Phenotypic-based Discovery and Exploration of a Resorufin Scaffold with Activity against Mycobacterium Tuberculosis.

Tuberculosis remains a leading cause of death by infectious disease. The long treatment regimen and the spread of drug-resistant strains of the causative agent Mycobacterium tuberculosis (Mtb) necessitates the development of new treatment options. In a phenotypic screen, a nitrofuran-resorufin conjugate 1 was identified as a potent sub-micromolar inhibitor of whole cell Mtb. Complete loss of activity was observed for this compound in Mtb mutants affected in enzyme cofactor F420 biosynthesis (fbiC), suggesting that 1 undergoes prodrug activation in a manner similar to anti-tuberculosis prodrug pretomanid. Exploration of the structure-activity relationship led to the discovery of novel resorufin analogues that do not rely on the deazaflavin-dependent nitroreductase (Ddn) bioactivation pathway for their antimycobacterial activity. These analogues are of interest as they work through an alternative, currently unknown mechanism that may expand our chemical arsenal towards the treatment of this devastating disease.

GBERT: A hybrid deep learning model based on GPT-BERT for fake news detection.

The digital era has expanded social exposure with easy internet access for mobile users, allowing for global communication. Now, people can get to know what is going on around the globe with just a click; however, this has also resulted in the issue of fake news. Fake news is content that pretends to be true but is actually false and is disseminated to defraud. Fake news poses a threat to harmony, politics, the economy, and public opinion. As a result, bogus news detection has become an emerging research domain to identify a given piece of text as genuine or fraudulent. In this paper, a new framework called Generative Bidirectional Encoder Representations from Transformers (GBERT) is proposed that leverages a combination of Generative pre-trained transformer (GPT) and Bidirectional Encoder Representations from Transformers (BERT) and addresses the fake news classification problem. This framework combines the best features of both cutting-edge techniques-BERT's deep contextual understanding and the generative capabilities of GPT-to create a comprehensive representation of a given text. Both GPT and BERT are fine-tuned on two real-world benchmark corpora and have attained 95.30 % accuracy, 95.13 % precision, 97.35 % sensitivity, and a 96.23 % F1 score. The statistical test results indicate the effectiveness of the fine-tuned framework for fake news detection and suggest that it can be a promising approach for eradicating this global issue of fake news in the digital landscape.

Long COVID among people with HIV: A systematic review and meta-analysis.

BACKGROUND: People with HIV might be at an increased risk of long COVID (LC) because of their immune dysfunction and chronic inflammation and alterations in immunological responses against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2; coronavirus disease 2019 [COVID-19]). This systematic review aimed to evaluate the association between HIV infection and LC and the prevalence and characteristics of and risk factors for LC among people with HIV. METHODS: Multiple databases, including Embase, PubMed, PsycINFO, Web of Science, and Sociological Abstracts, were searched to identify articles published before June 2023. Published articles were included if they presented at least one LC outcome measure among people with HIV and used quantitative or mixed-methods study designs. For effects reported in three or more studies, meta-analyses using random-effects models were performed using R software. RESULTS: We pooled 39 405 people with HIV and COVID-19 in 17 eligible studies out of 6158 publications in all the databases. It was estimated that 52% of people with HIV with SARS-CoV-2 infection developed at least one LC symptom. Results from the random-effects model showed that HIV infection was associated with an increased risk of LC (odds ratio 2.20; 95% confidence interval 1.25-3.86). The most common LC symptoms among people with HIV were cough, fatigue, and asthenia. Risk factors associated with LC among people with HIV included a history of moderate-severe COVID-19 illness, increased interferon-gamma-induced protein 10 or tumour necrosis factor-α, and decreased interferon-ß, among others. CONCLUSIONS: The COVID-19 pandemic continues to exacerbate health inequities among people with HIV because of their higher risk of developing LC. Our review is informative for public health and clinical communities to develop tailored strategies to prevent aggravated LC among people with HIV.

Unlocking Trehalose's versatility: A comprehensive Journey from biosynthesis to therapeutic applications.

