Combined Flow-Fluorescence in situ hybridization to HHV-8 and EBV reveals the viral heterogeneity of primary effusion lymphoma.

Primary effusion lymphoma (PEL) is a rare B-cell non-Hodgkin lymphoma associated with Kaposi Sarcoma-associated herpesvirus (KSHV/HHV8) infection. Lymphoma cells are coinfected with Epstein-Barr virus (EBV) in 60-80% of cases. Tools allowing a reliable PEL diagnosis are lacking. This study reports PEL diagnosis in 4 patients using a Flow-Fluorescence in situ hybridization (FlowFISH) technique that allowed detection of differentially expressed EBV and HHV8 transcripts within the same sample, revealing viral heterogeneity of the disease. Moreover, infected cells exhibited variable expressions of CD19, CD38, CD40, and CD138. Therefore, FlowFISH is a promising tool to diagnose and characterize complex viral lymphoproliferations.

Laminar organization of neocortical activities during systemic anoxia.

The neocortex is highly susceptible to metabolic dysfunction. When exposed to global ischemia or anoxia, it suffers a slowly propagating wave of collective neuronal depolarization that ultimately impairs its structure and function. While the molecular signature of anoxic depolarization (AD) is well documented, little is known about the brain states that precede and follow AD onset. Here, by means of multisite extracellular local field potentials and intracellular recordings from identified pyramidal cells, we investigated the laminar expression of cortical activities induced by transient anoxia in rat primary somatosensory cortex. Soon after the interruption of brain oxygenation, we observed a well-organized sequence of stereotyped activity patterns across all cortical layers. This sequence included an initial period of beta-gamma activity, rapidly replaced by delta-theta oscillations followed by a decline in all spontaneous activites, marking the entry into a sustained period of electrical silence. Intracellular recordings revealed that cortical pyramidal neurons were depolarized and highly active during high-frequency activity, became inactive and devoid of synaptic potentials during the isoelectric state, and showed subthreshold composite synaptic depolarizations during the low-frequency period. Contrasting with the strong temporal coherence of pre-AD activities along the vertical axis of the cortical column, the onset of AD was not uniform across layers. AD initially occurred in layer 5 or 6 and then propagated bidirectionally in the upward and downward direction. Conversely, the post-anoxic waves that indicated the repolarization of cortical neurons upon brain reoxygenation did not exhibit a specific spatio-temporal profile. Pyramidal neurons from AD initiation site had a more depolarized resting potential and higher spontaneous firing rate compared to superficial cortical cells. We also found that the propagation pattern of AD was reliably reproduced by focal injection of an inhibitor of sodium­potassium ATPases, suggesting that cortical AD dynamics could reflect layer-dependent variations in cellular metabolic regulations.

Allogeneic transplantation in acute myelogenous leukemia: a comprehensive single institution's experience.

Debates on the role and timing of allogeneic hemtopoietic stem cell transplantation (HSCT) in acute myelogenous leukemia (AML) have persisted for decades. Time to transplant introduces an immortal time and current treatment algorithm mainly relies on the European LeukemiaNet disease risk classification. Previous studies are also limited to age groups, remission status and other ill-defined parameters. We studied all patients at diagnosis irrespective of age and comorbidities to estimate the cumulative incidence and potential benefit or disadvantage of HSCT in a single center. As a time-dependent covariate, HSCT improved overall survival in intermediate- and poor-risk patients (hazard ratio =0.51; P=0.004). In goodrisk patients only eight were transplanted in first complete remission. Overall, the 4-year cumulative incidence of HSCT was only 21.9% but was higher (52.1%) for patients in the first age quartile (16-57 years old) and 26.4% in older patients (57-70 years old) (P<0.001). It was negligible in patients older than 70 years reflecting our own transplant policy but also barriers to transplantation (comorbidities and remission status). However, HSCT patients need to survive, be considered eligible both by the referring and the HSCT physicians and have a suitable donor to get transplantation. We, thus, comprehensively analyzed the complete decision-making and outcome of all our AML patients from diagnosis to last followup to decipher how patient allocation and therapy inform the value of HSCT. The role of HSCT in AML is shifting with broad access to different donors including haploidentical ones. Thus, it may (or may not) lead to increased numbers of allogeneic HSCT in AML in adults.

Machine learning-based improvement of MDS-CBC score brings platelets into the limelight to optimize smear review in the hematology laboratory.

