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Abstract Background With progressive understanding of the natural history of COVID-19 and accumulation of knowledge on clinical management, treatment guidelines recommended several options including remdesivir (RDV), a broad-spectrum antiviral. Given the evolving nature of COVID-19, it is critical to capture the totality of scientific evidence to inform clinical decision making. We conducted a systematic literature review (SLR) to summarize the mortality endpoint for RDV among hospitalized adults throughout COVID-19 eras and contrasted with evidence informing treatment recommendations in clinical guidelines. Methods We systematically searched MEDLINE, Embase and Cochrane Library databases for interventional and observational studies examining RDV efficacy. Clinical trial registries, Cochrane COVID-19 Study Register, and conference abstracts were hand-searched (Fig1). Case reports and case studies were excluded. A review of most recent RDV recommendations across guidelines was conducted. Results From Dec ’19 to Dec ’22, 123 relevant publications were identified. In ’23, the evidence grew significantly, with 70 new publications. In total, 193 publications were evaluated, and 122 unique studies were included. While early randomized clinical trials (RCT) and small sample size observational studies did not universally demonstrate a significant difference in mortality in all severity groups of RDV-treated patients, real-world studies with larger sample sizes showed a significant impact across disease severity levels, regardless of COVID-19 era (Table1). Guideline recommendations for COVID-19 treatment with RDV are based on early RCTs (Table2) and most have not been updated (Fig2). Conclusion Our comprehensive evaluation of scientific literature indicates that evidence of RDV impact on mortality in hospitalized COVID-19 patients continued to grow and cover full range of disease severity. Guideline recommendations have not evolved in parallel which may explain differing recommendations in certain subgroups (e.g. IMV/ECMO). To assure that providers in the hospital setting are aware of and deploy evidence-based optimal care for patients with COVID-19, recommendations should rely on current evidence, including real-world data. Disclosures Essy Mozaffari, PharmD, MPH, MBA, Gilead Sciences, Inc.: Employee|Gilead Sciences, Inc.: Stocks/Bonds (Public Company) Michele Bartoletti, MD, PhD, Advan pharma: Advisor/Consultant|Advan pharma: Honoraria|Biomereux: Honoraria|Gilead: Advisor/Consultant|Gilead: Honoraria|Infectopharma: Advisor/Consultant|Msd: Advisor/Consultant|Msd: Grant/Research Support|Msd: Honoraria|Pfizer: Honoraria Alpesh N. Amin, MD, MBA, Alexion: Advisor/Consultant|Aseptiscope: Advisor/Consultant|AstraZeneca: Advisor/Consultant|Bayer: Advisor/Consultant|Dexcom: Advisor/Consultant|Eli Lilly: Advisor/Consultant|Ferring: Advisor/Consultant|Gilead: Advisor/Consultant|GSK: Advisor/Consultant|Heartrite: Advisor/Consultant|Nova Nordisk: Advisor/Consultant|Pfizer: Advisor/Consultant|Renibus: Advisor/Consultant|Reprieve: Advisor/Consultant|Salix: Advisor/Consultant|Seres: Advisor/Consultant|Spero: Advisor/Consultant Yohei Doi, MD, PhD, bioMerieux: Lecture fees|Entasis: Grant/Research Support|Fujifilm: Advisor/Consultant|Gilead Sciences: Advisor/Consultant|GSK: Advisor/Consultant|KANTO CHEMICAL CO.,INC.: Grant/Research Support|KANTO CHEMICAL CO.,INC.: Patent for genotyping kit|MeijiSeika Pharma: Advisor/Consultant|Moderna: Advisor/Consultant|MSD: Lecture fees|Pfizer: Advisor/Consultant|Shionogi & Co., Ltd.: Grant/Research Support|Shionogi & Co., Ltd.: Lecture fees Paul LOUBET, MD, PhD, Astrazeneca: Advisor/Consultant|Gilead: Advisor/Consultant|Moderna: Advisor/Consultant|Pfizer: Advisor/Consultant Christina G. Rivera (O'Connor), Pharm.D, Gilead Sciences: Board Member Michael Roshon, MD/PhD, MD/PhD, Gilead: Honoraria Thomas F. Oppelt, PharmD, BCPS, Gilead Sciences, Inc: I am an employee of Gilead Sciences, Inc|Gilead Sciences, Inc: Stocks/Bonds (Public Company) Mel Chiang, Ph.D., Gilead Sciences: I am an employee of Gilead Sciences|Gilead Sciences: Stocks/Bonds (Public Company)

