Genetic and clinical characteristics of acute B-cell lymphoblastic leukemia with MEF2D fusions and report of two novel MEF2D rearrangements.

The MEF2D rearrangement is a recurrent chromosomal abnormality detected in approximately 2.4-5.3% of patients with acute B-cell lymphoblastic leukemia (B-ALL). Currently, MEF2D-rearranged B-ALL is not classified as an independent subtype in the WHO classification. Consequently, the clinical significance of MEF2D rearrangement in B-ALL remains largely unexplored. In this study, we retrospectively screened 260 B-ALL patients with RNA sequencing data collected between November 2018 and December 2022. Among these, 10 patients were identified with MEF2D rearrangements (4 with MEF2D::HNRNPUL1, 3 with MEF2D::BCL9, 1 with MEF2D::ARID1B, 1 with MEF2D::DAZAP1 and 1 with MEF2D::HNRNPM). Notably, HNRNPM and ARID1B are reported as MEF2D fusion partners for the first time. The patient with the MEF2D::HNRNPM fusion was resistant to chemotherapy and chimeric antigen receptor T-cell therapy and relapsed early after allogenic stem cell transplantation. The patient with MEF2D::ARID1B experienced early extramedullary relapse after diagnosis. All 10 patients achieved complete remission after induction chemotherapy. However, 9/10 (90%) of whom experienced relapse. Three of the 9 patients relapsed with aberrant expression of myeloid antigens. The median overall survival of these patients was only 11 months. This small cohort showed a high incidence of early relapse and short survival in patients with MEF2D rearrangements.

Clonal evolution from B-cell acute lymphoblastic leukemia with BCR::ABL1 multilineage involvement to acute myeloid leukemia after multiple anti-CD19 chimeric antigen receptor T-cell therapy.

Not available.

Optical mode manipulation using deep spatial diffractive neural networks.

In this paper, we investigate the theoretical models and potential applications of spatial diffractive neural network (SDNN) structures, with a particular focus on mode manipulation. Our research introduces a novel diffractive transmission simulation method that employs matrix multiplication, alongside a parameter optimization algorithm based on neural network gradient descent. This approach facilitates a comprehensive understanding of the light field manipulation capabilities inherent to SDNNs. We extend our investigation to parameter optimization for SDNNs of various scales. We achieve the demultiplexing of 5, 11 and 100 orthogonal orbital angular momentum (OAM) modes using neural networks with 4, 10 and 50 layers, respectively. Notably, the optimized 100 OAM mode demultiplexer shows an average loss of 0.52 dB, a maximum loss of 0.62 dB, and a maximum crosstalk of -28.24 dB. Further exploring the potential of SDNNs, we optimize a 10-layer structure for mode conversion applications. This optimization enables conversions from Hermite-Gaussian (HG) to Laguerre-Gaussian (LG) modes, as well as from HG to OAM modes, showing the versatility of SDNNs in mode manipulation. We propose an innovative assembly of SDNNs on a glass substrate integrated with photonic devices. A 10-layer diffractive neural network, with a size of 49 mm × 7 mm × 7 mm, effectively demultiplexes 11 orthogonal OAM modes with minimal loss and crosstalk. Similarly, a 20-layer diffractive neural network, with a size of 67 mm × 7 mm × 7 mm, serves as a highly efficient 25-channel OAM to HG mode converter, showing the potential of SDNNs in advanced optical communications.

Role of Nitrogenous Functional Group Identity in Accelerating 1,2,3-Trichloropropane Degradation by Pyrogenic Carbonaceous Matter (PCM) and Sulfide Using PCM-like Polymers.