BACKGROUND: Myelodysplastic syndromes (MDS) are clonal hematopoietic diseases of the elderly characterized by chronic cytopenias, ineffective and dysplastic haematopoiesis, recurrent genetic abnormalities and increased risk of progression to acute myeloid leukemia. A challenge of routine laboratory Complete Blood Counts (CBC) is to correctly identify MDS patients while simultaneously avoiding excess smear reviews. To optimize smear review, the latest generations of hematology analyzers provide new cell population data (CPD) parameters with an increased ability to screen MDS, among which the previously described MDS-CBC Score, based on Absolute Neutrophil Count (ANC), structural neutrophil dispersion (Ne-WX) and mean corpuscular volume (MCV). Ne-WX is increased in the presence of hypogranulated/degranulated neutrophils, a hallmark of dysplasia in the context of MDS or chronic myelomonocytic leukemia. Ne-WX and MCV are CPD derived from leukocytes and red blood cells, therefore the MDS-CBC score does not include any platelet-derived CPD. We asked whether this score could be improved by adding the immature platelet fraction (IPF), a CPD used as a surrogate marker of dysplastic thrombopoiesis. METHODS: Here, we studied a cohort of more than 500 individuals with cytopenias, including 168 MDS patients. In a first step, we used Breiman's random forests algorithm, a machine-learning approach, to identify the most relevant parameters for MDS prediction. We then designed Classification And Regression Trees (CART) to evaluate, using resampling, the effect of model tuning parameters on performance and choose the "optimal" model across these parameters. RESULTS: Using random forests algorithm, we identified Ne-WX and IPF as the strongest discriminatory predictors, explaining 37 and 33% of diagnoses respectively. To obtain "simplified" trees, which could be easily implemented into laboratory middlewares, we designed CART combining MDS-CBC score and IPF. Optimal results were obtained using a MDS-CBC score threshold equal to 0.23, and an IPF threshold equal to 3%. CONCLUSIONS: We propose an extended MDS-CBC score, including CPD from the three myeloid lineages, to improve MDS diagnosis on routine laboratory CBCs and optimize smear reviews.

Clinical and biological features of B-cell neoplasms with CDK6 translocations: an association with a subgroup of splenic marginal zone lymphomas displaying frequent CD5 expression, prolymphocytic cells, and TP53 abnormalities.

A translocation involving the cyclin-dependent kinase 6 (CDK6) gene [t(CDK6)] is a rare but recurrent abnormality in B-cell neoplasms. To further characterise this aberration, we studied 57 cases; the largest series reported to date. Fluorescence in situ hybridisation analysis confirmed the involvement of CDK6 in all cases, including t(2;7)(p11;q21) immunoglobulin kappa locus (IGK)/CDK6 (n = 51), t(7;14)(q21;q32) CDK6/immunoglobulin heavy locus (IGH) (n = 2) and the previously undescribed t(7;14)(q21;q11) CDK6/T-cell receptor alpha locus (TRA)/T-cell receptor delta locus (TRD) (n = 4). In total, 10 patients were diagnosed with chronic lymphocytic leukaemia, monoclonal B-cell lymphocytosis or small lymphocytic lymphoma, and 47 had small B-cell lymphoma (SmBL) including 36 cases of marginal zone lymphoma (MZL; 34 splenic MZLs, one nodal MZL and one bronchus-associated lymphoid tissue lymphoma). In all, 18 of the 26 cytologically reviewed cases of MZL (69%) had an atypical aspect with prolymphocytic cells. Among the 47 patients with MZL/SmBL, CD5 expression was found in 26 (55%) and the tumour protein p53 (TP53) deletion in 22 (47%). The TP53 gene was mutated in 10/30 (33%); the 7q deletion was detected in only one case, and no Notch receptor 2 (NOTCH2) mutations were found. Immunoglobulin heavy-chain variable-region (IGHV) locus sequencing revealed that none harboured an IGHV1-02*04 gene. Overall survival was 82% at 10 years and not influenced by TP53 aberration. Our present findings suggest that most t(CDK6)+ neoplasms correspond to a particular subgroup of indolent marginal zone B-cell lymphomas with distinctive features.

Registering Unmanned Aerial Vehicle Videos in the Long Term.

Unmanned aerial vehicles (UAVs) have become a very popular way of acquiring video within contexts such as remote data acquisition or surveillance. Unfortunately, their viewpoint is often unstable, which tends to impact the automatic processing of their video flux negatively. To counteract the effects of an inconsistent viewpoint, two video processing strategies are classically adopted, namely registration and stabilization, which tend to be affected by distinct issues, namely jitter and drifting. Following our prior work, we suggest that the motion estimators used in both situations can be modeled to take into account their inherent errors. By acknowledging that drifting and jittery errors are of a different nature, we propose a combination that is able to limit their influence and build a hybrid solution for jitter-free video registration. In this work, however, our modeling was restricted to 2D-rigid transforms, which are rather limited in the case of airborne videos. In the present paper, we extend and refine the theoretical ground of our previous work. This addition allows us to show how to practically adapt our previous work to perspective transforms, which our study shows to be much more accurate for this problem. A lightweight implementation enables us to automatically register stationary UAV videos in real time. Our evaluation includes traffic surveillance recordings of up to 2 h and shows the potential of the proposed approach when paired with background subtraction tasks.

