Modeling the electroluminescence of atomic wires from quantum dynamics simulations.

Static and time-dependent quantum-mechanical approaches have been employed in the literature to characterize the physics of light-emitting molecules and nanostructures. However, the electromagnetic emission induced by an input current has remained beyond the realm of molecular simulations. This is the challenge addressed here with the help of an equation of motion for the density matrix coupled to a photon bath based on a Redfield formulation. This equation is evolved within the framework of the driven-Liouville von Neumann approach, which incorporates open boundaries by introducing an applied bias and a circulating current. The dissipated electromagnetic power can be computed in this context from the time derivative of the energy. This scheme is applied in combination with a self-consistent tight-binding Hamiltonian to investigate the effects of bias and molecular size on the electroluminescence of metallic and semiconducting chains. For the latter, a complex interplay between bias and molecular length is observed: there is an optimal number of atoms that maximizes the emitted power at high voltages but not at low ones. This unanticipated behavior can be understood in terms of the band bending produced along the semiconducting chain, a phenomenon that is captured by the self-consistency of the method. A simple analytical model is proposed that explains the main features revealed by the simulations. The methodology, applied here at a self-consistent tight-binding level but extendable to more sophisticated Hamiltonians such as density functional tight binding and time dependent density functional theory, promises to be helpful for quantifying the power and quantum efficiency of nanoscale electroluminescent devices.

Citrus psorosis virus 24K protein inhibits the processing of miRNA precursors by interacting with components of the biogenesis machinery.

Sweet orange (Citrus sinensis) is one of the most important fruit crops worldwide. Virus infections in this crop can interfere with cellular processes, causing dramatic economic losses. By performing RT-qPCR analyses, we demonstrated that citrus psorosis virus (CPsV)-infected orange plants exhibited higher levels of unprocessed microRNA (miRNA) precursors than healthy plants. This result correlated with the reported reduction of mature miRNAs species. The protein 24K, the CPsV suppressor of RNA silencing (VSR), interacts with miRNA precursors in vivo. Thus, this protein becomes a candidate responsible for the increased accumulation of unprocessed miRNAs. We analyzed 24K RNA-binding and protein-protein interaction domains and described patterns of its subcellular localization. We also showed that 24K colocalizes within nuclear D-bodies with the miRNA biogenesis proteins DICER-LIKE 1 (DCL1), HYPONASTIC LEAVES 1 (HYL1), and SERRATE (SE). According to the results of bimolecular fluorescence complementation and co-immunoprecipitation assays, the 24K protein interacts with HYL1 and SE. Thus, 24K may inhibit miRNA processing in CPsV-infected citrus plants by direct interaction with the miRNA processing complex. This work contributes to the understanding of how a virus can alter the regulatory mechanisms of the host, particularly miRNA biogenesis and function.IMPORTANCESweet oranges can suffer from disease symptoms induced by virus infections, thus resulting in drastic economic losses. In sweet orange plants, CPsV alters the accumulation of some precursors from the regulatory molecules called miRNAs. This alteration leads to a decreased level of mature miRNA species. This misregulation may be due to a direct association of one of the viral proteins (24K) with miRNA precursors. On the other hand, 24K may act with components of the cell miRNA processing machinery through a series of predicted RNA-binding and protein-protein interaction domains.

CD62-L down-regulation after L18-MDP stimulation as a complementary flow cytometry functional assay for the diagnosis of XIAP deficiency.

X-linked inhibitor of apoptosis (XIAP) deficiency is an infrequent inborn error of immunity caused by mutations in XIAP gene. Most cases present with absence of XIAP protein which can be detected by flow cytometry (FC), representing a rapid diagnostic method. However, since some genetic defects may not preclude protein expression, it is important to include a complementary functional test in the laboratory workup of these patients. L-selectin (CD62-L) is a molecule that is cleaved from the surface membrane of leukocytes upon stimulation of different receptors such as toll like receptors (TLRs) and nucleotide-binding oligomerization domain-like receptors (NLRs), including NOD2. Considering that XIAP deficiency impairs NOD2 signaling, we decided to assess CD62-L down-regulation by FC post-stimulation of neutrophils and monocytes with L18-muramyl Di-Peptide (L18-MDP), a NOD2 specific agonist, in order to develop a novel assay for the functional evaluation of patients with suspicion of XIAP defects. Whole blood samples from 20 healthy controls (HC) and four patients with confirmed molecular diagnosis of XIAP deficiency were stimulated with 200 ng/mL of L18-MDP for 2 h. Stimulation with 100 ng/mL of lipopolysaccharide (LPS) was carried out in parallel as a positive control of CD62-L shedding. CD62-L expression was evaluated by FC using an anti CD62-L- antibody and down-regulation was assessed by calculating the difference in CD62-L expression before and after stimulation, both in terms of percentage of CD62-L expressing cells (Δ%CD62-L) and median fluorescence intensity (ΔMFI%). Neutrophils and monocytes from XIAP deficient patients displayed a significantly diminished response to L18-MDP stimulation compared with HC (p < 0.0001), indicating a severely altered mechanism of CD62-L down-regulation following activation of NOD2-XIAP axis. On the other hand, the response to LPS stimulation was comparable between patients and heathy controls, suggesting preserved CD62-L shedding with a different stimulus. FC detection of CD62-L down-regulation in monocytes and neutrophils after whole blood stimulation with L18-MDP results in an effective and rapid functional test for the identification of XIAP deficient patients.

