A systematic search for RNA structural switches across the human transcriptome.

RNA structural switches are key regulators of gene expression in bacteria, but their characterization in Metazoa remains limited. Here, we present SwitchSeeker, a comprehensive computational and experimental approach for systematic identification of functional RNA structural switches. We applied SwitchSeeker to the human transcriptome and identified 245 putative RNA switches. To validate our approach, we characterized a previously unknown RNA switch in the 3' untranslated region of the RORC (RAR-related orphan receptor C) transcript. In vivo dimethyl sulfate (DMS) mutational profiling with sequencing (DMS-MaPseq), coupled with cryogenic electron microscopy, confirmed its existence as two alternative structural conformations. Furthermore, we used genome-scale CRISPR screens to identify trans factors that regulate gene expression through this RNA structural switch. We found that nonsense-mediated messenger RNA decay acts on this element in a conformation-specific manner. SwitchSeeker provides an unbiased, experimentally driven method for discovering RNA structural switches that shape the eukaryotic gene expression landscape.

Geriatric Emergency Medication Safety Recommendations (GEMS-Rx): Modified Delphi Development of a High-Risk Prescription List for Older Emergency Department Patients.

STUDY OBJECTIVE: Half of emergency department (ED) patients aged 65 years and older are discharged with new prescriptions. Potentially inappropriate prescriptions contribute to adverse drug events. Our objective was to develop an evidence- and consensus-based list of high-risk prescriptions to avoid among older ED patients. METHODS: We performed a modified, 3-round Delphi process that included 10 ED physician experts in geriatrics or quality measurement and 1 pharmacist. Consensus members reviewed all 35 medication categories from the 2019 American Geriatrics Society Beers Criteria and ranked each on a 5-point Likert scale (5=highest) for overall priority for avoidance (Round 1), risk of short-term adverse events and avoidability (Round 2), and reasonable medical indications for high-risk medication use (Round 3). RESULTS: For each round, questionnaire response rates were 91%, 82%, and 64%, respectively. After Round 1, benzodiazepines (mean, 4.60 [SD, 0.70]), skeletal muscle relaxants (4.60 [0.70]), barbiturates (4.30 [1.06]), first-generation antipsychotics (4.20 [0.63]) and first-generation antihistamines (3.70 [1.49]) were prioritized for avoidance. In Rounds 2 and 3, hypnotic "Z" drugs (4.29 [1.11]), metoclopramide (3.89 [0.93]), and sulfonylureas (4.14 [1.07]) were prioritized for avoidability, despite lower concern for short-term adverse events. All 8 medication classes were included in the final list. Reasonable indications for prescribing high-risk medications included seizure disorders, benzodiazepine/ethanol withdrawal, end of life, severe generalized anxiety, allergic reactions, gastroparesis, and prescription refill. CONCLUSION: We present the first expert consensus-based list of high-risk prescriptions for older ED patients (GEMS-Rx) to improve safety among older ED patients.

Core requirements of frailty screening in the emergency department: an international Delphi consensus study.

INTRODUCTION: Frailty is associated with adverse outcomes among patients attending emergency departments (EDs). While multiple frailty screens are available, little is known about which variables are important to incorporate and how best to facilitate accurate, yet prompt ED screening. To understand the core requirements of frailty screening in ED, we conducted an international, modified, electronic two-round Delphi consensus study. METHODS: A two-round electronic Delphi involving 37 participants from 10 countries was undertaken. Statements were generated from a prior systematic review examining frailty screening instruments in ED (logistic, psychometric and clinimetric properties). Reflexive thematic analysis generated a list of 56 statements for Round 1 (August-September 2021). Four main themes identified were: (i) principles of frailty screening, (ii) practicalities and logistics, (iii) frailty domains and (iv) frailty risk factors. RESULTS: In Round 1, 13/56 statements (23%) were accepted. Following feedback, 22 new statements were created and 35 were re-circulated in Round 2 (October 2021). Of these, 19 (54%) were finally accepted. It was agreed that ideal frailty screens should be short (<5 min), multidimensional and well-calibrated across the spectrum of frailty, reflecting baseline status 2-4 weeks before presentation. Screening should ideally be routine, prompt (<4 h after arrival) and completed at first contact in ED. Functional ability, mobility, cognition, medication use and social factors were identified as the most important variables to include. CONCLUSIONS: Although a clear consensus was reached on important requirements of frailty screening in ED, and variables to include in an ideal screen, more research is required to operationalise screening in clinical practice.