Groundwater contamination by 1,2,3-trichloropropane (TCP) poses a unique challenge due to its human toxicity and recalcitrance to degradation. Previous work suggests that nitrogenous functional groups of pyrogenic carbonaceous matter (PCM), such as biochar, are important in accelerating contaminant dechlorination by sulfide. However, the reaction mechanism is unclear due, in part, to PCM's structural complexity. Herein, PCM-like polymers (PLPs) with controlled placement of nitrogenous functional groups [i.e., quaternary ammonium (QA), pyridine, and pyridinium cations (py+)] were employed as model systems to investigate PCM-enhanced TCP degradation by sulfide. Our results suggest that both PLP-QA and PLP-py+ were highly effective in facilitating TCP dechlorination by sulfide with half-lives of 16.91 ± 1.17 and 0.98 ± 0.15 days, respectively, and the reactivity increased with surface nitrogenous group density. A two-step process was proposed for TCP dechlorination, which is initiated by reductive ß-elimination, followed by nucleophilic substitution by surface-bound sulfur nucleophiles. The TCP degradation kinetics were not significantly affected by cocontaminants (i.e., 1,1,1-trichloroethane or trichloroethylene), but were slowed by natural organic matter. Our results show that PLPs containing certain nitrogen functional groups can facilitate the rapid and complete degradation of TCP by sulfide, suggesting that similarly functionalized PCM might form the basis for a novel process for the remediation of TCP-contaminated groundwater.

Observation of Chiral Symmetry Breaking in Toroidal Vortices of Light.

In this Letter, we explore the intersection of chirality and recently discovered toroidal spatiotemporal optical vortices (STOVs). We introduce "photonic conchs" theoretically as a new type of toroidal-like state exhibiting geometrical chirality, and experimentally observe these wave packets with controllable topological charges. Unlike toroidal STOVs, photonic conchs exhibit unique chirality-related dynamical evolution in free space and possess an orbital angular momentum correlated with all the dimensions of space-time. This research deepens our understanding of toroidal light states and potentially advances various fields by unveiling similar wave phenomena in a broader scope of physics systems, including acoustics and electronics.

Investigations of the prognostic value of RUNX1 mutation in acute myeloid leukemia patients: Data from a real-world study.

RUNX1 is one of the recurrent mutated genes in newly diagnosed acute myeloid leukemia (AML). Although historically recognized as a provisional distinct entity, the AML subtype with RUNX1 mutations (AML-RUNX1mut) was eliminated from the 2022 WHO classification system. To gain more insight into the characteristics of AML-RUNX1mut, we retrospectively analyzed 1065 newly diagnosed adult AML patients from the First Affiliated Hospital of Soochow University between January 2017 and December 2021. RUNX1 mutations were identified in 112 patients (10.5%). The presence of RUNX1 mutation (RUNX1mut) conferred a lower composite complete remission (CRc) rate (40.2% vs. 58.4%, P＜0.001), but no significant difference was observed in the 5-year overall survival (OS) rate (50.2% vs. 53.9%; HR=1.293; P=0.115) and event-free survival (EFS) rate (51.5% vs. 49.4%; HR=1.487, P=0.089), even within the same risk stratification. Multivariate analysis showed that RUNX1mut was not an independent prognostic factor for OS (HR=1.352, P=0.068) or EFS (HR=1.129, P=0.513). When patients were stratified according to induction regimen, RUNX1mut was an unfavorable factor for CRc both on univariate and multivariate analysis in patients receiving conventional chemotherapy, and higher risk stratification predicted worse OS. In those who received venetoclax plus hypomethylating agents, RUNX1mut was not predictive of CRc and comparable OS and EFS were seen between intermediate-risk and adverse-risk groups. The results of this study revealed that the impact of RUNX1mut is limited. Its prognostic value depended more on treatment and co-occurrent abnormalities. VEN-HMA may abrogate the prognostic impact of RUNX1, which merits a larger prospective cohort to illustrate.

Using blood transcriptome analysis for Alzheimer's disease diagnosis and patient stratification.

INTRODUCTION: Blood protein biomarkers demonstrate potential for Alzheimer's disease (AD) diagnosis. Limited studies examine the molecular changes in AD blood cells. METHODS: Bulk RNA-sequencing of blood cells was performed on AD patients of Chinese descent (n = 214 and 26 in the discovery and validation cohorts, respectively) with normal controls (n = 208 and 38 in the discovery and validation cohorts, respectively). Weighted gene co-expression network analysis (WGCNA) and deconvolution analysis identified AD-associated gene modules and blood cell types. Regression and unsupervised clustering analysis identified AD-associated genes, gene modules, cell types, and established AD classification models. RESULTS: WGCNA on differentially expressed genes revealed 15 gene modules, with 6 accurately classifying AD (areas under the receiver operating characteristics curve [auROCs] > 0.90). These modules stratified AD patients into subgroups with distinct disease states. Cell-type deconvolution analysis identified specific blood cell types potentially associated with AD pathogenesis. DISCUSSION: This study highlights the potential of blood transcriptome for AD diagnosis, patient stratification, and mechanistic studies. HIGHLIGHTS: We comprehensively analyze the blood transcriptomes of a well-characterized Alzheimer's disease cohort to identify genes, gene modules, pathways, and specific blood cells associated with the disease. Blood transcriptome analysis accurately classifies and stratifies patients with Alzheimer's disease, with some gene modules achieving classification accuracy comparable to that of the plasma ATN biomarkers. Immune-associated pathways and immune cells, such as neutrophils, have potential roles in the pathogenesis and progression of Alzheimer's disease.