Isometric Exercise Training and Arterial Hypertension: An Updated Review.

Hypertension is recognised as a leading attributable risk factor for cardiovascular disease and premature mortality. Global initiatives towards the prevention and treatment of arterial hypertension are centred around non-pharmacological lifestyle modification. Exercise recommendations differ between professional and scientific organisations, but are generally unanimous on the primary role of traditional aerobic and dynamic resistance exercise. In recent years, isometric exercise training (IET) has emerged as an effective novel exercise intervention with consistent evidence of reductions in blood pressure (BP) superior to that reported from traditional guideline-recommended exercise modes. Despite a wealth of emerging new data and endorsement by select governing bodies, IET remains underutilised and is not widely prescribed in clinical practice. This expert-informed review critically examines the role of IET as a potential adjuvant tool in the future clinical management of BP. We explore the efficacy, prescription protocols, evidence quality and certainty, acute cardiovascular stimulus, and physiological mechanisms underpinning its anti-hypertensive effects. We end the review with take-home suggestions regarding the direction of future IET research.

Barriers to Community-Based Eradication of Helicobacter pylori Infection.

Helicobacter pylori (HP) is a causative agent in gastric cancer (GC).1 In the United States, HP is more prevalent in racial and ethnic minorities, including African Americans, Asian Americans, Latinos, and immigrants, the same groups that are more likely to develop and die from GC.2 Although screening for HP is not presently performed in the United States, there are plausible benefits to doing so, because HP is considered a group 1 carcinogen by the World Health Organization, and its link to GC parallels that of human papilloma virus and cervical cancer.1 HP eradication as a means of preventing GC also fulfils the Wilson and Jungner criteria for a successful screening program, and literature has consistently demonstrated that HP eradication reduces GC risk and death from GC.3 In fact, in countries with a high burden of GC, HP eradication is considered primary prevention for GC. As such, targeted HP testing in the United States may reduce GC burden in high-risk groups.4 We evaluate the results of community-based HP testing in an at-risk, underserved population.

Elevated cord levels of ustekinumab following its use in the treatment of Crohn's disease in pregnancy.

Ustekinumab (USK) was used in the treatment of two pregnant patients with Crohn's disease. It was given in the third trimester and restarted postnatally for both women. One woman remained on USK and in remission throughout pregnancy. The second woman, took a treatment break, flared, and then had remission induced with reintroduction of USK. Both women delivered healthy term infants. The interval from last dose to birth was 11 and 8 weeks respectively. Interestingly, USK levels in cord blood was observed in higher concentrations than in the maternal serum taken in third trimester. While no adverse effect in infants has been observed, clinicians should remain aware of fetal transfer when using USK in pregnancy. An evaluation of risk and benefit may favour continuing USK in pregnancy in patients with refractory disease.

Support Through Remote Observation and Nutrition Guidance (STRONG), a digital health intervention to reduce malnutrition among pancreatic cancer patients: A study protocol for a pilot randomized controlled trial.