Making Advanced Electrogravimetry as an Affordable Analytical Tool for Battery Interface Characterization.

Numerous sophisticated diagnostic techniques have been designed to monitor electrode-electrolyte interfaces that mainly govern the lifetime and reliability of batteries. Among them is the electrochemical quartz crystal microbalance (EQCM) that offers valuable insights of the interfaces once the required conditions of the deposited film in terms of viscoelastic and hydrodynamic properties are fulfilled. Herein, we propose a friendly protocol that includes the elaboration of a homogeneous deposit by spray coating followed by QCM measurements at multiharmonic frequencies to ensure the film flatness and rigidity for collecting meaningful data. Moreover, for easiness of the measurements, we report the design of a versatile and airtight EQCM cell setup that can be used either with aqueous or non-aqueous electrolytes. We also present, using a model battery material, LiFePO4, how dual frequency and motional resistance monitoring during electrochemical cycling can be used as a well-suitable indicator for achieving reliable and reproducible electrogravimetric measurements. We demonstrate through this study the essential role of the solvent assisting lithium-ion insertion at the LiFePO4 interface with a major outcome of solvent-dependent interfacial behavior. Namely, in aqueous media, we prove a near-surface desolvation of lithium ions from their water solvation shell as compared with organic molecules. This spatial dissimilarity leads to a smoother Li-ion transport across the LFP-H2O interface, hence accounting for the difference in rate capability of LFP in the respective electrolytes. Overall, we hope our analytical insights on interfacial mechanisms will help in gaining a wider acceptance of EQCM-based methods from the battery community.

The bendamustine plus rituximab regimen is active against primary nodal marginal zone B-cell lymphoma.

Primary nodal marginal zone lymphoma (NMZL) is a rare disease. There is no current consensus on how to treat it. The bendamustine plus rituximab (BR) regimen is effective for the treatment of follicular and other indolent lymphomas, but its efficacy in NMZL is not known. We analyzed the outcome of 14 patients diagnosed with NMZL (median age 67 years) who were treated with 375 mg/m2 of rituximab on day 1 and 90 mg/m2 of bendamustine on days 1 and 2. The overall and complete response rates were 93% and 71%, respectively. Major toxicity (grade 3/4 neutropenia) occurred in 5% of treatment courses. After a median follow-up of 22 months (range: 18-55), the overall survival and the free survival rates were 100% and 93%, respectively. None of the patients showing a complete or partial response developed secondary myelodysplastic syndrome/acute myeloid leukemia. Bendamustine plus rituximab was found to be an active and well-tolerated regimen leading to the rapid control of disease.

Blastic Plasmacytoid Dendritic Cell Neoplasm: From Origin of the Cell to Targeted Therapies.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy with an aggressive clinical course. It is grouped with acute myeloid leukemia-related precursor neoplasms in the 2008 World Health Organization classification. Most patients with BPDCN have skin lesions at diagnosis and subsequent or simultaneous involvement of the bone marrow, peripheral blood, and lymph nodes. Patients usually respond to initial chemotherapy but often relapse. Stem cell transplantation may improve survival. This neoplasm is derived from precursors of plasmacytoid dendritic cells and is characterized by the coexpression of the immunophenotypic markers CD4, CD56, CD123, blood dendritic cell antigen-2, blood dendritic cell antigen-4, CD2AP, and lineage(-). Atypical immunophenotype expression may be present, making diagnosis difficult. BPDCN is often associated with a complex karyotype, frequent deletions of tumor suppressor genes, and mutations affecting either the DNA methylation or chromatin remodeling pathways. A better understanding of the etiology and pathophysiology of this neoplasm could open the way to new therapies targeting specific signaling pathways or involving epigenetics.

A mathematical model for predicting the adult height of girls with advanced puberty after spontaneous growth.