Risk of falls is associated with 30-day mortality among older adults in the emergency department.

OBJECTIVE: Falls in older adults correlate with heightened morbidity and mortality. Assessing fall risk in the emergency department (ED) not only aids in identifying candidates for prevention interventions but may also offer insights into overall mortality risk. We sought to examine the link between fall risk and 30-day mortality in older ED adults. METHODS: Observational cohort study of adults aged ≥ 75years who presented to an academic ED and who were assessed for fall risk using the Memorial Emergency Department Fall Risk Assessment Tool (MEDFRAT), a validated, ED-specific screening tool. The fall risk was classified as low (0-2 points), moderate (3-4 points), or high (≥5) risk. The primary outcome was 30-day mortality. Hazard ratios (HR) with 95% confidence intervals (CIs) were calculated. RESULTS: A total of 941 patients whose fall risk was assessed in the ED were included in the study. Median age was 83.7 years; 45.6% were male, 75.6% lived in private residences, and 62.7% were admitted. Mortality at 30 days among the high fall risk group was four times that of the low fall risk group (11.8% vs 3.1%; HR 4.00, 95% CI 2.18 to 7.34, p < 0.001). Moderate fall risk individuals had nearly double the mortality rate of the low-risk group (6.0% vs 3.1%), but the difference was not statistically significant (HR 1.98, 95% CI 0.91 to 4.32, p = 0.087). CONCLUSION: ED fall risk assessments are linked to 30-day mortality. Screening may facilitate the stratification of older adults at risk for health deterioration.

In adults aged ≥65 y with head injuries, use of warfarin, but not DOACs, was associated with delayed ICH.

SOURCE CITATION: Liu S, McLeod SL, Atzema CL, et al. Delayed intracranial hemorrhage after head injury among elderly patients on anticoagulation seen in the emergency department. CJEM. 2022;24:853-61. 36242733.

The Practice Change and Clinical Impact of Lung-Protective Ventilation Initiated in the Emergency Department: A Secondary Analysis of Individual Patient-Level Data From Prior Clinical Trials and Cohort Studies.

OBJECTIVES: Mechanically ventilated emergency department (ED) patients experience high morbidity and mortality. In a prior trial at our center, ED-based lung-protective ventilation was associated with improved care delivery and outcomes. Whether this strategy has persisted in the years after the trial remains unclear. The objective was to assess practice change and clinical outcomes associated with ED lung-protective ventilation. DESIGN: Secondary analysis of individual patient-level data from prior clinical trials and cohort studies. SETTING: ED and ICUs of a single academic center. PATIENTS: Mechanically ventilated adults. INTERVENTIONS: A lung-protective ventilator protocol used as the default approach in the ED. MEASUREMENTS AND MAIN RESULTS: The primary ventilator-related outcome was tidal volume, and the primary clinical outcome was hospital mortality. Secondary outcomes included ventilator-, hospital-, and ICU-free days. Multivariable logistic regression, propensity score (PS)-adjustment, and multiple a priori subgroup analyses were used to evaluate outcome as a function of the intervention. A total of 1,796 patients in the preintervention period and 1,403 patients in the intervention period were included. In the intervention period, tidal volume was reduced from 8.2 mL/kg predicted body weight (PBW) (7.3-9.1) to 6.5 mL/kg PBW (6.1-7.1), and low tidal volume ventilation increased from 46.8% to 96.2% ( p < 0.01). The intervention period was associated with lower mortality (35.9% vs 19.1%), remaining significant after multivariable logistic regression analysis (adjusted odds ratio [aOR], 0.43; 95% CI, 0.35-0.53; p < 0.01). Similar results were seen after PS adjustment and in subgroups. The intervention group had more ventilator- (18.8 [10.1] vs 14.1 [11.9]; p < 0.01), hospital- (12.2 [9.6] vs 9.4 [9.5]; p < 0.01), and ICU-free days (16.6 [10.1] vs 13.1 [11.1]; p < 0.01). CONCLUSIONS: ED lung-protective ventilation has persisted in the years since implementation and was associated with improved outcomes. These data suggest the use of ED-based lung-protective ventilation as a means to improve outcome.

Outcomes Associated With Rural Emergency Department Provider-to-Provider Telehealth for Sepsis Care: A Multicenter Cohort Study.