For over forty years, a sugar of rare configuration known as trehalose (two molecules of glucose linked at their 1-carbons), has been recognised for more than just its roles as a storage compound. The ability of trehalose to protect an extensive range of biological materials, for instance cell lines, tissues, proteins and DNA, has sparked considerable interest in the biotechnology and pharmaceutical industries. Currently, trehalose is now being investigated as a promising therapeutic candidate for human use, as it has shown potential to reduce disease severity in various experimental models. Despite its diverse biological effects, the precise mechanism underlying this observation remain unclear. Therefore, this review delves into the significance of trehalose biosynthesis pathway in the development of novel drug, investigates the inhibitors of trehalose synthesis and evaluates the binding efficiency of T6P with TPS1. Additionally, it also emphasizes the knowledge about the protective effect of trehalose on modulation of autophagy, combating viral infections, addressing the conditions like cancer and neurodegenerative diseases based on the recent advancement. Furthermore, review also highlight the trehalose's emerging role as a surfactant in delivering monoclonal antibodies that will further broadening its potential application in biomedicines.

Knowledge and Skill Retention in First-Year MBBS Students After Basic Life Support Training: A One-Year Longitudinal Study.

BACKGROUND: The Indian National Medical Council has incorporated the Basic Life Support (BLS) course in the foundation course of the undergraduate (MBBS) medical curriculum. However, medical teachers raise concerns about how training would affect the retention of Basic Life Support (BLS) abilities in the longer run. So, the current study assesses the knowledge and retention of BLS skills among first-year MBBS students over one year. METHODS: We included one hundred first-year MBBS students in our study who were trained for BLS, including theory, demonstrations and hands-on training using mannequins. Theoretical knowledge was assessed using pre-test and post-test questionnaires. At the same time, the skills were evaluated using Directly Observed Procedural Skills (DOPS) scores before, just after the training session, and again after one month, six months, and one year. Course feedback was also taken from the students after completing the sessions. RESULTS: There was a statistically significant difference between pre-and post-test knowledge scores, indicating that training improved their knowledge. (p < 0.001) There was also a statistically significant difference between pre-and post-test skills using DOPS (p < 0.001). There was no significant difference in the score when DOPS was conducted at one month, but a significant decrease in their skills was seen at six months and one year when compared with the Post Skill Score. (P < 0.001) CONCLUSIONS: The first-year medical students' knowledge and skills were enhanced by BLS training coupled with practical sessions. Such waning skills necessitate repeating the training at periodic intervals to reinform retention of skills acquired during BLS training.

Pulmonary mucormycosis as a presentation of COVID 19: Case series.

BACKGROUND: Pulmonary Mucormycosis (PM) is a relatively uncommon fungal disease, usually manifested in immunocompromised patients. It has an aggressive course, along with dilemmas in diagnosis and treatment. In view of the surge of Mucormycosis patients in COVID 19 pandemic, clinicians need to consider PM in suspected cases, and act in an expedited manner to avoid misdiagnosis and initiate prompt treatment. CASE PRESENTATION: In this case series, we present four cases of PM with varied presentation, clinical course and discuss management strategies. CONCLUSIONS: A strong suspicion of PM based on epidemiological and clinical findings should be considered, to ensure appropriate and timely treatment. It should be accompanied by judicious use of corticosteroids and aggressive control of comorbid conditions to decrease preventable morbidity and mortality.

Unveiling the Mysteries of the Blood-Brain Barrier: The Problem of the Brain/spinal Pharmacotherapy.

The most critical issue impeding the development of innovative cerebrospinal medications is the blood-brain barrier (BBB). The BBB limits the ability of most medications to penetrate the brain to the CNS. The BBB structure and functions are summarized, with the physical barrier generated by endothelial tight junctions and the transport barrier formed by transporters within the membrane and vesicular processes. The functions of connected cells, particularly the end feet of astrocytic glial cells, microglia, and pericytes, are described. The drugs that cross the blood brain barrier are explained below along with their mechanisms. Some of the associated conditions and problems are given.

Waldenström Macroglobulinaemia lymphoma patients have impaired platelet and coagulation function.

