Signaling dynamics in coexisting monoclonal cell subpopulations unveil mechanisms of resistance to anti-cancer compounds.

BACKGROUND: Tumor heterogeneity is a main contributor of resistance to anti-cancer targeted agents though it has proven difficult to study. Unfortunately, model systems to functionally characterize and mechanistically study dynamic responses to treatment across coexisting subpopulations of cancer cells remain a missing need in oncology. METHODS: Using single cell cloning and expansion techniques, we established monoclonal cell subpopulations (MCPs) from a commercially available epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer cell line. We then used this model sensitivity to the EGFR inhibitor osimertinib across coexisting cell populations within the same tumor. Pathway-centered signaling dynamics associated with response to treatment and morphological characteristics of the MCPs were assessed using Reverse Phase Protein Microarray. Signaling nodes differentially activated in MCPs less sensitive to treatment were then pharmacologically inhibited to identify target signaling proteins putatively implicated in promoting drug resistance. RESULTS: MCPs demonstrated highly heterogeneous sensitivities to osimertinib. Cell viability after treatment increased > 20% compared to the parental line in selected MCPs, whereas viability decreased by 75% in other MCPs. Reduced treatment response was detected in MCPs with higher proliferation rates, EGFR L858R expression, activation of EGFR binding partners and downstream signaling molecules, and expression of epithelial-to-mesenchymal transition markers. Levels of activation of EGFR binding partners and MCPs' proliferation rates were also associated with response to c-MET and IGFR inhibitors. CONCLUSIONS: MCPs represent a suitable model system to characterize heterogeneous biomolecular behaviors in preclinical studies and identify and functionally test biological mechanisms associated with resistance to targeted therapeutics.

Nb2C and Nb2CO2 MXenes as Anodes in Li-Ion Batteries: A Comparative Study by First-Principles Calculations.

The new generation of Li-ion batteries is based on integrating 2D materials into the electrodes to increase the energy density while reducing the charging time and size. The two-dimensional transition metal carbide or nitride (MXene) materials offer ideal electronic properties, such as metallic behavior, low energy barriers for Li-ion diffusion, and structural stability. This study focuses on Nb2C and Nb2CO2 MXenes, which have shown promising Li-storage capacity, especially the oxidized phase. By using density functional theory (DFT) and thermodynamic criteria, we studied the Li intercalation process in both MXenes. The results show that the Li intercalation process in the oxidized phase is more stable. Also, the Li diffusion barriers are 35 and 250 meV for the bare and oxidized phase, due to the strong interaction between Li ions and O functional groups. Nb2C and Nb2CO2 MXenes deliver a maximum gravimetric theoretical capacity of 275 and 233.26 mA h/g, respectively, with a stable performance.

Comparison between Classical- and Rotational-Mechanical-Chair-Assisted Maneuvers in a Population of Patients with Benign Paroxysmal Positional Vertigo.

Introduction: Benign paroxysmal positional vertigo (BPPV) stands as the most common cause of peripheral vertigo. Its treatment with repositioning maneuvers on an examination table is highly effective. However, patients with back or neck problems, paraplegia, or other conditions face challenges with these maneuvers, potentially experiencing longer healing times and creating additional difficulties for physicians diagnosing and treating BPPV in everyday practice. The emergence of mechanical rotational chairs (MRCs) offers a more convenient alternative for performing these maneuvers. Objectives: The primary objective was to compare the effectiveness of maneuvers on the examination table with those on MRCs in BPPV patients diagnosed in the emergency room and randomly classified into one of the treatment options. The secondary objectives included a comparison of patient quality of life during BPPV episodes and after their resolution and an analysis of recurrences and associated risk factors. Methods: This was a cohort study on sixty-three patients diagnosed with BPPV in the emergency department. Patients were classified into two cohorts depending on diagnostic and treatment maneuvers (MRC or conventional repositioning maneuvers (CRMs)) and received weekly follow-ups until positioning maneuvers became negative. Subsequent follow-ups were conducted at 1 month, 3 months, and 6 months after the resolution of vertigo. Patients were classified into two groups based on their assigned treatment method. Results: Thirty-one patients were treated with CRMs and 32 with TRV. Mean age was 62.29 ± 17.67 years and the most affected canal was the PSC (96.8%). The mean number of required maneuvers was two, while 55.56% only required one maneuver until resolution. Recurrence was present in 26.98% of the patients during the 6-month follow-up. Comparing both cohorts, there were no statistically significant differences between treatments (TRV vs. CRM) regarding the number of maneuvers, number of recurrences, and days until remission of BPPV. Dizziness Handicap Inventory and Visual Analogue Scale values decreased considerably after BPPV resolution, with no statistically significant differences between the groups. Age was identified as a covariable in the number of maneuvers and days until BPPV resolution, showing that an increase in age implies a greater need of maneuvers. Conclusions: There was no difference between the means of treatment for BPPV in our population ot There was no difference between the groups of treatments for BPPV in our population. The quality of life of patients improved six months after the resolution of BPPV, regardless of the treatment applied.