STUDY OBJECTIVE: To test the hypothesis that provider-to-provider tele-emergency department care is associated with more 28-day hospital-free days and improved Surviving Sepsis Campaign (SSC) guideline adherence in rural emergency departments (EDs). METHODS: Multicenter (n=23), propensity-matched, cohort study using medical records of patients with sepsis from rural hospitals in an established, on-demand, rural video tele-ED network in the upper Midwest between August 2016 and June 2019. The primary outcome was 28-day hospital-free days, with secondary outcomes of 28-day inhospital mortality and SSC guideline adherence. RESULTS: A total of 1,191 patients were included in the analysis, with tele-ED used for 326 (27%). Tele-ED cases were more likely to be transferred to another hospital (88% versus 8%, difference 79%, 95% confidence interval [CI] 75% to 83%). After matching and regression adjustment, tele-ED cases did not have more 28-day hospital-free days (difference 0.07 days more for tele-ED, 95% CI -0.04 to 0.17) or 28-day inhospital mortality (adjusted odds ratio [aOR] 0.51, 95% CI 0.16 to 1.60). Adherence with both the SSC 3-hour bundle (aOR 0.59, 95% CI 0.28 to 1.22) and complete bundle (aOR 0.45, 95% CI 0.02 to 11.60) were similar. An a priori-defined subgroup of patients treated by advanced practice providers suggested that the mortality was lower in the cohort with tele-ED use (aOR 0.11, 95% CI 0.02 to 0.73) despite no significant difference in complete SSC bundle adherence (aOR 2.88, 95% CI 0.52 to 15.86). CONCLUSION: Rural emergency department patients treated with provider-to-provider tele-ED care in a mature network appear to have similar clinical outcomes to those treated without.

In acute stroke with a large ischemic region, endovascular therapy improved functional status at 90 d.

SOURCE CITATION: Yoshimura S, Sakai N, Yamagami H, et al. Endovascular therapy for acute stroke with a large ischemic region. N Engl J Med. 2022;386:1303-13. 35138767.

In severe COVID-19, high-flow vs. conventional oxygen therapy reduced intubation and time to clinical recovery at 28 d.

SOURCE CITATION: Ospina-Tascón GA, Calderón-Tapia LE, García AF, et al. Effect of high-flow oxygen therapy vs conventional oxygen therapy on invasive mechanical ventilation and clinical recovery in patients with severe COVID-19: a randomized clinical trial. JAMA. 2021;326:2161-71. 34874419.

A Critical Appraisal of AHRQ's "Diagnostic Errors" Report.

The Agency for Healthcare Research and Quality (AHRQ) report "Diagnostic Errors in the Emergency Department" generated significant mass media interest with negative implications for the safety of contemporary emergency care. The assumptions and methodology underlying this report are problematic, while multiple ongoing efforts to improve the quality and quantity of diagnostic research are missed, neglected, or ignored. The AHRQ report identifies reasonable target diseases for targeting diagnostic quality improvement efforts, as well as viable methods by which to measure any initiatives impact on diagnostic error. We note additional opportunities to improve the status quo by funding emergency department-based diagnostic research and healthcare system-level patient safety research and highlighting innovative approaches to diagnostic science within emergency medicine.

Awareness With Paralysis Among Critically Ill Emergency Department Patients: A Prospective Cohort Study.

OBJECTIVES: In mechanically ventilated patients, awareness with paralysis (AWP) can have devastating consequences, including post-traumatic stress disorder (PTSD), depression, and thoughts of suicide. Single-center data from the emergency department (ED) demonstrate an event rate for AWP factors higher than that reported from the operating room. However, there remains a lack of data on AWP among critically ill, mechanically ventilated patients. The objective was to assess the proportion of ED patients experiencing AWP and investigate modifiable variables associated with its occurrence. DESIGN: An a priori planned secondary analysis of a multicenter, prospective, before-and-after clinical trial. SETTING: The ED of three academic medical centers. PATIENTS: Mechanically ventilated adult patients that received neuromuscular blockers. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: All data related to sedation and analgesia were collected. AWP was the primary outcome, assessed with the modified Brice questionnaire, and was independently adjudicated by three expert reviewers. Perceived threat, in the causal pathway for PTSD, was the secondary outcome. A total of 388 patients were studied. The proportion of patients experiencing AWP was 3.4% ( n = 13), the majority of whom received rocuronium ( n = 12/13; 92.3%). Among patients who received rocuronium, 5.5% ( n = 12/230) experienced AWP, compared with 0.6% ( n = 1/158) among patients who did not receive rocuronium in the ED (odds ratio, 8.64; 95% CI, 1.11-67.15). Patients experiencing AWP had a higher mean ( sd ) threat perception scale score, compared with patients without AWP (15.6 [5.8] vs 7.7 [6.0]; p < 0.01). CONCLUSIONS: AWP was present in a concerning proportion of mechanically ventilated ED patients, was associated with rocuronium exposure in the ED, and led to increased levels of perceived threat, placing patients at greater risk for PTSD. Studies that aim to further quantify AWP in this vulnerable population and eliminate its occurrence are urgently needed.