Clinical features in patients with the B-cell lymphoma, Waldenström Macroglobulinaemia (WM), include cytopenias, IgM-mediated hyperviscosity, fatigue, bleeding and bruising. Therapeutics such as Bruton's tyrosine kinase inhibitors (BTKis) exacerbate bleeding risk. Abnormal haemostasis arising from platelet dysfunction, altered coagulation or vascular impairment have not been investigated in WM patients. To evaluate haemostatic dysfunction in samples from WM patients. Whole blood (WB) samples were collected from 14 WM patients not receiving therapy, 5 patients receiving BTKis and 15 healthy donors (HDs). Platelet receptor levels and reticulation were measured by flow cytometry, plasma thrombin generation ± platelets by FRET assay, WB clotting potential by rotational thromboelastometry (ROTEM), and plasma soluble glycoprotein VI (sGPVI) and serum thrombopoietin (TPO) by ELISA. Donor platelet spreading, aggregation and ability to accelerate thrombin generation in the presence of WM-derived IgM were assessed. WM platelet receptor levels, responses to physiological agonists and plasma sGPVI were within normal ranges. WM platelets had reduced reticulation (p=0.0012) while serum TPO levels were increased (p=0.0040). WM plasma displayed slower thrombin generation (p=0.0080) and WM platelets contributed less to endogenous thrombin potential (ETP, p=0.0312). HD plasma or platelets incubated with IgM (50-60 mg/mL) displayed reduced spreading (p=0.0002), aggregation (p<0.0001) and ETP (p=0.0081). Alterations to thrombin potential and WB coagulation were detected in WM samples. WM IgM significantly impaired haemostasis in vitro. Platelet and coagulation properties are disturbed in well-managed WM patients.

Assessing Medical Students' Perspectives on Organ Donation: A Cross-Sectional Study.

Background Organ donation is a community service that not only saves lives but also improves the quality of life. The major concerns causing organ shortage in the country are the lack of awareness and correct knowledge among the public and myths and misconceptions clouding organ donation because of religious and cultural barriers. Material and methods A cross-sectional study was conducted among 300 medical students of a private medical college in the Telangana region, India, from July 2019 to October 2019 after approval from the Institutional Ethics Committee (IEC). A total of 300 participants (218 females (72.66%) and 82 males (27.33%)) were included in the study. Respondents completed a three-section questionnaire that included sociodemographic data, 15 questions on knowledge, and 12 questions on the attitude and ethical aspects of organ donation. Statistical tests utilized for investigation were the Student's t-test and one-way ANOVA to compare knowledge and attitude scores. Results The mean knowledge score among the participants was 10.85±1.79, with a P value of 0.45. The mean attitude score concerning organ donation among the participants was 45.5±4.47, with a P value of 0.44. The majority (87.1%) showed a positive attitude in this study. Conclusions The study emphasizes the necessity of interdisciplinary educational interventions for medical students to help them realize the complexities of the problem holistically. Their attitude regarding organ donation is not significantly affected by traditional educational interventions such as lectures and demonstrations. Educated healthcare professionals will play a critical role in motivating the public for the cause of organ donation promotion.

Adverse Childhood Experiences and HIV-Related Stigma: A Quantitative Survey of Tanzanian Men, June 2019.

Experiencing adverse childhood experiences (ACEs) may impact personal opinions, attitudes, and judgments, which can further result in HIV-related stigma. HIV-related stigma consequentially may impact HIV preventive measures such as HIV testing, pre-exposure prophylaxis uptake, and condom use. The extent to which ACEs influence HIV-related stigma perception has not been well studied. Therefore, the study aimed to examine the association between ACEs and perceived and interpersonal HIV-related stigma among Tanzanian HIV-negative men. Quantitative survey data were obtained from the Tanzania STEP (Self-Testing Education and Promotion) project established in four wards: Mabibo, Manzese, Tandale, and Mwanyanamala. A total of 507 men responded to the ACEs and HIV-related stigma questionnaires. ACEs were operationalized as types of ACEs (environmental, physical/psychological, sexual abuse) and ACE score (0 (reference) vs. 1, 2, 3, ≥ 4). Perceived HIV-related stigma was analyzed both as a binary (HIV stigma vs. no HIV stigma) and a continuous variable. Unadjusted and adjusted multinomial logistic and linear regression models were used to assess the associations between ACEs and HIV-related stigma. ACE types were associated with HIV stigma (b = 0.237, 95% CI [0.122-0.352], p = < .0001). Findings of the adjusted multinomial logistic regression model show that experiencing one ACE (aOR = 1.9; p-value = 0.023), two ACEs (aOR = 1.8; p-value = 0.044), four or more ACEs (aOR = 4.1; p-value = < 0.0001) were associated with greater perceived HIV-related stigma. Moreover, experiencing environmental (aOR = 8.6; p-value = 0.005), physical/psychological (aOR = 2.5; p-value = 0.004), and sexual abuse (aOR = 3.4; p-value = < 0.0001) were associated with higher odds of HIV-related stigma. Our study findings suggest that those who experience childhood trauma are more likely to have a higher perception of HIV-related stigma. Intervention programs targeting HIV stigma should consider addressing ACEs entailing the behavioral and psychological impact of childhood trauma.