Background: Malnutrition is a common and distressing condition among pancreatic cancer patients. Fewer than a quarter of pancreatic cancer patients receive medical nutrition therapy (MNT), important for improving nutritional status, weight maintenance, quality of life and survival. System, provider, and patient level barriers limit access to MNT. We propose to examine the feasibility of a 12-week multi-level, digital health intervention designed to expand MNT access among pancreatic cancer patients. Methods: Individuals with advanced pancreatic cancer starting chemotherapy (N = 80) will be 1:1 randomized to the intervention or usual care. The Support Through Remote Observation and Nutrition Guidance (STRONG) intervention includes system-level (e.g., routine malnutrition and screening), provider-level (e.g., dietitian training and web-based dashboard), and patient-level strategies (e.g., individualized nutrition plan, self-monitoring of dietary intake via Fitbit, ongoing goal monitoring and feedback). Individuals receiving usual care will be referred to dietitians based on their oncologists' discretion. Study assessments will be completed at baseline, 4-, 8-, 12-, and 16-weeks. Results: Primary outcomes will be feasibility (e.g., recruitment, retention, assessment completion) and acceptability. We will collect additional implementation outcomes, such as intervention adherence, perceived usability, and feedback on intervention quality via an exit interview. We will collect preliminary data on outcomes that may be associated with the intervention including malnutrition, quality of life, treatment outcomes, and survival. Conclusion: This study will advance our knowledge on the feasibility of a digital health intervention to reduce malnutrition among individuals with advanced pancreatic cancer. Trial registration: NCT05675059, registered on December 9, 2022.

Complement-mediated thrombotic microangiopathy treated with anticomplement protein 5 therapy, a retrospective study.

BACKGROUND: Complement-mediated thrombotic microangiopathy (CM-TMA), also called atypical hemolytic uremic syndrome (aHUS), is a difficult-to-diagnose rare disease that carries severe morbidity and mortality. Anti-C5 monoclonal antibodies (aC5-mab) are standard treatments, but large studies and long-term data are scarce. Here, we report our single institution experience to augment the knowledge of CM-TMA treated with aC5-mab therapy. METHODS: We aimed to assess the short and long-term effects of aC5-mab in patients diagnosed with CM-TMA treated outside of a clinical trial. This was a retrospective study. We included all patients diagnosed with CM-TMA and treated with aC5-mab at our institution. There were no exclusion criteria. Endpoints included complete TMA response (CR) defined as normalization of hematological parameters and ≥25% improvement in serum creatinine (Cr) from baseline in patients with renal disease, relapse defined as losing the previously achieved CR, morbidity, adverse events, and survival. RESULTS: We found 28 patients with CM-TMA treated with aC5-mab. The median age was 50 years. Baseline laboratories: platelet counts 93 × 109 /L, hemoglobin 8.6 g/dL, lactate dehydrogenase 1326 U/L, serum Cr 4.7 mg/dL, and estimated glomerular filtration rate 19 mL/min. One individual was on renal replacement therapy (RRT) and 10 initiated RRT within 5 days of the first dose of aC5-mab. Genetic variants associated with CM-TMA included mutations in C3, CFB, CFH, CFHR1/3, CFI, and MCP. The mean duration of hospitalization was 24 days. The median time to initiation of aC5-mab was 10 days. Sixteen subjects received RRT. At the time of hospital discharge, 27 were alive, 14 remained on RRT, and 4 had a CR. At 6 months, 23 patients were alive, 18 continued aC5-mab, 8 remained on RRT, and 9 had a CR. At the last follow-up visit past 6 months, 20 were alive, 14 continued aC5-mab, 5 remained on RRT, 12 had a CR, and 1 was lost to follow-up. CONCLUSIONS: Our study provides real-world experience and insight into the long-term outcomes of CM-TMA treated with aC5-mab. Our findings validate that CM-TMA is an aggressive disease with significant morbidity and mortality, and confirm that aC5-mab is a relatively effective therapy for CM-TMA. Our study adds practical, real-world experience to the literature, but future research remains imperative.

Enhanced Efficacy of Chemotherapy by Addition of Immune Checkpoint Inhibitors in Stage IV Large Cell Neuroendocrine Carcinoma of the Lung: A Real-World Analysis.

