and ICG-based contractility metrics (pre-ejection period (PEP) and Heather index (HI)) using a controlled twin study design with a laboratory-based traumatic reminder stressor. PTSD status was assessed using structured clinical interviews. We acquired synchronized electrocardiograms and ICG data while playing personalized-trauma scripts. Using linear mixed-effects models, we examined twins as individuals and within PTSD-discordant pairs. We studied 137 male veterans (48 pairs, 41 unpaired singles) from Vietnam War Era with a mean (standard deviation) age of 68.5(2.5) years. HI during trauma stress was lower in the PTSD vs. non-PTSD individuals (7.2 vs. 9.3 [ohm/s2 ], p = .003). PEP reactivity (trauma minus neutral) was also more negative in PTSD vs. non-PTSD individuals (-7.4 vs. -2.0 [ms], p = .009). The HI and PEP associations with PTSD persisted for adjusted models during trauma and reactivity, respectively. For within-pair analysis of eight PTSD-discordant twin pairs (out of 48 pairs), PTSD was associated with lower HI in neutral, trauma, and reactivity, whereas no association was found between PTSD and PEP. PTSD was associated with reduced HI and PEP, especially with trauma recall stress. This combination of increased sympathetic activation and decreased cardiac contractility combined may be concerning for increased heart failure risk after recurrent trauma re-experiencing in PTSD.

Data-driven approach for automatic detection of aortic valve opening: B point detection from impedance cardiogram.

Pre-ejection period (PEP), an indicator of sympathetic nervous system activity, is useful in psychophysiology and cardiovascular studies. Accurate PEP measurement is challenging and relies on robust identification of the timing of aortic valve opening, marked as the B point on impedance cardiogram (ICG) signals. The ICG sensitivity to noise and its waveform's morphological variability makes automated B point detection difficult, requiring inefficient and cumbersome expert visual annotation. In this article, we propose a machine learning-based automated algorithm to detect the aortic valve opening for PEP measurement, which is robust against noise and ICG morphological variations. We analyzed over 60 hr of synchronized ECG and ICG records from 189 subjects. A total of 3657 averaged beats were formed using our recently developed ICG noise removal algorithm. Features such as the averaged ICG waveform, its first and second derivatives, as well as high-level morphological and critical hemodynamic parameters were extracted and fed into the regression algorithms to estimate the B point location. The morphological features were extracted from our proposed "variable" physiologically valid search-window related to diverse B point shapes. A subject-wise nested cross-validation procedure was performed for parameter tuning and model assessment. After examining multiple regression models, Adaboost was selected, which demonstrated superior performance and higher robustness to five state-of-the-art algorithms that were evaluated in terms of low mean absolute error of 3.5 ms, low median absolute error of 0.0 ms, high correlation with experts' estimates (Pearson coefficient = 0.9), and low standard deviation of errors of 9.2 ms. For reproducibility, an open-source toolbox is provided.

The temporal relationships between sleep disturbance and autonomic dysregulation: A co-twin control study.

INTRODUCTION: Sleep disturbance is associated with autonomic dysregulation, but the temporal directionality of this relationship remains uncertain. The objective of this study was to evaluate the temporal relationships between objectively measured sleep disturbance and daytime or nighttime autonomic dysregulation in a co-twin control study. METHODS: A total of 68 members (34 pairs) of the Vietnam Era Twin Registry were studied. Twins underwent 7-day in-home actigraphy to derive objective measures of sleep disturbance. Autonomic function indexed by heart rate variability (HRV) was obtained using 7-day ECG monitoring with a wearable patch. Multivariable vector autoregressive models with Granger causality tests were used to examine the temporal directionality of the association between daytime and nighttime HRV and sleep metrics, within twin pairs, using 7-day collected ECG data. RESULTS: Twins were all male, mostly white (96%), with mean (SD) age of 69 (2) years. Higher daytime HRV across multiple domains was bidirectionally associated with longer total sleep time and lower wake after sleep onset; these temporal dynamics were extended to a window of 48 h. In contrast, there was no association between nighttime HRV and sleep measures in subsequent nights, or between sleep measures from previous nights and subsequent nighttime HRV. CONCLUSIONS: Daytime, but not nighttime, autonomic function indexed by HRV has bidirectional associations with several sleep dimensions. Dysfunctions in autonomic regulation during wakefulness can lead to subsequent shorter sleep duration and worse sleep continuity, and vice versa, and their influence on each other may extend beyond 24 h.