Childhood sexual trauma and opioid use among older adults living with HIV.

Childhood sexual abuse (CSA) has been linked to substance use and substance use disorders in adulthood. However, there have been limited studies examining the relationship between CSA and opioid use among older adults living with HIV (OALH). Therefore, the aim of this study was to determine the association between CSA and opioid use among OALH (n = 91). Data were obtained from an HIV clinic population in South Carolina using paper-and-pen, and online questionnaires. CSA was operationalized using six questions from the Early Trauma Inventory-Self Report Form (Yes vs. No). Opioid use was self-report of the use of opioids including: heroin, fentanyl, Oxycontin, Vicodin, codeine, morphine (used vs. never used). Nested crude and multivariable logistic regression models adjusting for sociodemographic confounders were used to determine the association between CSA and opioid use. After adjusting for race, gender, age, and education, OALH who were CSA survivors were 21 times more likely to currently use opioids compared to OALH who were not exposed to CSA (adjusted OR: 21.1; 95% CI: 1.78-250.0). The association seen between CSA history and opioid use may be due to unresolved trauma among OALH. Trauma-informed interventions addressing CSA may help to reduce opioid use among OALH.

Review on Synthesis of 2-(2-Hydroxyaryl) Benzothiazoles (HBT) for Excited-State Intra-molecular Proton Transfer (ESIPT)-Based Detection of Ions and Biomolecules.

In this review, we present a systematic and comprehensive summary of the recent developments in the synthetic strategies of 2-(2-hydroxyarylsubstituted)-benzothiazole (HBT) framework along with incorporation of various substituents on phenolic and benzothiazole rings which affect the emission process. The literature, spanning the years 2015-2024, on excited-state intramolecular proton transfer (ESIPT)-based studies of HBT derivatives comprising the effects of solvent polarity, substituents, and extended conjugation on fluorophores has been searched. ESIPT, intramolecular charge transfer, and aggregation-induced emissions enable these fluorescent probes to specifically interact with analytes, thereby altering their luminescence characteristics to achieve analyte detection. These fluorescent probes exhibit large Stokes shifts, high quantum yields, and excellent color transitions. Finally, the applications of HBTs as ESIPT-based fluorescent probes for the detection of cations, anions, and biomolecules have been summarized. We anticipate that this review will provide a comprehensive overview of the current state of research in this field and encourage researchers to develop novel ESIPT-based fluorophores with new applications.

Phylodynamic Insights into Global Emergence and Diversification of the Tomato Pathogen Xanthomonas hortorum pv. gardneri.

The emergence of plant pathogens is often associated with waves of unique evolutionary and epidemiological events. Xanthomonas hortorum pv. gardneri is one of the major pathogens causing bacterial spot disease of tomatoes. After its first report in the 1950s, there were no formal reports on this pathogen until the 1990s, despite active global research on the pathogens that cause tomato and pepper bacterial spot disease. Given the recently documented global distribution of X. hortorum pv. gardneri, our objective was to examine genomic diversification associated with its emergence. We sequenced the genomes of X. hortorum pv. gardneri strains collected in eight countries to examine global population structure and pathways of emergence using phylodynamic analysis. We found that strains isolated post-1990 group by region of collection and show minimal impact of recombination on genetic variation. A period of rapid geographic expansion in X. hortorum pv. gardneri is associated with acquisition of a large plasmid conferring copper tolerance by horizontal transfer and coincides with the burgeoning hybrid tomato seed industry through the 1980s. The ancestry of X. hortorum pv. gardneri is consistent with introduction to hybrid tomato seed production and dissemination during the rapid increase in trade of hybrid seeds.