Background: Large Cell Neuroendocrine Carcinoma (LCNEC) is a high-grade malignancy with limited treatment options. Despite promising results of immunotherapy in non-small cell and small cell lung cancers, its benefit in LCNEC remains elusive. Methods: We included 24 patients diagnosed with stage IV LCNEC from the Moffitt Cancer Center database who received systemic therapy between January 2016 and May 2021. Group A comprised patients who received first-line CT and ICI (anti-PD-1 or anti-PD-L1 therapy for ICI, n = 11), and Group B received first-line CT only (n = 13). The collected data encompassed overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and toxicities since treatment initiation. Results: Kaplan-Meier survival analysis revealed median OS was 56 weeks (95%CI = 22.2-89.8) and 28 weeks (95% CI=16.3-39.7) in groups A and B, respectively. Log-rank test showed the difference was statistically significant (p=0.029). Median PFS was 32 weeks (95%CI=14.7-49.3) in group A and 20 weeks (95% CI=13.8-26.2) in groups B, but the difference was not statistically significant (p= 0.136). Univariate Cox analysis confirmed that the addition of ICI to CT significantly improved OS in patients with stage IV LCNEC (HR=0.35, 95% CI=0.13-0.95, p = 0.039). The ORR (63.6% vs 45.4%, p= 0.670) and DCR (81.8% vs 63.6%, p= 0.635) tended to be higher in group A than in group B but the difference was not statistically significant. Importantly, the combined treatment demonstrated a satisfactory safety profile, with only two patients reporting grade 2 or higher adverse events. Conclusions: Our results suggest that the combination of immunotherapy with chemotherapy holds potential for improving outcomes in stage IV LCNEC. Despite the retrospective nature and limited sample size of our study, these preliminary findings provide a valuable insight into the potential of immunotherapy in LCNEC treatment and encourage further research through larger, prospective trials.

Molecular dynamics study of the mechanical properties of drug loaded model systems: A comparison of a polymersome with a bilayer.

In this work we implement a new methodology to study structural and mechanical properties of systems having spherical and planar symmetries throughout Molecular Dynamics simulations. This methodology is applied here to a drug delivery system based in polymersomes, as an example. The chosen model drug was the local anesthetic prilocaine due to previous parameterization within the used coarse grain scheme. In our approach, mass density profiles (MDPs) are used to obtain key structural parameters of the systems, and pressure profiles are used to estimate the curvature elastic parameters. The calculation of pressure profiles and radial MPDs required the development of specific methods, which were implemented in an in-house built version of the GROMACS 2018 code. The methodology presented in this work is applied to characterize poly(ethylene oxide)-poly(butadiene) polymersomes and bilayers loaded with the model drug prilocaine. Our results show that structural properties of the polymersome membrane could be obtained from bilayer simulations, with significantly lower computational cost compared to whole polymersome simulations, but the bilayer simulations are insufficient to get insights on their mechanical aspects, since the elastic parameters are canceled out for the complete bilayer (as consequence of the symmetry). The simulations of entire polymersomes, although more complex, offer a complementary approach to get insights on the mechanical behavior of the systems.

Quality by Design (QbD) and Design of Experiments (DOE) as a Strategy for Tuning Lipid Nanoparticle Formulations for RNA Delivery.

The successful development of nonviral delivery systems for nucleic acids has been reported extensively over the past years. Increasingly employed to improve the delivery efficiency and therapeutic efficacy of RNA are lipid nanoparticles (LNPs). Many of the various critical formulation parameters can affect the quality attributes and effectiveness of these nano-formulations. Therefore, the systematic drug development approach (QbD) and multivariate design and statistical analysis (DOE) can be very helpful and recommended for the optimization of the composition and production of RNA-LNPs. This review addresses the concepts and applications of QbD and/or DOE for the development of lipid nanoparticles for the delivery of different types of RNA, reporting examples published in the ten recent years presenting the latest trends and regulatory requirements as well as the modern mathematical and statistical design methods. As the topic explored in this review is a novel approach, the full QbD has been described in only a few papers, and a few refer only to some aspects of QbD. In contrast, the DOE approach has been used in most of the optimization works. Different approaches and innovations in DOE have been observed. Traditional statistical tests and modeling (ANOVA, regression analysis) are slowly being replaced by artificial intelligence and machine learning methods.

Biointerfacial behavior of stallion spermatozoa adhered to hydrogel surfaces: Impact of the hydrogel chemical composition and the culture medium.

Novel soft materials based on hydrogel are proposed to enhance the selection of high-quality stallion sperm based on their adhesion capacity. The hydrogel surfaces are derived from polyacrylamide (PAAm), which is copolymerized with neutral and ionic co-monomers to modify the interfacial properties. The hydrogels undergo characterization through FTIR spectroscopy, assessment of swelling capacity, and wettability under various experimental conditions. Sperm adhesion capacity on the hydrogels is examined through several parameters including the percentage of bound sperm (%Sp) to hydrogels, tail oscillation intensity and flagellar movement. The biointerfacial properties of sperm-hydrogel systems vary based on the chemical composition of hydrogel as well as the components present in the culture medium. High %Sp and excellent metabolic activity of the spermatozoa are observed on hydrogel surfaces that possess moderate hydrophilicity. Specifically, a cationic hydrogel in BGM3 culture medium and a neutral surface in BGM3 medium supplemented with BSA exhibit favorable outcomes. Scanning Electron Microscopy (SEM) reveals the normal morphology of the head and tail in spermatozoa adhered to the hydrogel. Therefore, these hydrogel surfaces are potential materials for selecting stallion sperm with high quality, and their application could be extended to the study of other mammalian reproductive cells.

