Citations

Abstract Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiD). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance. Significance: These results highlight the dependence of MM on IKZF1-bound super-enhancers, which can be effectively targeted by a potent therapeutic combination pairing IMiD-mediated degradation of IKZF1 and IKZF3 with EP300 inhibition. They also identify AP-1 factors as an unrecognized mechanism of IMiD resistance in MM. See related article by Neri, Barwick, et al., p. 56. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4

OBJECTIVES: A number of trials related to critical care pharmacotherapy were published in 2022. We aimed to summarize the most influential publications related to the pharmacotherapeutic care of critically ill patients in 2022. DATA SOURCES: PubMed/Medical Literature Analysis and Retrieval System Online and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update. STUDY SELECTION: Randomized controlled trials, prospective studies, or systematic review/meta-analyses of adult critically ill patients assessing a pharmacotherapeutic intervention and reporting clinical endpoints published between January 1, 2022, and December 31, 2022, were included in this article. DATA EXTRACTION: Articles from a systematic search and the Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update were included and stratified into clinical domains based upon consistent themes. Consensus was obtained on the most influential publication within each clinical domain utilizing an a priori defined three-round modified Delphi process with the following considerations: 1) overall contribution to scientific knowledge and 2) novelty to the literature. DATA SYNTHESIS: The systematic search and Clinical Pharmacy and Pharmacology Pharmacotherapy Literature Update yielded a total of 704 articles, of which 660 were excluded. The remaining 44 articles were stratified into the following clinical domains: emergency/neurology, cardiovascular, gastroenterology/fluids/nutrition, hematology, infectious diseases/immunomodulation, and endocrine/metabolic. The final article selected from each clinical domain was summarized following a three-round modified Delphi process and included three randomized controlled trials and three systematic review/meta-analyses. Article topics summarized included dexmedetomidine versus other sedatives during mechanical ventilation, beta-blocker treatment in the critically ill, restriction of IV fluids in septic shock, venous thromboembolism prophylaxis in critically ill adults, duration of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia, and low-dose methylprednisolone treatment in severe community-acquired pneumonia. CONCLUSIONS: This concise review provides a perspective on articles published in 2022 that are relevant to the pharmacotherapeutic care of critically ill patients and their potential impact on clinical practice.

INTRODUCTION: The American Gastroenterological Association (AGA) has compiled risk factors that may be predictive of disease complications in Crohn's disease (CD) and ulcerative colitis (UC). The aim of this study was to evaluate the performance of the AGA risk factors for risk stratification in UC and CD. METHODS: We included participants of 2 cohorts: the Ocean State Crohn's and Colitis Area Registry cohort and the Mayo Clinic cohort. Baseline clinical risk factors were extracted according to the AGA pathway. Our primary end point was defined as follows: (i) any inflammatory bowel disease related–hospitalization, (ii) any inflammatory bowel disease–related bowel surgery, or (iii) any progression of disease. We analyzed the association of the number of AGA risk factors with our end point. Statistical multivariable modeling was performed with Cox proportional hazards model. RESULTS: A total of 412 patients with CD were included. Comparing ≥3 risk factors with 0–1 risk factor, we found a significantly increased risk of complications in both the Ocean State Crohn's and Colitis Area Registry cohort (hazard ratio [HR] 2.75, 95% confidence interval 1.71–4.41) and Mayo Clinic cohort (HR 2.07, 95% confidence interval 1.11–3.84). Diagnosis at younger age (HR 2.07), perianal disease (HR 1.99), and B2/B3 behavior (HR 1.92) were significantly associated with disease complications. We did not observe a consistent association between number of risk factors nor any specific individual risk factors and risk of disease complications in the 265 patients with UC included. DISCUSSION: We found a significant association between the number of AGA risk factors and the risk of disease complication in CD; this association was not significant in UC. The presence of ≥ 3 risk factors in CD leads to the highest risk of complications. The AGA care pathway is a useful tool to stratify patients who are at higher risk of disease complications in patients with CD.

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1 *04 subtypes best accounted for the association, strongest with HLA-DRB1 *04:04 and HLA-DRB1 *04:07, and intermediary with HLA-DRB1 *04:01 and HLA-DRB1 *04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1 *04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1 *04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

Abstract Background Time spent awaiting discharge after the acute need for hospitalization has resolved is an important potential contributor to hospital length of stay (LOS). Objective To measure the prevalence, impact, and context of patients who remain hospitalized for prolonged periods after completion of acute care needs. Design, Setting, and Participants We conducted a cross‐sectional “point‐in‐time” survey at each of 15 academic US hospitals using a structured data collection tool with on‐service acute care medicine attending physicians in fall 2022. Main Outcomes and Measures Primary outcomes were number and percentage of patients considered “medically ready for discharge” with emphasis on those who had experienced a “major barrier to discharge” (medically ready for discharge for ≥1 week). Estimated LOS attributable to major discharge barriers, contributory discharge needs, and associated hospital characteristics were measured. Results Of 1928 patients sampled, 35.0% ( n = 674) were medically ready for discharge including 9.8% ( n = 189) with major discharge barriers. Many patients with major discharge barriers (44.4%; 84/189) had spent a month or longer medically ready for discharge and commonly (84.1%; 159/189) required some form of skilled therapy or daily living support services for discharge. Higher proportions of patients experiencing major discharge barriers were found in public versus private, nonprofit hospitals (12.0% vs. 7.2%; p = .001) and county versus noncounty hospitals (14.5% vs. 8.8%; p = .002). Conclusions Patients experience major discharge barriers in many US hospitals and spend prolonged time awaiting discharge, often for support needs that may be outside of clinician control.

Background: Transcatheter pulmonary valve implantation (TPVI) is an effective non-surgical treatment method for patients with right ventricle outflow tract dysfunction. The Medtronic Melody and the Edwards Sapien are the two valves approved for use in TPVI. Since TPVI patients are typically younger, even a modest annual incidence of infective endocarditis (IE) is significant. Several previous studies have shown a growing risk of IE after TPVI. There is uncertainty regarding the overall incidence of IE and differences in the risk of IE between the valves. Methods: A systematic search was conducted in the MEDLINE, EMBASE, PubMed, and Cochrane databases from inception to 1 January 2023 using the search terms ‘pulmonary valve implantation’, ‘TPVI’, or ‘PPVI’. The primary outcome was the pooled incidence of IE following TPVI in Melody and Sapien valves and the difference in incidence between Sapien and Melody valves. Fixed effect and random effect models were used depending on the valve. Meta-regression with random effects was conducted to test the difference in the incidence of IE between the two valves. Results: A total of 22 studies (including 10 Melody valve studies, 8 Sapien valve studies, and 4 studies that included both valves (572 patients that used the Sapien valve and 1395 patients that used the Melody valve)) were used for the final analysis. Zero IE incidence following TPVI was reported by eight studies (66.7%) that utilized Sapien valves compared to two studies (14.3%) that utilized Melody valves. The pooled incidence of IE following TPVI with Sapien valves was 2.1% (95% CI: 0.9% to 5.13%) compared to 8.5% (95% CI: 4.8% to 15.2%) following TPVI with Melody valves. Results of meta-regression indicated that the Sapien valve had a 79.6% (95% CI: 24.2% to 94.4%, p = 0.019; R2 = 34.4) lower risk of IE incidence compared to the Melody valve. Conclusions: The risk of IE following TPVI differs significantly. A prudent valve choice in favor of Sapien valves to lower the risk of post-TPVI endocarditis may be beneficial.

AbstractBackgroundThere are limited national‐level data on the contemporary practices of mechanical circulatory support (MCS) use in acute myocardial infarction‐cardiogenic shock (AMI‐CS).MethodsWe utilized the Healthcare Cost and Utilization Project‐National/Nationwide Inpatient Sample data (2005–2017) to identify adult admissions (>18 years) with AMI‐CS. MCS devices were classified as intra‐aortic balloon pump (IABP), percutaneous left ventricular assist devices (pLVAD), or extracorporeal membrane oxygenation (ECMO). We evaluated trends in the initial device used (IABP alone, pLVAD alone or ≥2 MCS devices), device escalation, bridging to durable LVAD/heart transplantation, and predictors of in‐hospital mortality and device escalation.ResultsAmong 327,283 AMI‐CS admissions, 131,435 (40.2%) had an MCS device placed with available information on timing of placement. IABP, pLVAD, and ≥2 MCS devices were used as initial device in 120,928 (92.0%), 8202 (6.2%), and 2305 (1.7%) admissions, respectively. Most admissions were maintained on the initial MCS device with 1%–1.5% being escalated (IABP to pLVAD/ECMO, pLVAD to ECMO). Urban, medium, and large‐sized hospitals and acute multiorgan failure were significant independent predictors of MCS escalation. In admissions receiving MCS, escalation of MCS device was associated with higher in‐hospital mortality (adjusted odds ratio: 1.56, 95% confidence interval: 1.38–1.75; p < 0.001). Admissions receiving durable LVAD/heart transplantation increased over time in those initiated on pLVAD and ≥2 MCS devices, resulting in lower in‐hospital mortality.ConclusionsIn this 13‐year study, escalation of MCS in AMI‐CS was associated with higher in‐hospital mortality suggestive of higher acuity of illness. The increase in number of durable LVAD/heart transplantations alludes to the role of MCS as successful bridge strategies.

PURPOSE The COVID-19 pandemic has profoundly affected cancer care worldwide, including radiation therapy (RT) for breast cancer (BC), because of risk-based resource allocation. We report the evolution of international breast RT practices during the beginning of the pandemic, focusing on differences in treatment recommendations between countries. MATERIALS AND METHODS Between July and November 2020, a 58-question survey was distributed to radiation oncologists (ROs) through international professional societies. Changes in RT decision making during the first surge of the pandemic were evaluated across six hypothetical scenarios, including the management of ductal carcinoma in situ (DCIS), early-stage, locally advanced, and metastatic BC. The significance of changes in responses before and during the pandemic was examined using chi-square and McNemar-Bowker tests. RESULTS One thousand one hundred three ROs from 54 countries completed the survey. Incomplete responses (254) were excluded from the analysis. Most respondents were from the United States (285), Japan (117), Italy (63), Canada (58), and Brazil (56). Twenty-one percent (230) of respondents reported treating at least one patient with BC who was COVID-19–positive. Approximately 60% of respondents reported no change in treatment recommendation during the pandemic, except for patients with metastatic disease, for which 57.7% (636/1,103; P < .0005) changed their palliative practice. Among respondents who noted a change in their recommendation during the first surge of the pandemic, omitting, delaying, and adopting short-course RT were the most frequent changes, with most transitioning to moderate hypofractionation for DCIS and early-stage BC. CONCLUSION Early in the COVID-19 pandemic, significant changes in global RT practice patterns for BC were introduced. The impact of published results from the FAST FORWARD trial supporting ultrahypofractionation likely confounded the interpretation of the pandemic's independent influence on RT delivery.

Objective: To describe outcomes after elective and non-elective fenestrated-branched endovascular aortic repair (FB-EVAR) for thoracoabdominal aortic aneurysms (TAAAs). Background: FB-EVAR has been increasingly utilized to treat TAAAs; however, outcomes after non-elective versus elective repair are not well described. Methods: Clinical data of consecutive patients undergoing FB-EVAR for TAAAs at 24 centers (2006–2021) were reviewed. Endpoints including early mortality and major adverse events (MAEs), all-cause mortality, and aortic-related mortality (ARM), were analyzed and compared in patients who had non-elective versus elective repair. Results: A total of 2603 patients (69% males; mean age 72±10 year old) underwent FB-EVAR for TAAAs. Elective repair was performed in 2187 patients (84%) and non-elective repair in 416 patients [16%; 268 (64%) symptomatic, 148 (36%) ruptured]. Non-elective FB-EVAR was associated with higher early mortality (17% vs 5%, P<0.001) and rates of MAEs (34% vs 20%, P<0.001). Median follow-up was 15 months (interquartile range, 7–37 months). Survival and cumulative incidence of ARM at 3 years were both lower for non-elective versus elective patients (50±4% vs 70±1% and 21±3% vs 7±1%, P<0.001). On multivariable analysis, non-elective repair was associated with increased risk of all-cause mortality (hazard ratio, 1.92; 95% CI] 1.50–2.44; P<0.001) and ARM (hazard ratio, 2.43; 95% CI, 1.63–3.62; P<0.001). Conclusions: Non-elective FB-EVAR of symptomatic or ruptured TAAAs is feasible, but carries higher incidence of early MAEs and increased all-cause mortality and ARM than elective repair. Long-term follow-up is warranted to justify the treatment.

AbstractObjectivesAlthough hemispheric surgeries are among the most effective procedures for drug‐resistant epilepsy (DRE) in the pediatric population, there is a large variability in seizure outcomes at the group level. A recently developed HOPS score provides individualized estimation of likelihood of seizure freedom to complement clinical judgement. The objective of this study was to develop a freely accessible online calculator that accurately predicts the probability of seizure freedom for any patient at 1‐, 2‐, and 5‐years post‐hemispherectomy.MethodsRetrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time‐to‐seizure recurrence. A multivariate Cox proportional‐hazards regression model was developed to predict the likelihood of post‐hemispheric surgery seizure freedom at three time points (1‐, 2‐ and 5‐ years) based on a combination of variables identified by clinical judgment and inferential statistics predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the International Network for Epilepsy Surgery and Treatment (iNEST) website (https://hops‐calculator.com/).ResultsThe selected variables for inclusion in the final model included the five original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non‐hemispheric resective surgery, and contralateral fluorodeoxyglucose–positron emission tomography [FDG‐PET] hypometabolism) and three additional variables (age at surgery, history of infantile spasms, and magnetic resonance imaging [MRI] lesion). Predictors of shorter time‐to‐seizure recurrence included younger age at seizure onset, prior resective surgery, generalized seizure semiology, FDG‐PET hypometabolism contralateral to the side of surgery, contralateral MRI lesion, non‐lesional MRI, non‐stroke etiologies, and a history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%.SignificanceOnline calculators are useful, cost‐free tools that can assist physicians in risk estimation and inform joint decision‐making processes with patients and families, potentially leading to greater satisfaction. Although the HOPS data was validated in the original analysis, the authors encourage external validation of this new calculator.