Institutional Experience of Routine Radiation Surveillance of Delay and Decay Tanks Facility in a Department Having High-dose Iodine Therapy Unit.

Background: Radioactive solid and liquid waste generated by patients after high-dose iodine therapy may lead to significant radiation exposure if not properly handled. Aims and Objectives: This study was conducted to monitor the radiation exposure along the sewerage drainage system of the high-dose iodine therapy ward and to rule out leakage if any, that might pose a potential radiation hazard to the general public (sewerage workers) and radiation health professional. Materials and Methods: The sewerage drainage system from isolation wards has multiple gate valves to regulate sewerage flow from the high-dose iodine therapy ward into delay and decay tanks (DDT) built, especially for the purpose. Radiation surveillance was done using a Geiger-Muller counter-based survey meter at 11 different locations on a weekly basis for 12 weeks. Results: A total of 26 patients underwent high-dose iodine ablation therapy during the study period in our department, with the highest recorded radiation exposure rate in the sewerage draining system in the 9th week of patient admission. This was at the common gate valve junction (location B) that directed sewerage waste from all four isolation rooms into the common pipeline leading to DDT. Minimal radiation exposure was recorded within Atomic Energy Regulatory Board -prescribed limits with no evidence of leakage. Conclusion: A routine radiation survey is an important component of overall radiation safety in the nuclear medicine department, including sewerage delay tank facilities, which helps keep the radiation exposure to acceptable levels by identifying timely leakage.

Molecular Mapping and Transfer of Quantitative Trait Loci (QTL) for Sheath Blight Resistance from Wild Rice Oryza nivara to Cultivated Rice (Oryza sativa L.).

Sheath blight (ShB) is the most serious disease of rice (Oryza sativa L.), caused by the soil-borne fungus Rhizoctonia solani Kühn (R. solani). It poses a significant threat to global rice productivity, resulting in approximately 50% annual yield loss. Managing ShB is particularly challenging due to the broad host range of the pathogen, its necrotrophic nature, the emergence of new races, and the limited availability of highly resistant germplasm. In this study, we conducted QTL mapping using an F2 population derived from a cross between a partially resistant accession (IRGC81941A) of Oryza nivara and the susceptible rice cultivar Punjab rice 121 (PR121). Our analysis identified 29 QTLs for ShB resistance, collectively explaining a phenotypic variance ranging from 4.70 to 48.05%. Notably, a cluster of four QTLs (qRLH1.1, qRLH1.2, qRLH1.5, and qRLH1.8) on chromosome 1 consistently exhibit a resistant response against R. solani. These QTLs span from 0.096 to 420.1 Kb on the rice reference genome and contain several important genes, including Ser/Thr protein kinase, auxin-responsive protein, protease inhibitor/seed storage/LTP family protein, MLO domain-containing protein, disease-responsive protein, thaumatin-like protein, Avr9/Cf9-eliciting protein, and various transcription factors. Additionally, simple sequence repeats (SSR) markers RM212 and RM246 linked to these QTLs effectively distinguish resistant and susceptible rice cultivars, showing great promise for marker-assisted selection programs. Furthermore, our study identified pre-breeding lines in the advanced backcrossed population that exhibited superior agronomic traits and sheath blight resistance compared to the recurrent parent. These promising lines hold significant potential for enhancing the sheath blight resistance in elite cultivars through targeted improvement efforts.

"I Don't Believe That One": A Qualitative Study of Undetectable = Untransmittable Views Among Older Adults Living With HIV in South Carolina.

ABSTRACT: Undetectable = Untransmittable (U = U) means that people with HIV who achieve and maintain an undetectable viral load have effectively zero risk of sexually transmitting the virus to others. However, research on how U = U is perceived by older adults living with HIV (OAH) is currently lacking. This study explored U = U views among OAH. From October 2019 to February 2020, we conducted open-ended interviews with 24 OAH recruited at an HIV clinic in South Carolina. Interviews were audio-recorded and transcribed. We employed thematic analysis in this study. Three themes emerged from the analysis: (a) Conflicting beliefs in U = U; (b) Use condoms regardless; and (c) Fear of HIV reinfection. Despite strong scientific evidence supporting U = U, some OAH do not believe in U = U. This lack of belief could deprive OAH of the benefits U = U offers. Therefore, it is vital to educate OAH about U = U to enhance their understanding and belief in U = U.