Synthesis of silver-palladium Janus nanoparticles using co-sputtering of independent sources: experimental and theorical study.

Janus-type nanoparticles are important because of their ability to combine distinct properties and functionalities in a single particle, making them extremely versatile and valuable in various scientific, technological, and industrial applications. In this work, bimetallic silver-palladium Janus nanoparticles were obtained for the first time using the inert gas condensation technique. In order to achieve this, an original synthesis equipment built by Mantis Ltd. was modified by the inclusion of an additional magnetron in a second chamber, which allowed us to use two monometallic targets to sputter the two metals independently. With this arrangement, we could find appropriate settings at room temperature to promote the synthesis of bimetallic Janus nanoparticles. The structural properties of the resulting nanoparticles were investigated by transmission electron microscopy (TEM), and the chemical composition was analyzed by TEM energy dispersive spectroscopy (TEM-EDS), which, together with structural analysis, confirmed the presence of Janus-type nanostructures. Results of molecular dynamics and TEM simulations show that the differences between the crystalline structures of the Pd and Ag regions observed in the TEM micrographs can be explained by small mismatches in the orientations of the two regions of the particle. A density functional theory structural aims to understand the atomic arrangement at the interface of the Janus particle.

Atomic-Scale Description of the Magnetic TiN|FeCo Multilayers.

Motivated by the experimental findings of Wolff et al., we investigated the TiN|FeCo multilayers at the atomic scale. Four different models were employed to investigate the interface, considering both Fe and Co surface terminations of the FeCo compounds. The interface formation energy formalism was employed to study the thermodynamic stability of these models. The results show that an interface mediated by Co atoms is most likely to appear in the experiment. Also, the Fe surface termination is more viable than a Co surface termination. The magnetic moments of Co at the interface are 1.48 µB/atom, which denotes a decay compared to bulk (1.76 µB/atom). Besides, Ti acquires a very small induced magnetization of -0.05 µB/atom. Our proposed atomistic model of the TiN|FeCo multilayer system fits perfectly with the structure obtained in experiments, and it is a step forward in the theoretical-experimental design of wear-resistant coatings with outstanding magnetic and mechanical properties.

Histone deacetylase inhibition mitigates fibrosis-driven disease progression in recessive dystrophic epidermolysis bullosa.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a blistering disease caused by mutations in the gene encoding type VII collagen (C7). RDEB is associated with fibrosis, which is responsible for severe complications. The phenotypic variability observed in RDEB siblings suggests that epigenetic modifications contribute to disease severity. Identifying epigenetic changes may help to uncover molecular mechanisms underlying RDEB pathogenesis and new therapeutic targets. OBJECTIVES: To investigate histone acetylation in RDEB skin and to explore histone deacetylase inhibitors (HDACis) as therapeutic molecules capable of counteracting fibrosis and disease progression in RDEB mice. METHODS: Acetylated histone levels were detected in human skin by immunofluorescence and in RDEB fibroblasts by ELISA. The effects of Givinostat and valproic acid (VPA) on RDEB fibroblast fibrotic behaviour were assessed by collagen-gel contraction assay, Western blot and immunocytofluorescence for α-smooth muscle actin, ELISA for released transforming growth factor-ß1 (TGF-ß1). RNA-seq was performed in HDACi- and vehicle-treated RDEB fibroblasts. VPA was systemically administered to RDEB mice, and effects on overt phenotype were monitored. Fibrosis was investigated in the skin using histological and immunofluorescence analyses. Eye and tongue defects were examined microscopically. Mass spectrometry proteomics was performed on skin protein extracts from VPA-treated RDEB and control mice. RESULTS: Histone acetylation decreases in RDEB skin and primary fibroblasts. RDEB fibroblasts treated with HDACis lowered fibrotic traits including contractility, TGF-ß1 release, and proliferation. VPA administration to RDEB mice mitigated severe manifestations affecting eyes and paws. These effects were associated with fibrosis inhibition. Proteomic analysis of mouse skin revealed that VPA almost normalised protein sets involved in protein synthesis and immune response, processes linked to the increased susceptibility to cancer and bacterial infections observed in RDEB patients. CONCLUSIONS: Dysregulated histone acetylation contributes to RDEB pathogenesis by facilitating the progression of fibrosis. Repurposing of HDACi could be considered for disease-modifying treatments of RDEB.