The Feasibility of Implementing Targeted SEDation in Mechanically Ventilated Emergency Department Patients: The ED-SED Pilot Trial.

OBJECTIVES: Deep sedation in the emergency department (ED) is common, increases deep sedation in the ICU, and is negatively associated with outcome. Limiting ED deep sedation may, therefore, be a high-yield intervention to improve outcome. However, the feasibility of conducting an adequately powered ED-based clinical sedation trial is unknown. Our objectives were to assess trial feasibility in terms of: 1) recruitment, 2) protocol implementation and practice change, and 3) safety. Patient-centered clinical outcomes were assessed to better plan for a future large-scale clinical trial. DESIGN: Pragmatic, multicenter ( n = 3), prospective before-after pilot and feasibility trial. SETTING: The ED and ICUs at three medical centers. PATIENTS: Consecutive, adult mechanically ventilation ED patients. INTERVENTIONS: An educational initiative aimed at reliable ED sedation depth documentation and reducing the proportion of deeply sedated patients (primary outcome). MEASUREMENTS AND MAIN RESULTS: Sedation-related data in the ED and the first 48 ICU hours were recorded. Deep sedation was defined as a Richmond Agitation-Sedation Scale of -3 to -5 or a Sedation-Agitation Scale of 1-3. One thousand three hundred fifty-six patients were screened; 415 comprised the final population. Lighter ED sedation was achieved in the intervention group, and the proportion of deeply sedated patients was reduced from 60.2% to 38.8% ( p < 0.01). There were no concerning trends in adverse events (i.e., inadvertent extubation, device removal, and awareness with paralysis). Mortality was 10.0% in the intervention group and 20.4% in the preintervention group ( p < 0.01). Compared with preintervention, the intervention group experienced more ventilator-free days [22.0 (9.0) vs 19.9 (10.6)] and ICU-free days [20.8 (8.7) vs 18.1 (10.4)], p < 0.05 for both. CONCLUSIONS: This pilot trial confirmed the feasibility of targeting the ED in order to improve sedation practices and reduce deep sedation. These findings justify an appropriately powered clinical trial regarding ED-based sedation to improve clinical outcomes.

Reach and Adoption of a Geriatric Emergency Department Accreditation Program in the United States.

STUDY OBJECTIVE: The objectives of this study were to describe the reach and adoption of Geriatric Emergency Department Accreditation (GEDA) program and care processes instituted at accredited geriatric emergency departments (EDs). METHODS: We analyzed a cross-section of a cohort of US EDs that received GEDA from May 2018 to March 2021. We obtained data from the American College of Emergency Physicians and publicly available sources. Data included GEDA level, geographic location, urban/rural designation, and care processes instituted. Frequencies and proportions and median and interquartile ranges were used to summarize categorical and continuous data, respectively. RESULTS: Over the study period, 225 US geriatric ED accreditations were issued and included in our analysis-14 Level 1, 21 Level 2, and 190 Level 3 geriatric EDs; 5 geriatric EDs reapplied and received higher-level accreditation after initial accreditation at a lower level. Only 9 geriatric EDs were in rural regions. There was significant heterogeneity in protocols enacted at geriatric EDs; minimizing urinary catheter use and fall prevention were the most common. CONCLUSION: There has been rapid growth in geriatric EDs, driven by Level 3 accreditation. Most geriatric EDs are in urban areas, indicating the potential need for expansion beyond these areas. Future research evaluating the impact of GEDA on health care utilization and patient-oriented outcomes is needed.

Geriatric emergency medicine-a model for frailty friendly healthcare.