A trivalent protein-based pan-Betacoronavirus vaccine elicits cross-neutralizing antibodies against a panel of coronavirus pseudoviruses.

The development of broad-spectrum coronavirus vaccines is essential to prepare for future respiratory virus pandemics. We demonstrated broad neutralization by a trivalent subunit vaccine, formulating the receptor-binding domains of SARS-CoV, MERS-CoV, and SARS-CoV-2 XBB.1.5 with Alum and CpG55.2. Vaccinated mice produced cross-neutralizing antibodies against all three human Betacoronaviruses and others currently exclusive to bats, indicating the epitope preservation of the individual antigens during co-formulation and the potential for epitope broadening.

A Comparison between Farm-Related Stress, Mental Health, and Social Support between Men and Women Farmers.

Agricultural producers have worse mental health than the general population; however, recent research has not considered differences in stressors and mental health conditions by gender. A survey was mailed to a random sample of farmers in Illinois to screen for symptoms of anxiety and depression and identify sources of stress and social support. Men experienced more stress related to environmental and economic conditions than women, while women tended to have slightly higher levels of geographic isolation stress than men. Overall, there were no significant differences by gender in the proportion meeting the criteria for depression or anxiety; however, the results are higher than what is observed in the general population. Among those farmers who experience higher levels of stress about geographic isolation, the odds for women farmers to experience depressive symptoms are four times more than men farmers (OR 4.46 (0.91, 21.8); p = 0.06). Additional research should examine the relationship between social support and mental health. Interventions to reduce stress by gender should be considered.

Dormant carbohydrate reserves enhance pecan tree spring freeze tolerance: controlled environment observations.

Pecan (Carya illinoensis), an economically important deciduous tree, bears commercially valuable nutritional nuts. Spring freezes in April can severely injure pecan buds, decreasing bloom, and fruit set. This study determined how low temperatures affect pecan buds/flowers at different growth stages in several pecan scion/rootstock combinations. This study focused on three pecan scion/rootstock combinations: Pawnee/Peruque (PP), Kanza/Giles (KG), and Maramec/Colby (MC), grown at the Cimarron Valley Research Station, Perkins, Oklahoma. Branches at three different growth stages, i.e., outer bud scale shed, one week after bud break, and early bloom stages were collected from PP, MC, and KG. Branches were held in a Conviron E8 freezing unit at 4 temperatures (-2, 0, 2, and 4°C) for 4 and 8 hours; A total of 8 treatments. One sample set was kept as an untreated control. After 2-3 weeks, branch samples from all the temperature treatments were observed and categorized into two groups. Group one with number of branches had healthy buds/formation of healthy leaves/flowers and group two with number of dead branches. The carbohydrate content reserved from dormant was analyzed using an Anthrone reagent. Visual observations and carbohydrate analyses revealed differences in damage and carbohydrate content among the scion/rootstock combinations, low-temperature treatments, and growth stages. The MC combination had minimum visual damage to leaves, buds, and flowers and significantly lower soluble sugars and starch in bark phloem as well as significantly lower soluble sugars in woody tissue xylem. The KG combination had maximum visual damage and significantly higher soluble sugars and starches in the bark, and soluble sugars in the woody tissues. These results indicate the MC combination is more tolerant to spring freeze damage at all three growth stages compared to the other two pecan scion/rootstock combinations. The results also demonstrate the MC combination is using more non-structural carbohydrates, soluble sugars and starches, suggesting this is a possible mechanism in its freeze tolerance.

Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms.

Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender (P = 0.026), ≥2 autosomal monosomies (P < 0.001), -17/17p (P = 0.011), multi-hit TP53 allelic state (P < 0.001) and CUX1 co-alterations (P = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies (P = 0.004), TP53 VAF > 25% (P = 0.002), TP53 splice junction mutations (P = 0.007) and antecedent treated myeloid neoplasm (P = 0.001). In addition, mutations/deletions in CUX1, U2AF1, EZH2, TET2, CBL, or KRAS ('EPI6' signature) predicted inferior OS24 (HR = 2.0 [1.5-2.8]; P < 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals (N = 144), TP53 VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including TP53 splice junction mutations, EPI6 and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival (P < 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.