ChatGPT as an information tool in rhinology. Can we trust each other today?

PURPOSE: ChatGPT (Chat-Generative Pre-trained Transformer) has proven to be a powerful information tool on various topics, including healthcare. This system is based on information obtained on the Internet, but this information is not always reliable. Currently, few studies analyze the validity of these responses in rhinology. Our work aims to assess the quality and reliability of the information provided by AI regarding the main rhinological pathologies. METHODS: We asked to the default ChatGPT version (GPT-3.5) 65 questions about the most prevalent pathologies in rhinology. The focus was learning about the causes, risk factors, treatments, prognosis, and outcomes. We use the Discern questionnaire and a hexagonal radar schema to evaluate the quality of the information. We use Fleiss's kappa statistical analysis to determine the consistency of agreement between different observers. RESULTS: The overall evaluation of the Discern questionnaire resulted in a score of 4.05 (± 0.6). The results in the Reliability section are worse, with an average score of 3.18. (± 1.77). This score is affected by the responses to questions about the source of the information provided. The average score for the Quality section was 3.59 (± 1.18). Fleiss's Kappa shows substantial agreement, with a K of 0.69 (p < 0.001). CONCLUSION: The ChatGPT answers are accurate and reliable. It generates a simple and understandable description of the pathology for the patient's benefit. Our team considers that ChatGPT could be a useful tool to provide information under prior supervision by a health professional.

Human Hsp70 Substrate-Binding Domains Recognize Distinct Client Proteins.

The 13 Hsp70 proteins in humans act on unique sets of substrates with diversity often being attributed to J-domain-containing protein (Hsp40 or JDP) cofactors. We were therefore surprised to find drastically different binding affinities for Hsp70-peptide substrates, leading us to probe substrate specificity among the 8 canonical Hsp70s from humans. We used peptide arrays to characterize Hsp70 binding and then mined these data using machine learning to develop an algorithm for isoform-specific prediction of Hsp70 binding sequences. The results of this algorithm revealed recognition patterns not predicted based on local sequence alignments. We then showed that none of the human isoforms can complement heat-shocked DnaK knockout Escherichia coli cells. However, chimeric Hsp70s consisting of the human nucleotide-binding domain and the substrate-binding domain of DnaK complement during heat shock, providing further evidence in vivo of the divergent function of the Hsp70 substrate-binding domains. We also demonstrated that the differences in heat shock complementation among the chimeras are not due to loss of DnaJ binding. Although we do not exclude JDPs as additional specificity factors, our data demonstrate substrate specificity among the Hsp70s, which has important implications for inhibitor development in cancer and neurodegeneration.

Bow and Lean Test for Rare Variants of Vertical Semicircular Canal BPPV.