Impact of Normal and Overweight Pregnancy in GLUT4 and Glucose-Dependent Vascular Contractility.

INTRODUCTION: Obesity during pregnancy can contribute to hypertensive complications through changes in glucose utilization. We investigated the impact of vascular glucose uptake, GLUT4 density, and endothelium on agonist-induced vasoconstriction in the aortas of overweight pregnant rats. METHODS: Isolated aortic rings with or without endothelium from pregnant or nonpregnant rats fed a standard (SD) or hypercaloric diet (HD) were contracted with phenylephrine or serotonin (10-9 to 10-4M) using standard (11 mm) or without (0 mm) glucose Krebs solution. GLUT4 density in the aortas was measured using the en face method. RESULTS: Aortas from overweight pregnant animals (PHD) showed increased Phe-induced vasoconstriction (p < 0.05 vs. pregnant standard diet [PSD]), which was endothelium-independent. The contraction decreased significantly in the absence of glucose. In contrast, vessels from pregnant SD rats maintained their contraction in glucose-free Krebs solution. 5-HT increases PHD aortic contraction only in the absence of glucose. The fetal aortas from PHD mothers showed blunted vasoconstriction. Overweight significantly reduced GLUT4 expression in maternal and fetal aortas (p < 0.05 vs. PSD). CONCLUSIONS: Aortic contractility is independent of glucose uptake during healthy pregnancy. In contrast, overweight pregnancy increases contractility. This increase depends directly on smooth muscle glucose uptake and inversely on GLUT-4 density. The increased contraction observed in the vasculature of overweight mothers was inverted in the fetal aortas.

Anticoagulation With Platelet Transfusions for Acute Limb Ischemia With Severe Thrombocytopenia.

Acute limb ischemia (ALI) is a medical and surgical emergency, and the mainstays of treatment are therapeutic anticoagulation and surgery. These interventions require adequate platelet count and functionality. Anticoagulation and surgery can be complicated in thrombocytopenic patients and require interdisciplinary management for optimal outcomes, as literature is limited in this population. We present a case of a patient with severe thrombocytopenia who developed limb ischemia from cancer-associated thrombosis (CAT). We propose a management strategy for anticoagulation and perioperative platelet transfusion, with successful revascularization without adverse bleeding events. While successful, more data is required to investigate long-term outcomes.

Nanobubble Stability and Formation on Solid-Liquid Interfaces in Open Environments.

Are surface nanobubbles transient or thermodynamically stable structures? This question remained controversial until recently, when the stability of gas nanobubbles at solid-liquid interfaces was demonstrated from thermodynamic arguments in closed systems, establishing that bubbles with radii of hundreds of nanometers can be stable at modest supersaturations if the gas amount is finite. Here we develop a grand-canonical description of bubble formation that predicts that nanobubbles can nucleate and remain thermodynamically stable in open boundaries at high supersaturations when pinned to hydrophobic supports as small as a few nanometers. While larger bubbles can also be stable at lower supersaturations, the corresponding barriers are orders of magnitude above kT, meaning that their formation cannot proceed via heterogeneous nucleation on a uniform solid interface but must follow some alternative path. Moreover, we conclude that a source of growth-limiting mechanism, such as pinning or gas availability, is necessary for the thermodynamic stabilization of surface bubbles.

Insights into the Impact of Hesitancy on Cancer Care and COVID-19.

World Health Organization findings indicate that the COVID-19 pandemic adversely affected cancer diagnosis and management. The COVID-19 pandemic disrupted the optimal management of outpatient appointments, scheduled treatments, and hospitalizations for cancer patients because of hesitancy among patients and health-care providers. Travel restrictions and other factors likely affected medical, surgical, and radiation treatments during the COVID-19 pandemic. Cancer patients were more likely to be affected by severe illness and complications if they contracted COVID-19. A compromised immune system and comorbidities in cancer patients may have contributed to this increased risk. Hesitancy or reluctance to receive appropriate therapy or vaccination advice might have played a major role for cancer patients, resulting in health-care deficits. The purpose of this review is to evaluate the impact of COVID-19 on screening, entry into clinical trials, and hesitancy among patients and health-care professionals, limiting adjuvant and metastatic cancer treatment.