Validation of a new impedance cardiography analysis algorithm for clinical classification of stress states.

Pre-ejection period (PEP) is an index of sympathetic nervous system activity that can be computed from electrocardiogram (ECG) and impedance cardiogram (ICG) signals, but sensitive to speech/motion artifact. We sought to validate an ICG noise removal method, three-stage ensemble-average algorithm (TEA), in data acquired from a clinical trial comparing active versus sham non-invasive vagal nerve stimulation (tcVNS) after standardized speech stress. We first compared TEA's performance versus the standard conventional ensemble-average algorithm (CEA) approach to classify noisy ICG segments. We then analyzed ECG and ICG data to measure PEP and compared group-level differences in stress states with each approach. We evaluated 45 individuals, of whom 23 had post-traumatic stress disorder (PTSD). We found that the TEA approach identified artifact-corrupted beats with intraclass correlation coefficient > 0.99 compared to expert adjudication. TEA also resulted in higher group-level differences in PEP between stress states than CEA. PEP values were lower in the speech stress (vs. baseline rest) group using both techniques, but the differences were greater using TEA (12.1 ms) than CEA (8.0 ms). PEP differences in groups divided by PTSD status and tcVNS (active vs. sham) were also greater when using the TEA versus CEA method, although the magnitude of the differences was lower. In conclusion, TEA helps to accurately identify noisy ICG beats during speaking stress, and this increased accuracy improves sensitivity to group-level differences in stress states compared to CEA, suggesting greater clinical utility.

Low-Grade Primary Splenic CD10-Positive Small B-Cell Lymphoma/Follicular Lymphoma.

Primary splenic lymphoma (PSL) is a rare malignancy representing about 1% of all lymphoproliferative disorders, when using a strict definition that allows only involvement of spleen and hilar lymph nodes. In contrast, secondary low-grade B-cell lymphomas in the spleen, such as follicular lymphomas (FL), lymphoplasmacytic lymphoma and chronic lymphocytic leukemia/ small lymphocytic lymphoma, particularly as part of advanced stage disease, are more common. Indolent B cell lymphomas expressing CD10 almost always represent FL, which in its primary splenic form is the focus of this review. Primary splenic follicular lymphoma (PSFL) is exceedingly infrequent. This type of lymphoproliferative disorder is understudied and, in most cases, clinically characterized by splenomegaly or cytopenias related to hypersplenism. The diagnosis requires correlation of histopathology of spleen, blood and/or bone marrow with the correct immunophenotype (determined by flow cytometry and/or immunohistochemistry) and if necessary, additional molecular profiling. Management of this incurable disease is evolving, and splenectomy remains the mainstream treatment for stage I PSFL.

Novel Mutations in a Lethal Case of Lymphomatous Adult T Cell Lymphoma with Cryptic Myocardial Involvement.

The autopsy of a 65-year-old diabetic African American male revealed significant left myocardial involvement by adult T-cell leukemia/lymphoma (ATLL) despite normal pre-mortem fluorodeoxyglucose (FDG) uptake by positron emission tomography/computed tomography (PET/CT). Due to pre-existing diabetic cardiomyopathy with reduced ejection fraction (EF) and compatible imaging studies, cardiac lymphomatous involvement was not suspected. While peripheral blood was negative for leukemia, next-generation sequencing of a lymph node revealed at least eight novel mutations (AXIN1, R712Q, BARD1 R749K, CTNNB1 I315V, CUX1 P102T, DNMT3A S199R, FGFR2 S431L, LRP1B Y2560C and STAG2 I771M). These findings underscore a diagnostic pitfall in a rare lymphomatous variant of ATLL infiltrating myocardium and contribute to its molecular characterization.

An unbiased, efficient sleep-wake detection algorithm for a population with sleep disorders: change point decoder.

STUDY OBJECTIVES: The usage of wrist-worn wearables to detect sleep-wake states remains a formidable challenge, particularly among individuals with disordered sleep. We developed a novel and unbiased data-driven method for the detection of sleep-wake and compared its performance with the well-established Oakley algorithm (OA) relative to polysomnography (PSG) in elderly men with disordered sleep. METHODS: Overnight in-lab PSG from 102 participants was compared with accelerometry and photoplethysmography simultaneously collected with a wearable device (Empatica E4). A binary segmentation algorithm was used to detect change points in these signals. A model that estimates sleep or wake states given the changes in these signals was established (change point decoder, CPD). The CPD's performance was compared with the performance of the OA in relation to PSG. RESULTS: On the testing set, OA provided sleep accuracy of 0.85, wake accuracy of 0.54, AUC of 0.67, and Kappa of 0.39. Comparable values for CPD were 0.70, 0.74, 0.78, and 0.40. The CPD method had sleep onset latency error of -22.9 min, sleep efficiency error of 2.09%, and underestimated the number of sleep-wake transitions with an error of 64.4. The OA method's performance was 28.6 min, -0.03%, and -17.2, respectively. CONCLUSIONS: The CPD aggregates information from both cardiac and motion signals for state determination as well as the cross-dimensional influences from these domains. Therefore, CPD classification achieved balanced performance and higher AUC, despite underestimating sleep-wake transitions. The CPD could be used as an alternate framework to investigate sleep-wake dynamics within the conventional time frame of 30-s epochs.

Peripheral Vasoconstriction During Mental Stress and Adverse Cardiovascular Outcomes in Patients With Coronary Artery Disease.

RATIONALE: Excessive vasoconstriction in response to mental stress may be a potential mechanism by which acute psychological stress leads to adverse cardiac events. OBJECTIVES: We investigated whether excessive digital vasoconstriction during acute mental stress predicts adverse cardiovascular outcomes among patients with coronary artery disease. METHODS AND RESULTS: Five hundred forty-nine patients with stable coronary artery disease (age 63±9, 76% male, 29% black) underwent mental stress testing with a standardized public speaking stressor and followed prospectively for cardiovascular end points. Digital pulse wave amplitude was continuously measured using peripheral artery tonometry (PAT, Itamar Inc). Stress/rest PAT ratio (sPAT) of pulse wave amplitude during mental stress/baseline was calculated and dichotomized by the median value into low and high sPAT ratio groups. Upon 3-year follow-up, Fine and Gray's subdistribution hazard ratios were used to examine the association between sPAT ratio and the composite end point of cardiovascular death, myocardial infarction, revascularization, and hospitalization for heart failure. The median sPAT ratio was 0.68 (interquartile range, 0.48-0.88), indicating 32% vasoconstriction with mental stress. Men were more likely to have low sPAT ratio than women (odds ratio, 1.79; P=0.007) while those on ß-blockers were less likely to have low sPAT ratio (odds ratio, 0.52; P=0.003). After adjusting for demographic and cardiovascular risk factors, medications, and rate-pressure product change during mental stress, those with low sPAT ratio were at significantly higher risk of adverse outcomes (subdistribution hazard ratio, 1.77 [95% CI, 1.12-2.80]). CONCLUSIONS: Greater peripheral vasoconstriction with mental stress, denoted by a low sPAT ratio, is associated with a higher risk of adverse cardiovascular outcomes in patients with coronary artery disease.