BACKGROUND: Advanced puberty in girls is defined as the onset of puberty between the ages of 8 yr and 10 yr. The objective was to predict adult height (AH) at initial evaluation and to characterize patients with an actual AH below -2 SD (152 cm) and/or lower than their target height (TH) by > one SD (5.6 cm). METHODS: Data analysis using multiple linear regression models was performed in 50 girls with advanced puberty who reached their AH after spontaneous puberty. RESULTS: The actual AH (159.0 ± 6.1 cm) was similar to the TH (161.2 ± 4.6 cm) and to the AH predicted at the initial evaluation (160.8 ± 6.0 cm), and the actual AH correlated positively with both (R = 0.76, P = 0.0003; R = 0.71, P = 0.008, respectively).The AH was below 152 cm in 7 girls, of whom 3 were characterized by paternal transmission of the advanced puberty. The AH was lower than the TH by >5.6 cm in 8 girls.The AH (cm) could be calculated at the initial evaluation: 1.8822 age + 3.3510 height (SD) - 0.7465 bone age - 1.7993 pubic hair stage + 2.8409 TH (SD) + 150.32.The formula is available online at http://www.kamick.org/lemaire/med/girls-advpub.html.The calculated AH (159.0 ± 5.7 cm) and the actual AH were highly correlated (R = 0.93). The actual AH was lower than the calculated AH by > 0.5 SD in only one case (4.35 cm). CONCLUSION: We established a formula that can be used at an initial evaluation to predict the AH, and then to assess the risk of reduced AH as a result of advanced puberty. According to this formula, the actual AH was lower than the calculated AH by more than 2.8 cm (0.5 SD) in only one girl. The AHs of the untreated girls with advanced puberty did not differ from those predicted at the initial evaluation by the Bayley and Pinneau table or from the THs. However, this study provides a useful and ready-to-use formula that can be an additional assessment of girls with advanced puberty.

Accurate Internal Monitoring of Batteries by Embedded Piezoelectric Sensors.

Advancements in operando techniques have unraveled the complexities of the Electrode Electrolyte Interface (EEI) in electrochemical energy storage devices. However, each technique has inherent limitations, often necessitating adjustments to experimental conditions, which may compromise accuracy. To address this challenge, a novel battery cell design is introduced, integrating piezoelectric sensors with electrochemical analysis for surface-sensitive operando measurements. This innovative approach aims to overcome conventional limitations by accommodating commercial-grade battery electrodes within a single body, alongside a piezoelectric sensor. This enables operando electrogravimetric measurements to be realized, and the electrochemistry of a battery to be more faithfully reproduced at the sensor level. A proof of concept is carried out on both Li-ion (LiFePO4//Graphite) and Na-ion (Na3V2(PO4)2F3//Hard carbon) systems, utilizing commercially available powder electrodes. In both cases, the results reveal rational mass variations at the sensor level during the cycling of commercial electrodes with mass loadings several orders of magnitude higher, while performing Galvanostatic Charge Discharge (GCD) tests across various C-rates. This innovative design opens up possibilities for a broader application of operando electrogravimetry within the battery community, to enhance the understanding of EEI behavior and facilitate the development of more efficient energy storage solutions.

Early detection of critical urban events using mobile phone network data.

Network Signalling Data (NSD) have the potential to provide continuous spatio-temporal information about the presence, mobility, and usage patterns of cell phone services by individuals. Such information is invaluable for monitoring large urban areas and supporting the implementation of decision-making services. When analyzed in real time, NSD can enable the early detection of critical urban events, including fires, large accidents, stampedes, terrorist attacks, and sports and leisure gatherings, especially if these events significantly impact mobile phone network activity in the affected areas. This paper presents empirical evidence that advanced NSD can detect anomalies in mobile traffic service consumption, attributable to critical urban events, with fine spatial (a spatial resolution of a few decameters) and temporal (minutes) resolutions. We introduce two methodologies for real-time anomaly detection from multivariate time series extracted from large-scale NSD, utilizing a range of algorithms adapted from the state-of-the-art in unsupervised machine learning techniques for anomaly detection. Our research includes a comprehensive quantitative evaluation of these algorithms on a large-scale dataset of NSD service consumption for the Paris region. The evaluation uses an original dataset of documented critical or unusual urban events. This dataset has been built as a ground truth basis for assessing the algorithms' performance. The obtained results demonstrate that our framework can detect unusual events almost instantaneously and locate the affected areas with high precision, largely outperforming random classifiers. This efficiency and effectiveness underline the potential of NSD-based anomaly detection in significantly enhancing emergency response strategies and urban planning. By offering a proactive approach to managing urban safety and resilience, our findings highlight the transformative potential of leveraging NSD for anomaly detection in urban environments.

Deciphering bone marrow engraftment after allogeneic stem cell transplantation in humans using single-cell analyses.