Water Self-Dissociation is Insensitive to Nanoscale Environments.

Nanoconfinement effects on water dissociation and reactivity remain controversial, despite their importance to understand the aqueous chemistry at interfaces, pores, or aerosols. The pKw in confined environments has been assessed from experiments and simulations in a few specific cases, leading to dissimilar conclusions. Here, with the use of carefully designed ab initio simulations, we demonstrate that the energetics of bulk water dissociation is conserved intact to unexpectedly small length-scales, down to aggregates of only a dozen molecules or pores of widths below 2 nm. The reason is that most of the free-energy involved in water autoionization comes from breaking the O-H covalent bond, which has a comparable barrier in the bulk liquid, in a small droplet of nanometer size, or in a nanopore in the absence of strong interfacial interactions. Thus, dissociation free-energy profiles in nanoscopic aggregates or in 2D slabs of 1 nm width reproduce the behavior corresponding to the bulk liquid, regardless of whether the corresponding nanophase is delimited by a solid or a gas interface. The present work provides a definite and fundamental description of the mechanism and thermodynamics of water dissociation at different scales with broader implications on reactivity and self-ionization at the air-liquid interface.

Association of Age With Treatment-Related Adverse Events and Survival in Patients With Metastatic Colorectal Cancer.

Importance: While the incidence of early-onset metastatic colorectal cancer (mCRC) has been increasing, studies on the age-related disparity in this group of patients are limited. Objective: To evaluate the association of age with treatment-related adverse events and survival in patients with mCRC and explore the potential underlying factors. Design, Setting, and Participants: This cohort study included 1959 individuals. Individual data on 1223 patients with mCRC who received first-line fluorouracil and oxaliplatin therapy in 3 clinical trials, and clinical and genomic data of 736 patients with mCRC from Moffitt Cancer Center were used to assess genomic alterations and serve as an external validation cohort. All statistical analyses were conducted from October 1, 2021, through November 12, 2022. Exposures: Metastatic colorectal cancer. Main Outcomes and Measures: Survival outcomes and treatment-related adverse events were compared among patients in 3 age groups: younger than 50 (early onset), 50 to 65, and older than 65 years. Results: In the total population of 1959 individuals, 1145 (58.4%) were men. Among 1223 patients from previous clinical trials, 179 (14.6%) in the younger than 50 years group, 582 (47.6%) in the 50 to 65 years group, and 462 (37.8%) in the older than 65 years group had similar baseline characteristics except for sex and race. The younger than 50 years group had significantly shorter progression-free survival (PFS) (hazard ratio [HR], 1.46; 95% CI, 1.22-1.76; P < .001) and overall survival (OS) (HR, 1.48; 95% CI, 1.19-1.84; P < .001) compared with the 50 to 65 years group after adjustment for sex, race, and performance status. Significantly shorter OS in the younger than 50 years group was confirmed in the Moffitt cohort. The younger than 50 years group had a significantly higher incidence of nausea and vomiting (69.3% vs 57.6% [50-65 years] vs 60.4% [>65 years]; P = .02), severe abdominal pain (8.4% vs 3.4% vs 3.5%; P = .02), severe anemia (6.1% vs 1.0% vs 1.5%; P < .001), and severe rash (2.8% vs 1.2% vs 0.4% P = .047). The younger than 50 years group also had earlier onset of nausea and vomiting (1.0 vs 2.1 vs 2.6 weeks; P = .01), mucositis (3.6 vs 5.1 vs 5.7 weeks; P = .05), and neutropenia (8.0 vs 9.4 vs 8.4 weeks; P = .04), and shorter duration of mucositis (0.6 vs 0.9 vs 1.0 weeks; P = .006). In the younger than 50 years group, severe abdominal pain and severe liver toxic effects were associated with shorter survival. The Moffitt genomic data showed that the younger than 50 years group had a higher prevalence of CTNNB1 mutation (6.6% vs 3.1% vs 2.3%; P = .047), ERBB2 amplification (5.1% vs 0.6% vs 2.3%; P = .005), and CREBBP mutation (3.1% vs 0.9% vs 0.5%; P = .05), but lower prevalence of BRAF mutation (7.7% vs 8.5% vs 16.7%; P = .002). Conclusions and Relevance: In this cohort study of 1959 patients, those with early-onset mCRC showed worse survival outcomes and unique adverse event patterns, which could be partially attributed to distinct genomic profiles. These findings may inform individualized management approaches in patients with early-onset mCRC.