OBJECTIVE: The objective of this study was to assess the clinical significance of the Bow and Lean Test (BLT) for the diagnosis of different variants of vertical canal Benign Paroxysmal Positional Vertigo (BPPV). BLT is commonly used for diagnoses of lateral semicircular canal (LSC) BPPV. However, vertical nystagmus in the BLT may indicate the presence of other variants such as PSC-BPPV. METHODS: 567 patients with vertical canal BPPV were recruited. Patients with anterior semicircular canal (ASC) or PSC-BPPV were weekly examined until the negativization of BPPV. Nystagmus characteristics during BLT were analyzed. RESULTS: Of 567 patients with vertical canal BPPV, 1.4% had ASC-BPPV. BLT was positive in 155 patients, showing patterns like down-beating nystagmus in bowing and no nystagmus in leaning (15.52% of patients), and down-beating in bowing and up-beating in leaning (6.17%), which was predominantly present in PSC-canalolithiasis. Statistically significant differences were observed in the direction of nystagmus provoked by BLT in PSC-BPPV subtypes. No significant differences were found in nystagmus latency or duration during BLT positions. Among BPPV subtypes, there was a significant difference in nystagmus duration and latency, especially between cupulolithiasis and other variants. BLT's sensitivity was 0.93 in bowing and 1 in a leaning position, while specificity was 0.93 and 0.82 respectively. CONCLUSION: Beyond the LSC, the BLT has expanded to other variants. However, study results differ likely due to variations in patient characteristics and test execution. Currently, no specific features for ASC have been found to differentiate it from PSC-BPPV limiting the test's use for this variant. LEVEL OF EVIDENCE: 3, according to Oxford Center for Evidence-Based Medicine Laryngoscope, 134:2405-2410, 2024.

Atomic-scale study of TiO2-GR nanohybrid formation by ALD: the effect of the gas phase precursor.

In the present work, we report on a theoretical-computational study of the growth mechanism of the TiO2-Graphene nanohybrid by atomic layer deposition. Hydroxyl groups (OH) are anchoring sites for interacting with the main ALD titanium precursors (Tetrakis (dimethylamino) Titanium, Titanium Tetrachloride, and Titanium Isopropoxide). Results demonstrate that the chemical nature of the precursor directly affects the reaction mechanism in each ALD growth step. Tetrakis(dimethylamino)titanium is the precursor that presents a higher affinity (lower energy barriers for the reaction) to hydroxylated graphene in the growth process. A complete reaction mechanism for each precursor was proposed. The differences between precursors were discussed through the non-covalent interactions index. Finally, the water molecules help reduce the energy barriers and consequently favor the formation of the TiO2-graphene nanohybrid.

Transfusion with Blood Plasma from Young Mice Affects rTg4510 Transgenic Tau Mice Modeling of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by the buildup of plaques and tangles in the brain. Tangles are formed when the stabilizing protein, tau, becomes hyperphosphorylated and clumps together. There are limited treatments for AD; therefore, the exploration of new treatments is warranted. Previous research showed that plasma transfusion from young donor mice improved spatial memory and increased synaptic proteins in old transgenic APP/PS1 mice, suggesting a remediation of memory and synaptic function. In the current study, plasma was transfused from 2-3-month-old young wildtype mice (WT) to 8-month-old rTg4510 mice expressing human tau (Tau). One week after the transfusions, behavior and tau pathology were examined. We found that Tau mice injected with plasma had lower expression of phosphorylated tau (ptau) in the brain, accompanied by fewer tau tangles in the cortex and CA1 region of the hippocampus and smaller tau tangles in the cortex, when compared to Tau mice injected with saline. Despite no improvement in behavior, the decreased level of ptau and tangles open the door to future studies involving plasma transfusions.

Potential long consequences from internal and external ecology: loss of gut microbiota antifragility in children from an industrialized population compared with an indigenous rural lifestyle.

Human health is strongly mediated by the gut microbiota ecosystem, which, in turn, depends not only on its state but also on its dynamics and how it responds to perturbations. Healthy microbiota ecosystems tend to be in criticality and antifragile dynamics corresponding to a maximum complexity configuration, which may be assessed with information and network theory analysis. Under this complex system perspective, we used a new analysis of published data to show that a children's population with an industrialized urban lifestyle from Mexico City exhibits informational and network characteristics similar to parasitized children from a rural indigenous population in the remote mountainous region of Guerrero, México. We propose then, that in this critical age for gut microbiota maturation, the industrialized urban lifestyle could be thought of as an external perturbation to the gut microbiota ecosystem, and we show that it produces a similar loss in criticality/antifragility as the one observed by internal perturbation due to parasitosis by the helminth A. lumbricoides. Finally, several general complexity-based guidelines to prevent or restore gut ecosystem antifragility are discussed.