BACKGROUNDDonor cell engraftment is a prerequisite of successful allogeneic hematopoietic stem cell transplantation. Based on peripheral blood analyses, it is characterized by early myeloid recovery and T and B cell lymphopenia. However, cellular networks associated with bone marrow engraftment of allogeneic human cells have been poorly described.METHODSMass cytometry and CITE-Seq analyses were performed on bone marrow cells 3 months after transplantation in patients with acute myelogenous leukemia.RESULTSMass cytometric analyses in 26 patients and 20 healthy controls disclosed profound alterations in myeloid and B cell progenitors, with a shift toward terminal myeloid differentiation and decreased B cell progenitors. Unsupervised analysis separated recipients into 2 groups, one of them being driven by previous graft-versus-host disease (R2 patients). We then used single-cell CITE-Seq to decipher engraftment, which resolved 36 clusters, encompassing all bone marrow cellular components. Hematopoiesis in transplant recipients was sustained by committed myeloid and erythroid progenitors in a setting of monocyte-, NK cell-, and T cell-mediated inflammation. Gene expression revealed major pathways in transplant recipients, namely, TNF-α signaling via NF-κB and the IFN-γ response. The hallmark of allograft rejection was consistently found in clusters from transplant recipients, especially in R2 recipients.CONCLUSIONBone marrow cell engraftment of allogeneic donor cells is characterized by a state of emergency hematopoiesis in the setting of an allogeneic response driving inflammation.FUNDINGThis study was supported by the French National Cancer Institute (Institut National du Cancer; PLBIO19-239) and by an unrestricted research grant by Alexion Pharmaceuticals.

UBTF tandem duplications define a distinct subtype of adult de novo acute myeloid leukemia.

Tandem duplications (TDs) of the UBTF gene have been recently described as a recurrent alteration in pediatric acute myeloid leukemia (AML). Here, by screening 1946 newly diagnosed adult AML, we found that UBTF-TDs occur in about 3% of patients aged 18-60 years, in a mutually exclusive pattern with other known AML subtype-defining alterations. The characteristics of 59 adults with UBTF-TD AML included young age (median 37 years), low bone marrow (BM) blast infiltration (median 25%), and high rates of WT1 mutations (61%), FLT3-ITDs (51%) and trisomy 8 (29%). BM morphology frequently demonstrates dysmyelopoiesis albeit modulated by the co-occurrence of FLT3-ITD. UBTF-TD patients have lower complete remission (CR) rates (57% after 1 course and 76% after 2 courses of intensive chemotherapy [ICT]) than UBTF-wild-type patients. In patients enrolled in the ALFA-0702 study (n = 614 patients including 21 with UBTF-TD AML), the 3-year disease-free survival (DFS) and overall survival of UBTF-TD patients were 42.9% (95%CI: 23.4-78.5%) and 57.1% (95%CI: 39.5-82.8%) and did not significantly differ from those of ELN 2022 intermediate/adverse risk patients. Finally, the study of paired diagnosis and relapsed/refractory AML samples suggests that WT1-mutated clones are frequently selected under ICT. This study supports the recognition of UBTF-TD AML as a new AML entity in adults.

Probing the Electrode-Electrolyte Interface of a Model K-Ion Battery Electrode─The Origin of Rate Capability Discrepancy between Aqueous and Non-Aqueous Electrolytes.

Li-ion batteries are the electrochemical energy storage technology of choice of today's electrical vehicles and grid applications with a growing interest for Na-ion and K-ion systems based on either aqueous or non-aqueous electrolyte for power, cost, and sustainable reasons. The rate capability of alkali-metal-ion batteries is influenced by ion transport properties in the bulk of the electrolyte, as well as by diverse effects occurring at the vicinity of the electrode and electrolyte interface. Therefore, identification of the predominant factor affecting the rate capability of electrodes still remains a challenge and requires suitable experimental and computational methods. Herein, we investigate the mechanistic of the K+ insertion process in the Prussian blue phase, Fe4III[FeII(CN)6]3 in both aqueous and non-aqueous electrolytes, which reveals drastic differences. Through combined electrochemical characterizations, electrochemical-quartz-crystal-microbalance and ac-electrogravimetric analyses, we provide evidences that what matters the most for fast ion transport is the positioning of the partially solvated cations adsorbed at the material surface in aqueous as opposed to non-aqueous electrolytes. We rationalized such findings by molecular dynamics simulations that establish the K+ repartition profile within the electrochemical double layer. A similar trend was earlier reported by our group for the aqueous versus non-aqueous insertion of Li+ into LiFePO4. Such a study unveils the critical but overlooked role of the electrode-electrolyte interface in ruling ion transport and insertion processes. Tailoring this interface structuring via the proper salt-solvent interaction is the key to enabling the best power performances in alkali-metal-ion batteries.