As the world's population continues to age over the decades ahead, medical educators and researchers in every adult medical and surgical specialty will need to 'geriatricise' their clinical science. Many have already engaged with geriatrics. Here we describe the progress that has been made and the opportunities ahead in the field of Geriatric Emergency Medicine (GEM), a field that has taken large steps in integrating holistic care. Future opportunities exist in the three domains of evidence-based medicine: including patient preferences and needs, generating scientific evidence, and improving physician knowledge and expertise. Implementation requires new innovations also in the organisation of care. Similar strategies may be useful in other fields of medicine, in making holistic care the standard for older people.

Novel Approach to Ultrasound-Guided Thoracostomy.

OBJECTIVES: Thoracostomy is often a required treatment in patients with thoracic trauma; however, performing a thoracostomy using traditional techniques can have complications. Ultrasound can be a beneficial tool for identifying the correct thoracostomy insertion site. We designed a randomized prospective study to assess if ultrasound guidance can improve thoracostomy site identification over traditional techniques. METHODS: Emergency medicine residents were randomly assigned to use palpation or ultrasound to identify a safe insertion site for thoracostomy placement. The target population comprised of hemodynamically stable trauma patients who received an extended focused assessment with sonography for trauma (EFAST) and a chest computed tomography (CT) exam. The resident placed a radiopaque marker on the skin of the patient where a safe intercostal space was believed to be located, either by palpation or ultrasound. Clinical ultrasound faculty reviewed the CT to confirm marker placement relative to the diaphragm. A Fischer's exact test was used to analyze the groups. RESULTS: One hundred and forty-seven patients were enrolled in the study, 75 in the ultrasound group and 72 in the landmark group. This resulted in the placement of 271 total thoracostomy site markers, 142 by ultrasound and 129 by palpation and landmarks. The ultrasound group correctly identified thoracostomy insertion sites above the diaphragm in 97.2% (138/142) of patients, while the palpation group identified a safe insertion site in 88.4% (114/129) of patients (P = .0073). CONCLUSION: This study found that emergency medicine residents are more likely to identify a safe tube thoracostomy insertion site in trauma patients by using ultrasound, as compared to using landmarks and palpation.

Extending the Theory of Normative Social Behavior: Collective Norms, Opinion Leadership, and Masking During the COVID-19 Pandemic.

Novel, public behaviors, such as masking, should be susceptible to normative influence. This paper advances the theory of normative social behavior by considering a new set of moderators of normative influence - superdiffuser traits - and by clarifying the antecedents and consequences of exposure to collective norms. We use data from a two-wave survey of a cohort living in one U.S. county during the pandemic (N = 913) to assess normative effects on masking. We also used a bipartite network (based on people shopping for food in the same stores) to examine exposure to collective norms. The results show different superdiffuser traits have distinct effects on the relationship between perceived injunctive norms and masking intentions. Exposure to collective norms influences masking, but this influence depends on how people interact with their social environments. Network analysis shows that behavioral homophily is a significant predictor of selective exposure to collective norms earlier (but not later) in the pandemic. Implications for understanding normative influence in a context where opinion leadership matters are discussed.

Balancing Vision With Pragmatism: The Geriatric Emergency Department Guidelines-Realistic Expectations From Emergency Medicine and Geriatric Medicine.

BACKGROUND: In 2014, the Geriatric Emergency Department (GED) Guidelines were published and endorsed by four major medical organizations. The multidisciplinary GED Guidelines characterized the complex needs of the older emergency department (ED) patient and current best practices, with the goal of promoting more cost-effective and patient-centered care. The recommendations are extensive and most EDs then and now have neither the resources nor the hospital administrative support to provide this additional service. DISCUSSION: At the 2021 American Academy of Emergency Medicine's Scientific Assembly, a panel of emergency physicians and geriatricians discussed the GED Guidelines and the current realities of EDs' capacity to provide best practice and guideline-recommended care of GED patients. This article is a synthesis of the panel's presentation and discussion. With the substantial challenges in providing guideline-recommended care in EDs, this article will explore three high-impact GED clinical conditions to highlight guideline recommendations, challenges, and opportunities, and discuss realistically achievable expectations for non-GED-accredited institutions. CONCLUSIONS: In 2014, the GED Guidelines were published, describing the current best practices for GED patients. Unfortunately, most of the EDs worldwide do not provide the level of service recommended by the GED Guidelines. The GED Guidelines can best be termed aspirational for U.S. EDs at the present time.

Anti-tumor effects of RTX-240: an engineered red blood cell expressing 4-1BB ligand and interleukin-15.

Recombinant agonists that activate co-stimulatory and cytokine receptors have shown limited clinical anticancer utility, potentially due to narrow therapeutic windows, the need for coordinated activation of co-stimulatory and cytokine pathways and the failure of agonistic antibodies to recapitulate signaling by endogenous ligands. RTX-240 is a genetically engineered red blood cell expressing 4-1BBL and IL-15/IL-15Rα fusion (IL-15TP). RTX-240 is designed to potently and simultaneously stimulate the 4-1BB and IL-15 pathways, thereby activating and expanding T cells and NK cells, while potentially offering an improved safety profile through restricted biodistribution. We assessed the ability of RTX-240 to expand and activate T cells and NK cells and evaluated the in vivo efficacy, pharmacodynamics and tolerability using murine models. Treatment of PBMCs with RTX-240 induced T cell and NK cell activation and proliferation. In vivo studies using mRBC-240, a mouse surrogate for RTX-240, revealed biodistribution predominantly to the red pulp of the spleen, leading to CD8 + T cell and NK cell expansion. mRBC-240 was efficacious in a B16-F10 melanoma model and led to increased NK cell infiltration into the lungs. mRBC-240 significantly inhibited CT26 tumor growth, in association with an increase in tumor-infiltrating proliferating and cytotoxic CD8 + T cells. mRBC-240 was tolerated and showed no evidence of hepatic injury at the highest feasible dose, compared with a 4-1BB agonistic antibody. RTX-240 promotes T cell and NK cell activity in preclinical models and shows efficacy and an improved safety profile. Based on these data, RTX-240 is now being evaluated in a clinical trial.

Effects of the Colorectal Cancer Control Program.

Although colorectal cancer (CRC) screening is highly effective, screening rates lag far below recommended levels, particularly for low-income people. The Colorectal Cancer Control Program (CRCCP) funded $100 million in competitively awarded grants to 25 states from 2009-2015 to increase CRC screening rates among low-income, uninsured populations, in part by directly providing and paying for screening services. Using data from the 2001-2015 Behavioral Risk Factor Surveillance System (BRFSS) and a difference-in-differences strategy, we find no effects of CRCCP on the use of relatively cheap fecal occult blood tests (FOBT). We do, however, find that the CRCCP significantly increased the likelihood that uninsured 50-64-year-olds report ever having a relatively expensive endoscopic CRC screening (sigmoidoscopy or colonoscopy) by 2.9 percentage points, or 10.7%. These effects are larger for women, minorities, and individuals who did not undertake other types of preventive care. We do not find that the CRCCP led to significant changes in CRC cancer detection. Our results indicate that the CRCCP was effective at increasing CRC screening rates among the most vulnerable.

BET inhibitor resistance emerges from leukaemia stem cells.

Bromodomain and extra terminal protein (BET) inhibitors are first-in-class targeted therapies that deliver a new therapeutic opportunity by directly targeting bromodomain proteins that bind acetylated chromatin marks. Early clinical trials have shown promise, especially in acute myeloid leukaemia, and therefore the evaluation of resistance mechanisms is crucial to optimize the clinical efficacy of these drugs. Here we use primary mouse haematopoietic stem and progenitor cells immortalized with the fusion protein MLL-AF9 to generate several single-cell clones that demonstrate resistance, in vitro and in vivo, to the prototypical BET inhibitor, I-BET. Resistance to I-BET confers cross-resistance to chemically distinct BET inhibitors such as JQ1, as well as resistance to genetic knockdown of BET proteins. Resistance is not mediated through increased drug efflux or metabolism, but is shown to emerge from leukaemia stem cells both ex vivo and in vivo. Chromatin-bound BRD4 is globally reduced in resistant cells, whereas the expression of key target genes such as Myc remains unaltered, highlighting the existence of alternative mechanisms to regulate transcription. We demonstrate that resistance to BET inhibitors, in human and mouse leukaemia cells, is in part a consequence of increased Wnt/ß-catenin signalling, and negative regulation of this pathway results in restoration of sensitivity to I-BET in vitro and in vivo. Together, these findings provide new insights into the biology of acute myeloid leukaemia, highlight potential therapeutic limitations of BET inhibitors, and identify strategies that may enhance the clinical utility of these unique targeted therapies.