Strain Effects on the Two-Dimensional Cr2N MXene: An Ab Initio Study.

Structural, electronic, and magnetic properties of two-dimensional Cr2N MXene under strain were studied. The uniaxial and biaxial strain was considered from -5 to 5%. Phonon dispersion was calculated; imaginary frequency was not found for both kinds of strain. Phonon density of states displays an interesting relation between strain and optical phonon gaps (OPGs), that it implies tunable thermal conductivity. When we apply biaxial tensile strain, the OPG increases; however, this is not appreciable under uniaxial strain. The electronic properties of the dynamically stable systems were investigated by calculating the band structure and electron localization function (ELF) along the (110) plane. The band structure showed a metallic behavior under compressive strain; nevertheless, under tensile strain, the system has a little indirect band gap of 0.16 eV. By analyzing, the ELF interactions between Cr-N are determined to be a weaker covalent bonding Cr2N under tensile strain. On the other hand, if the Cr atoms reduce or increase their self-distance, the magnetization alignment changes, also the magnetic anisotropy energy displays out-of-plane spin alignment. These properties extend the potential applications of Cr2N in the spintronic area as long as they can be grown on substrates with high lattice mismatch, conserving their magnetic properties.

Long-Term Evolution of Vestibular Compensation, Postural Control, and Perceived Disability in a Population of Patients with Vestibular Neuritis.

OBJECTIVES: The aim was to analyze and compare the compensatory process, vestibular dysfunction, postural control, and perceived disability in a population of patients with vestibular neuritis (VN). MATERIAL AND METHODS: This is a prospective and longitudinal study of 67 patients diagnosed with VN. Inclusion criteria were sudden onset of vertigo, unidirectional spontaneous horizontal nystagmus, and impairment in vestibular test. Exclusion criteria were imaging or clinical findings of any neurotologic disorder. All vestibular tests were performed; vHIT, vestibular evoked myogenic potentials (VEMPs), caloric test and computerized dynamic posturography (CDP), dizziness handicap inventory (DHI), and visual analogue scale (VAS) were also performed at every follow up. RESULTS: We observed a correlation between the composite score of CDP and baseline vestibular function elicited either by caloric test, VEMPs, or vHIT. There was a significant correlation between baseline vestibular function and first visit questionnaire scores. The main gain recovery for the horizontal canal was 0.1 ± 0.04 for the first three months. After that, the gain recovery significantly decreased. The presence of covert and overt saccades', latency and amplitude decreased, respectively, after the 6-month period, when compared to the baseline results. We also observed a decrease in the PR score from 3 months after the vestibular insult until the last follow up. We observed a significant decrease in DHI and VAS from the first visit until the last one. Those patients with an initial HC gain below 0.5 had significantly higher DHI and VAS scores at every follow up. CONCLUSIONS: There are different measurements that could become a complete measurement of the state of compensation, postural control, and disability of the patients. There is a time window in which the vestibular restoration could give us clinical insights regarding the management of VN patients.

Incorporating the Concept of Relevance in Clinical Rehabilitation Research and Its Reviews May Improve Uptake by Stakeholders.

ABSTRACT: The "relevance" of research to stakeholders is an important factor in influencing the uptake of new knowledge into practice; however, this concept is neither well defined nor routinely incorporated in clinical rehabilitation research. Developing a uniform definition, measurement standards, stakeholder engagement strategies, and guiding frameworks that bolster relevance may help incorporate the concept as a key element in research planning and design. This article presents a conceptual argument for why relevance matters, proposes a working definition, and suggests strategies for operationalizing the construct in the context of clinical rehabilitation research. We place special emphasis on the importance of promoting relevance to patients, caregivers, and clinicians and provide preliminary frameworks and innovative study designs that can assist clinical rehabilitation researchers in doing so. We argue that researchers who include a direct statement regarding why and to whom a study is relevant and who incorporate considerations of relevance throughout all phases of study design produce more useful research for patients, caregivers, and clinicians, increasing its chance of uptake into practice. Consistent consideration of relevance, particularly to nonacademic audiences, during the conceptualization, study design, presentation, and dissemination of clinical rehabilitation research may promote the uptake of findings by patients, caregivers, and providers.