AbstractEUS-guided gallbladder drainage (EUS-GBD) using lumen apposing metal stents (LAMS) has excellent technical and short-term clinical success for acute cholecystitis (AC). The goals of this study were to determine the long-term clinical outcomes and adverse events (AEs) of EUS-GBD with LAMS.A multicenter, retrospective study was conducted at 18 US tertiary care institutions. Inclusion criteria: any AC patient with attempted EUS-GBD with LAMS and minimum 30-day post-procedure follow-up. Long-term clinical success was defined as absence of recurrent acute cholecystitis (RAC) > 30 days and long-term AE was defined as occurring > 30 days from the index procedure.A total of 109 patients were included. Technical success was achieved in 108 of 109 (99.1%) and initial clinical success in 106 of 109 (97.2%). Long-term clinical success was achieved in 98 of 109 (89.9%) over a median follow-up of 140 days (range 30–1188). On multivariable analysis (MVA), acalculous cholecystitis (odds ratio [OR] 15.93, 95% confidence interval [CI] 1.22–208.52, P = 0.04) and the occurrence of a LAMS-specific AE (OR 63.60, 95% CI 5.08–799.29, P <0.01) were associated with RAC. AEs occurred in 38 of 109 patients (34.9%) at any time, and in 10 of 109 (9.17%) > 30 days from the index procedure. Most long-term AEs (7 of 109; 6.42%) were LAMS-specific. No technical or clinical factors were associated with occurrence of AEs. LAMS were removed in 24 of 109 patients (22%). There was no difference in RAC or AEs whether LAMS was removed or not.EUS-GBD with LAMS has a high rate of long-term clinical success and modest AE rates in patients with AC and is a reasonable destination therapy for high-risk surgical candidates.

Abstract Objective The goal is to provide an overview of artificial intelligence (AI) and machine learning (ML) methodology and appraisal tailored to clinicians and researchers in the headache field to facilitate interdisciplinary communications and research. Background The application of AI to the study of headache and other healthcare challenges is growing rapidly. It is critical that these findings be accurately interpreted by headache specialists, but this can be difficult for non‐AI specialists. Methods This paper is a narrative review of the fundamentals required to understand ML/AI headache research. Using guidance from key leaders in the field of headache medicine and AI, important references were reviewed and cited to provide a comprehensive overview of the terminology, methodology, applications, pitfalls, and bias of AI. Results We review how AI models are created, common model types, methods for evaluation, and examples of their application to headache medicine. We also highlight potential pitfalls relevant when consuming AI research, and discuss ethical issues of bias, privacy and abuse generated by AI. Additionally, we highlight recent related research from across headache‐related applications. Conclusion Many promising current and future applications of ML and AI exist in the field of headache medicine. Understanding the fundamentals of AI will allow readers to understand and critically appraise AI‐related research findings in their proper context. This paper will increase the reader's comfort in consuming AI/ML‐based research and will prepare them to think critically about related research developments.

OBJECTIVE This study aimed to evaluate local control (LC) of tumors, patient overall survival (OS), and the safety of stereotactic radiosurgery (SRS) for esophageal cancer brain metastases (EBMs). METHODS This retrospective cohort study used data from 15 International Radiosurgery Research Foundation facilities encompassing 67 patients with 185 EBMs managed using SRS between January 2000 and May 2022. The median patient age was 63 years, with a male predominance (92.5%). Most patients (64.2%) had a single brain metastasis, while 7.5% had more than 5 metastases. The median tumor volume was 0.9 cm 3 , and the median margin dose delivered to the tumor was 20 Gy. RESULTS The median OS post-SRS was 15.2 months, with 1- and 2-year OS rates of 65.7% and 32.3%, respectively. A significant inverse correlation was found between the number of EBMs and OS in the univariable analysis. LC rates at 1 and 2 years were 89% and 76%, respectively. Adverse radiation effects (AREs) were observed in 17.9% of patients, with 13.4% being mild and transient and 4.5% severely symptomatic (Common Terminology Criteria for Adverse Events grade 3). New intracranial disease developed in 58.2% of patients, with 1- and 2-year rates of 58% and 73%, respectively. CONCLUSIONS SRS for EBMs demonstrated high survival rates and effective tumor control, with a low incidence of severe AREs. These findings highlight the potential role of SRS in the multidisciplinary multimodality management paradigm of EBM.

Background: Zanubrutinib and acalabrutinib are next-generation Bruton's tyrosine kinase (BTK) inhibitors used in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). They have demonstrated lower cardiotoxicity compared to first-generation BTK inhibitor ibrutinib. However, there is limited data comparing cardiovascular outcomes between zanubrutinib and acalabrutinib. This study aims to investigate the cardiovascular risks associated with these two agents in a real-world setting. Method: A retrospective, propensity score-matched study was conducted using the TriNetX database, which includes de-identified electronic health records from over 101 million individuals across 70 healthcare organizations. Patients with CLL and SLL treated with either zanubrutinib or acalabrutinib were included, excluding those who received ibrutinib. The primary outcome of interest was major cardiovascular adverse events, composed of heart failure, myocardial infarction, and cardiac arrest. Other outcomes of interest were new-onset hypertension, new-onset atrial fibrillation/flutter, ventricular arrhythmia, myocardial infarction, new-onset heart failure, conduction block, and stroke within 18 months of therapy initiation. Propensity score matching accounted for demographics, comorbidities, disease status, other CLL/SLL-directed therapies, and concomitant cardiovascular agents. Relative risk and 95% confidence intervals were calculated to assess the outcomes. Results: A total of 907 patients treated with zanubrutinib were matched to 907 patients treated with acalabrutinib. At 18 months, the zanubrutinib group experienced 106 major cardiovascular adverse events, compared to 144 in the acalabrutinib group (RR (relative risk), 0.73 [95% CI: 0.58-0.93]; p=0.009). New-onset hypertension occurred in 35 zanubrutinib and 31 acalabrutinib patients (RR, 1.14 [95% CI: 0.72-1.82]; p=0.579). New-onset atrial fibrillation/flutter occurred in 15 zanubrutinib and 30 acalabrutinib patients (RR, 0.49 [95% CI: 0.27-0.91]; p=0.020). Ventricular arrhythmia occurred in 13 zanubrutinib and 9 acalabrutinib patients (RR, 1.44 [95% CI: 0.62-3.36]; p=0.402). Myocardial infarction occurred in 18 zanubrutinib and 25 acalabrutinib patients (RR, 0.72 [95% CI: 0.40-1.31]; p=0.286). New-onset heart failure occurred in 34 zanubrutinib and 40 acalabrutinib patients (RR, 0.82 [95% CI: 0.52-1.28]; p=0.385). Conduction block occurred in 43 zanubrutinib and 48 acalabrutinib patients (RR, 0.90 [95% CI: 0.60-1.34]; p=0.593). Stroke occurred in 20 zanubrutinib and 19 acalabrutinib patients (RR, 1.05 [95% CI: 0.57-1.96]; p=0.873). Conclusion: Zanubrutinib was associated with a 27% lower risk of major cardiovascular adverse events and a 51% lower risk of new-onset atrial fibrillation/flutter compared to acalabrutinib, suggesting its preference for patients with high cardiovascular risks. The risks of new-onset hypertension, ventricular arrhythmia, myocardial infarction, new-onset heart failure, conduction block, and stroke were similar between the two groups. Further studies with long-term follow-up data will be valuable for evaluating the safety of next-generation BTK inhibitors.

Background: Patients with immunocompromising conditions, including those affected by hematologic malignancies, have a disproportionately high burden of morbidity and mortality related to COVID-19 compared to individuals without such conditions.Clinical practice guidelines (CPGs) recommend the use of remdesivir, a broad-spectrum antiviral, for treatment of mild to severeCOVID-19 in immunocompetent patients not requiring invasive mechanical ventilation. While the CPGs issued by the World Health Organization (WHO, 2023), National Institutes of Health (NIH, 2023) and the Infectious Diseases Society of America (IDSA, 2022) also recommended the use of remdesivir in patients with immunocompromising conditions at high risk for severe disease, there was limited evidence available at the time the recommendations were communicated, more than two years after the start of the pandemic. The European Conference on Infections in Leukemia (ECIL, 2022) guidelines include remdesivir among the treatment options for mild to moderate COVID-19 patients with hematologic malignancies. The lack of evidence for treatment efficacy and safety in patients with immunocompromising conditions, a population underrepresented or excluded from clinical trials, was mentioned in CPGs as a knowledge gap and as need for further research. In this research, we summarize the evidence for remdesivir efficacy and safety for treatment of COVID-19 in hospitalized patients with hematologic malignancies accumulated since the start of the pandemic. Methods: We systematically searched MEDLINE, Embase and Cochrane Library databases from January 2019 through December 2023 for interventional and observational studies examining remdesivir efficacy and safety. Case reports and case studies were excluded. A dual-reviewer approach was used for screening and data extraction. Results: Of the 7,654 references retrieved through the implementation of the extensive search strategy 59 (0.8%) reporting on patients with hematologic malignancies, unspecified cancers, or immunodeficiencies were identified and reviewed in full text. Only eight unique studies (8 of 59) were conducted in patients with hematologic malignancies, of which two reported remdesivir use in a minority of participants (n&lt;5) and were excluded from further analyses. The remaining six studies, of which four were peer-reviewed original articles, one was a letter to editor and the last was a conference abstract, used a retrospective cohort design and reported efficacy outcomes for a combined total of 1,579 individuals across the studies. Three of the six studies were conducted during the pre-Omicron variant era (November 2021) while the remaining three started data collection in December 2021. There were four studies reporting number of deaths or the mortality rate, while a fifth study based on medical chart reviews of 313 patients in Israel found a significantly reduced risk of mortality among remdesivir recipients compared to patients not receiving remdesivir (OR: 0.297; 95% CI: 0.105, 0.834). In addition, a study including 466 patients from the Spanish Hematopoietic Stem Cell Transplantation and Cell Therapy Registry reported mortality among remdesivir treated group related to baseline disease progression, use of corticosteroids for COVID-19 therapy and the presence of coinfections while B-cell malignancy as underlying disease, severe COVID-19, late antiviral initiation (≥5 days after first positive PCR) and longer treatment duration (≥5 days) were factors significantly associated with prolonged viral shedding. The same Spanish study reported safety outcomes indicating that adverse events of grade 3 or above were rare, occurring in 0.5% of remdesivir treated patients. Conclusion: Despite the call for research to fill the knowledge gap signaled by the CPGs, our comprehensive systematic literature review identified only a few publications conducted since the start of the pandemic in patients with hematological malignancies. In the current endemic era, these patients are among the most at risk for severe outcomes and COVID-19 related hospitalizations. While the limited evidence suggests that remdesivir use can reduce mortality in patients with hematologic malignancies, additional research will be instrumental to inform development and updating of evidence-based recommendations to support and guide clinical management of oncology patients.

There is an increased risk of infection in patients with cancer that results in higher morbidity and mortality. Several risk factors can predispose these patients to infectious complications. Some such factors include immunocompromised states like neutropenia, allogeneic hematopoietic cell transplantation, and graft-versus-host disease, while others include immunosuppressive agents like corticosteroids, purine analogs, monoclonal antibodies, and other emerging cancer therapeutics like CAR T-cell therapy. The NCCN Guidelines for the Prevention and Treatment of Cancer-Related Infections address infection concerns that may be observed in these immunocompromised populations and characterize the major pathogens to which patients with cancer are susceptible, with a focus on the prevention, diagnosis, and treatment of major common and opportunistic infections. This paper highlights 2 recently updated sections of the guidelines, namely, infection concerns related to CAR T-cell therapy and antimicrobial prophylaxis recommendations, including vaccination, in patients at high-risk for infections.

BACKGROUND: Cognitive impairment is common in patients with heart failure and preserved ejection fraction but its clinical correlates and prognostic associations are poorly understood. METHODS: We analyzed cognitive function, using the Mini-Mental State Examination (MMSE), in patients with heart failure and preserved ejection fraction enrolled in a prespecified substudy of the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in Heart Failure With Preserved Ejection Fraction). Logistic regression analyses were performed to determine the variables associated with lower MMSE scores at baseline and postbaseline decline in MMSE scores at 48 weeks. Cox proportional hazards regression and semiparametric proportional rates models were used to examine the risk of clinical outcomes related to baseline MMSE scores, and decline in MMSE scores during follow-up, adjusted for prognostic variables including NT-proBNP (N-terminal pro-B-type natriuretic peptide). RESULTS: At baseline, cognitive function was normal (MMSE score 28–30) in 1809 of 2895 patients (62.5%), borderline (score 24–27) in 794 (27.4%), and impaired (score <24) in 292 (10.1%). Variables associated with both a lower MMSE score at baseline and a decline in score from baseline included older age, a history of stroke or transient ischemic attack, and lower serum albumin. Compared with those with baseline MMSE scores of 28 to 30, patients in the lower MMSE score categories had a stepwise increase in the risk of the composite of time to first heart failure hospitalization or cardiovascular death, with an adjusted hazard ratio of 1.27 (95% CI, 1.06–1.53) for those with scores of 24 to 27 and 1.58 (95% CI, 1.21–2.06) for those with scores <24, respectively. These associations were also found for the individual components of the composite and all-cause death. Likewise, cognitive impairment was associated with a 50% higher risk of total (first and repeat) heart failure hospitalizations and cardiovascular deaths. Examining the change in MMSE score from baseline, a decrease in MMSE score during follow-up was associated with a higher risk of death. CONCLUSIONS: In patients with heart failure and preserved ejection fraction, even modest baseline impairment of cognitive function was associated with worse outcomes, including death. A decline in MMSE score during follow-up was a strong predictor of mortality, independent of other prognostic variables.