A primer on the use of machine learning to distil knowledge from data in biological psychiatry.

Applications of machine learning in the biomedical sciences are growing rapidly. This growth has been spurred by diverse cross-institutional and interdisciplinary collaborations, public availability of large datasets, an increase in the accessibility of analytic routines, and the availability of powerful computing resources. With this increased access and exposure to machine learning comes a responsibility for education and a deeper understanding of its bases and bounds, borne equally by data scientists seeking to ply their analytic wares in medical research and by biomedical scientists seeking to harness such methods to glean knowledge from data. This article provides an accessible and critical review of machine learning for a biomedically informed audience, as well as its applications in psychiatry. The review covers definitions and expositions of commonly used machine learning methods, and historical trends of their use in psychiatry. We also provide a set of standards, namely Guidelines for REporting Machine Learning Investigations in Neuropsychiatry (GREMLIN), for designing and reporting studies that use machine learning as a primary data-analysis approach. Lastly, we propose the establishment of the Machine Learning in Psychiatry (MLPsych) Consortium, enumerate its objectives, and identify areas of opportunity for future applications of machine learning in biological psychiatry. This review serves as a cautiously optimistic primer on machine learning for those on the precipice as they prepare to dive into the field, either as methodological practitioners or well-informed consumers.

Ixekizumab-induced urticaria is associated with the short duration of remission in psoriasis by activation of mast cells.

BACKGROUND: Mast cell degranulation plays a pivotal role in urticaria and is also an early histologic characteristic of psoriasis. However, whether the activation of mast cells contributes to psoriasis recurrence after discontinuation of interleukin (IL)-17A blockers remains unclear. OBJECTIVE: To investigate the role of mast cells in ixekizumab treatment-associated urticaria (ITAUR) and assess the effect of urticaria eruption on psoriasis relapse. METHODS: A retrospective analysis was performed on biopsies of patients who experienced psoriasis relapse after discontinuation of ixekizumab. Transcriptomic and histopathologic features were assessed. Patterns were compared between patients with ITAUR and nonurticaria (NUR) as well as psoriasis-like mice with mast cell activation or inactivation. RESULTS: Patients with ITAUR experienced early relapse compared with NUR group after treatment withdrawal. Transcriptomic and histopathologic analyses revealed that patients with ITAUR had an elevated proportion of mast cells in resolved skin. Especially, the proportion of IL-17A+ mast cells was inversely correlated with the duration of remission. LIMITATIONS: The mechanism of mast cell activation in ITAUR has not been precisely elucidated. CONCLUSION: Ixekizumab treatment increases IL-17A+ mast cells in lesions of ITAUR, which is associated with early psoriasis relapse after ixekizumab withdrawal.

Serum lipidomic study of long-chain fatty acids in psoriasis patients prior to and after anti-IL-17A monoclonal antibody treatment by quantitative GC‒MS analysis with in situ extraction.

BACKGROUND: Long-chain fatty acids (LCFAs) are involved in regulating multiple physiological processes as signalling molecules. Gas chromatography-mass spectrometry (GC-MS) is widely used to quantify LCFAs. However, current quantitative methods for LCFAs using GC-MS have demonstrated complicated issues. Psoriasis is a chronic inflammatory skin disease, and its pathogenesis may be related to the overproduction of interleukin-17A (IL-17A). Clinical efficacy of anti-IL-17A monoclonal antibody (mAb) treatment in psoriasis patients has been demonstrated. Recent studies suggest that LCFAs play varying roles in the pathogenesis of psoriasis. However, more comprehensive research is needed to illuminate the mechanism of LCFAs in psoriasis. METHODS: The established in situ derivatization method for analysing LCFAs with a GC-MS platform was utilized to conduct serum lipidomics analysis of healthy volunteers and psoriasis patients receiving pretherapy and posttreatment with of anti-IL-17A mAb. Imiquimod (IMQ)-treated wild type (WT) and T-cell receptor delta chain knock-out (Tcrd-/-) mice were used to investigate the correlation between IL-17A and abnormal changes in LCFAs in psoriasis patients. RESULTS: A rapid and sensitive in situ extraction derivatization method for quantifying LCFAs using GC-MS was established. Serum lipidomic results showed that psoriasis patients had higher levels of saturated fatty acids (SFAs) and ω-6 polyunsaturated fatty acids (PUFAs) but lower levels of monounsaturated fatty acids (MUFAs) and ω-3 PUFAs than healthy individuals, indicating impaired serum LCFA metabolism. Anti-IL-17A mAb treatment affected most of these LCFA changes. Analysis of LCFAs in IMQ-treated mice showed that LCFAs increased in the serum of WT mice, while there were no significant changes in the Tcrd-/- mice. SFAs increased in IMQ-treated WT mice, while MUFAs showed the opposite trend, and PUFAs did not change significantly. CONCLUSIONS: This study presented a dependable method for quantifying LCFAs that enhanced sensitivity and reduced analysis time. The lipidomic analysis results showed that anti-IL-17A mAb not only ameliorated skin lesions in psoriasis patients but also affected abnormal LCFAs metabolism. Furthermore, the study indicated a potential correlation between IL-17A and abnormal LCFA metabolism in psoriasis patients, which was supported by the alterations in serum LCFAs observed in IMQ-treated WT and Tcrd-/- mice.

A rabies mRNA vaccine with H270P mutation in its glycoprotein induces strong cellular and humoral immunity.

Rabies is a lethal zoonotic disease that kills approximately 60,000 people each year. As the sole virion-surface protein, the rabies virus glycoprotein (RABV-G) mediates its host-cell entry. RABV-G's pre-fusion conformation displays major known neutralizing antibody epitopes, which can be used as immunogen for prophylaxis. H270P targeted mutation can stabilize RABV-G in the pre-fusion conformation. Herein, we report the development of a highly promising rabies mRNA vaccine composed of H270P targeted mutation packaged in lipid nanoparticle (LNP), named LNP-mRNA-G-H270P. Humoral and cellular immunity of this vaccine were assessed in mice comparing to the unmodified LNP-mRNA-G and a commercially available inactivated vaccine using one-way analysis of variance (ANOVA) followed by Dunnett's multiple comparisons test. The results show the titer of RABV-G-specific IgG and virus-neutralization antibody titers (VNTs) in LNP-mRNA-G-H270P group were significant higher than those in LNP-mRNA-G and inactivated vaccine groups. Likewise, IFN-γ-secreting splenocytes, level of IL-2 in the supernatant of spleen cells, as well as IFN-γ-producing CD4+ T cells in LNP-mRNA-G-H270P group were significant higher than those in the other two vaccine groups. Hence, these results demonstrated that targeting the H270P mutation in RABV-G through an mRNA-LNP vaccine platform represents a promising strategy for developing a more efficacious rabies vaccine.

Validation for the effect of intra-exposure patient motion on the assessment of radiostereometric implant migration in a tibial component phantom study.

BACKGROUND: An increasing number of radiostereometry (RSA) research studies have long-term follow-up implant migration outcomes, which show ascending curves of implant migration with occasionally decreasing migration. After scrutinizing images and RSA scenes related to the alternating curves, we suppose that intra-exposure patient motion may contribute to that. The main purposes of this in vitro study were 1) to identify whether the patient motion in different directions could result in the inaccurate assessment of implant migration, and 2) to figure out which direction(s) accounted for the alternating curves. HYPOTHESIS: It was hypothesized that the assessments of implant migration would be less precise and accurate than they could be when patient motion occurred, and such motion would contribute to the alternating curves of radiostereometric implant migration. MATERIALS AND METHODS: A customized phantom, assembled with a tibial component, was designed for simulating intra-exposure patient motion during follow-up RSA examinations. Two different Roentgen tubes were used as the current standard of radiology departments. Radiographs were acquired in a uniplanar technical arrangement. Two defined protocols were conducted: one is to simulate implant migration outcomes at post-op, the early stage (6months), and the later stage (2 to 10years) ; during the later stage, the other is to mimic patient motion by phantom motion in the medial-lateral (x), distal-proximal (y), and anterior-posterior (z) axes. RESULTS: Phantom motion could result in the inaccurate assessment of implant migration, and translations along the medial-lateral (x) axis were the most influenced by patient motion. Motion along the medial-lateral (x) axis could account for the curves with decreasing migration. DISCUSSION: Our assessments of implant migration may be less precise and accurate than they could be when intra-exposure patient motion occurs. We probably neglect the importance of 100% simultaneous exposures, and the influence of patient motion on RSA accuracy and data reliability, due to the difficulty in detecting patient (micro)motion. Electronically synchronized exposures of two paired Roentgen tubes are 100% simultaneous for image acquisition, and they are thus highly recommended for the assessment of implant migration in RSA. TYPE OF STUDY AND LEVEL OF PROOF: not applicable.

Preemptive inotuzumab ozogamicin eradicated measurable residual disease in Ph-negative acute lymphoblastic leukemia relapsed post CD19 CART therapy.

There are no reports of application of inotuzumab ozogamicin (InO) for the treatment of MRD in r/r B-ALL. We firstly report the efficacy of InO for a patient experienced morphological relapse after HSCT and molecular relapse after CART therapy.

Robust optical edge detection enabled by a twisted reflective q-plate.

Optical edge detection significantly reduces the image information load and is highly sought after in instant image processing. Robustness to the wavelength and polarization of light as well as mechanical vibration is a key requirement for practical applications. Here, a robust optical edge detector is proposed and demonstrated based on a reflective twisted liquid crystal q-plate. The device is composed of a mirror and a 1.46-µm-thick liquid crystal layer with a twist angle of 69.2°. The backtracking of the light inside the twisted medium forms a mirror symmetric twisted design and thus leads to a broadband self-compensated spiral phase modulation. By this means, an optical edge detector with excellent wavelength and polarization independence is presented for both coherent and partially coherent light sources. Additionally, the reflective design makes the system more compact and stable. This work supplies a practical design for robust optical edge detection, which may upgrade existing image processing techniques.

Time course from cochlear implant surgery to non-use for congenitally deaf recipients implanted as children over ten years ago.

Objective: To determine the time-course from first cochlear implantation to non-use, to characterise non-users' receptive and expressive communication, and document known risk factors for inconsistent use, for congenitally deaf non-users of cochlear implants implanted as children at least ten years ago. Methods: Retrospective service evaluation. All congenitally deaf patients who received a first cochlear implant as children at least ten years ago at a regional service, and were currently non-users, were identified. They were characterised in terms of ages at implantation and non-use, known risk factors for inconsistent CI use or CI non-use, and outcome measures were the Meaningful Auditory Integration Scale (MAIS) and Meaningful Use of Speech Scale (MUSS) scores. Results: Seventeen patients met the inclusion criteria. They were implanted from 1990 to 2006. Median age at implantation was 4 years (range: 2-11), median age at non-use was 17 years (range: 9-31), and median duration of use was 8.5 years (range: 4-25). All used sign or gesture as their primary expressive and receptive communication modes. In addition, each child had at least one other known risk factor for inconsistent CI use. At 3 years post-implantation, mean Parent-rated MAIS scores were 76.5% (N = 14), and mean MUSS scores were 43.1% (N = 9). Discussion: This cohort included cases where CI use was rejected following longer periods of time than previously reported, highlighting a need for long-term support, particularly around the ages of life transitions. Studies conducted when the earliest cohort of paediatric CI users were younger, and studies reliant on parent or patient reports, may under-estimate long-term non-use rates. No non-users were identified among congenitally-deaf children implanted 10-15 years ago. Further research is warranted to explore relationships between risk factors, including communication mode, and non-use to inform expectation setting and candidacy selection.

Evaluation of the Immunological Efficacy of an LNP-mRNA Vaccine Prepared from Varicella Zoster Virus Glycoprotein gE with a Double-Mutated Carboxyl Terminus in Different Untranslated Regions in Mice.

Cell-mediated immunity (CMI) plays a key role in the effectiveness of varicella zoster virus (VZV) vaccines, and mRNA vaccines have an innate advantage in inducing CMI. Glycoprotein E (gE) has been used widely as an antigen for VZV vaccines, and carboxyl-terminal mutations of gE are associated with VZV titer and infectivity. In addition, the untranslated regions (UTRs) of mRNA affect the stability and half-life of mRNA in the cell and are crucial for protein expression and antigenic translational efficiency. In this study, three UTRs were designed and connected to the nucleic acid sequence of gE-M, which is double mutated in the extracellular region of gE. Then, mRNA with different nucleic acids was encapsulated in lipid nanoparticles (LNPs), forming three LNP-mRNA VZV vaccines, named gE-M-Z, gE-M-M, and gE-M-P. The immune response elicited by these vaccines in mice was evaluated at intervals of 4 weeks, and the mice were sacrificed 2 weeks after the final immunization. In the results, the gE-M-P group, which retains the nucleic acid sequence of gE-M and is connected to Pfizer/BioNTech's BNT162b2 UTRs, induced the strongest humoral immune response and CMI. Because CMI is crucial for protection against VZV and for the design of VZV vaccines, this study provides a feasible strategy for improving the effectiveness and economy of future VZV vaccines.

Interrelation between the lipid accumulation product index and diabetic kidney disease in patients with type 2 diabetes mellitus.

Objective: The purpose of this study was to determine the relation between the lipid accumulation product index (LAPI) and diabetic kidney disease (DKD) in patients with type 2 diabetes mellitus (T2DM). Methods: Herein, 931 patients were enrolled and their data were collected. Then the interrelation between LAPI and DKD was assessed using multivariate logistic regression analyses (LRAs) and by a restricted cubic spline (RCS). Results: In total, 931 participants (352 females and 579 males) aged 55 years on average were included in the study. After adjusting for several confounders, the odds ratio for DKD was increased evidently in the third LAPI tertile compared with that in the first LAPI tertile. In addition, the RCS revealed a positive interrelation between LAPI and DKD. In the subgroup analyses, age, sex, hyperlipidemia, hypertension, and HbA1c did not significantly interact with LAPI. Conclusions: LAPI was higher in the DKD group than in the no-DKD group, and LAPI is positively linked with DKD, which may have potential value to diagnose DKD in clinical practice.

Associations between depressive, anxiety, stress symptoms and elevated blood pressure: Findings from the CHCN-BTH cohort study and a two-sample Mendelian randomization analysis.

BACKGROUND: We aimed to determine whether depressive, anxiety, stress symptoms were associated with the risk of elevated blood pressure by performing longitudinal cohort and Mendelian Randomization (MR) analyses. METHODS: We used data from the Cohort Study on Chronic Disease of Community Natural Population in the Beijing-Tianjin-Hebei region (CHCN-BTH) from 2017 to 2021. The Depression-Anxiety-Stress Scale was used to evaluate the depressive, anxiety, stress symptoms. The longitudinal associations between depressive, anxiety, stress symptoms and elevated blood pressure were estimated using Cox proportional regression models. Two-sample MR analysis was performed using the Inverse-variance weighted (IVW), weighted median, and MR-Egger to explore the causal relationships between depressive, anxiety, stress symptoms and elevated blood pressure. RESULTS: In total, 5624 participants were included. The risk of SBP ≥ 140 mmHg or DBP ≥ 90 mmHg was significantly higher in participants with baseline anxiety symptoms (HR = 1.48, 95 % CI: 1.03 to 2.12, P = 0.033; HR = 1.56, 95 % CI: 1.05 to 2.32, P = 0.028), especially in men and individuals with higher educational levels, independent of baseline depression and anxiety at the two-year follow-up. The two-sample MR analysis showed positive associations between depressive, anxiety, stress symptoms and elevated blood pressure. LIMITATION: Self-reported mental health symptoms, relatively shorter follow-up duration and the European-derived genome-wide association study data for MR analysis. CONCLUSIONS: Anxiety symptoms were positively associated with elevated blood pressures in the longitudinal analysis independent of depression, stress, and other confounders. The results were verified in MR analysis, providing evidence for causal effects of anxiety symptoms on the risk of elevated blood pressure.