A Biomechanical Analysis of Prophylactic Mesh Reinforced Porcine Laparotomy Incisions.

INTRODUCTION: Research indicates that prophylactic mesh may help prevent incisional hernia after laparotomy, but best practice patterns in these situations are still evolving. Here, we compare the failure loads (FLs) and biomechanical stiffness (BMS) of 35 porcine abdominal wall laparotomy incisions reinforced with meshes of various widths and fixation distances using biomechanical testing. METHODS: In each specimen, a 10-cm incision was made and closed using continuous 1-0 Maxon suture. Specimens were randomized to mesh width (none, 2.5 cm, 3 cm, 4 cm, 6 cm, 8 cm) and tack separation (1.5 cm, 2 cm apart) and the meshes secured in an onlay fashion. Cyclic loads oscillating from 15 N to 140 N were applied to simulate abdominal wall stress, and the specimens subsequently loaded to failure. FLs (N) and BMS (N/mm) were comparatively analyzed. RESULTS: All specimens failed via suture pull-through. FLs and BMS were lowest in specimens with suture-only (421.43 N; 11.69 N/mm). FLs and BMS were significantly higher in 4-cm mesh specimens (567.51 N) than those with suture, 2.5-cm, and 3.0-cm mesh (all P < 0.05). FLs in specimens with a greater number of tacks were consistently higher in meshes of similar sizes, although these did not reach significance. CONCLUSIONS: A 4-cm mesh reenforcement was superior to suture-only and smaller meshes at preserving strength in laparotomy closure in a porcine model but larger meshes (6 cm, 8 cm) did not provide an additional benefit. Meshes with more fixation points may be advantageous, but additional data are needed to make definitive conclusions.

High-Resolution Structure of the Nuclease Domain of the Human Parvovirus B19 Main Replication Protein NS1.

Two new structures of the N-terminal domain of the main replication protein, NS1, of human parvovirus B19 (B19V) are presented here. This domain (NS1-nuc) plays an important role in the "rolling hairpin" replication of the single-stranded B19V DNA genome, recognizing origin of replication sequences in double-stranded DNA, and cleaving (i.e., nicking) single-stranded DNA at a nearby site known as the terminal resolution site (trs). The three-dimensional structure of NS1-nuc is well conserved between the two forms, as well as with a previously solved structure of a sequence variant of the same domain; however, it is shown here at a significantly higher resolution (2.4 Å). Using structures of NS1-nuc homologues bound to single- and double-stranded DNA, models for DNA recognition and nicking by B19V NS1-nuc are presented that predict residues important for DNA cleavage and for sequence-specific recognition at the viral origin of replication. IMPORTANCE The high-resolution structure of the DNA binding and cleavage domain of the main replicative protein, NS1, from the human-pathogenic virus human parvovirus B19 is presented here. Included also are predictions of how the protein recognizes important sequences in the viral DNA which are required for viral replication. These predictions can be used to further investigate the function of this protein, as well as to predict the effects on viral viability due to mutations in the viral protein and viral DNA sequences. Finally, the high-resolution structure facilitates structure-guided drug design efforts to develop antiviral compounds against this important human pathogen.

Predicting the stability and electronic structure of alkali metal aurides.

Density functional theory calculations of phonon modes predict that some compounds of the alkali metal aurides family, general formulaA2MAu6(A= K, Rb or Cs;M= Ti, Zr, Hf, Sn or Pb), have stable three-dimensional phase with a double perovskite-type structure and cubicFm3¯mspace group (K2PtCl6-type). Bader's charge analysis shows that most electron density is located within the six atoms at the octahedra vertices like double perovskite halides. However, the short spacing between Au anions enables d-orbital interactions between them. Compounds of this family, with group 4 metals only, carry conduction states around the Γ point (k= 0). On the other hand, compounds with group 14 metals possess more conduction states around all the Brillouin zone and have electron pockets in their band structures. These compounds provide further insights into the unusual anionic behavior of gold and present other alternatives for the construction of divergent nanodevices.

Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML.

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P = .01; HR, 1.71; P < .001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P = .002, and HR, 1.47; P < .001), as was overall survival (HR, 1.32; P < .001, and HR, 1.45; P < .001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease.