Citations

Importance Bioenergetic failure has been proposed as a driver of amyotrophic lateral sclerosis (ALS). CNM-Au8 is a suspension of gold nanocrystals that catalyzes the conversion of nicotinamide adenine dinucleotide hydride into NAD + , resulting in an increase of cellular adenosine triphosphate production. Objective To determine the effects of CNM-Au8 on ALS disease progression. Design, Setting, and Participants CNM-Au8 was tested as a regimen of the HEALEY ALS Platform Trial, a phase 2/3, multicenter, randomized, double-blind platform trial. The study was conducted at 54 sites in the US from July 2020 to March 2022 (final follow-up, March 17, 2022). A total of 161 participants with ALS were randomized to receive CNM-Au8 (n = 120) or regimen-specific placebo (n = 41). Data from 123 concurrently randomized placebo participants in other regimens were combined for analyses. Interventions Eligible participants were randomized in a 3:3:2 ratio to receive CNM-Au8 60 mg daily (n = 61), CNM-Au8 30 mg daily (n = 59), or matching placebo (n = 41) for 24 weeks. Main Outcomes and Measures The primary efficacy outcome was change from baseline through week 24 in ALS disease severity measured by a bayesian shared parameter model of function (based on the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale) and survival, which provided an estimate of the rate of disease progression measured by the disease rate ratio (DRR), with a DRR of less than 1 indicating treatment benefit. Secondary end points included a Combined Assessment of Function and Survival using a joint-rank test, rate of decline in slow vital capacity (percent predicted), and survival free of permanent assisted ventilation. Results Among 161 participants who were randomized within the CNM-Au8 regimen (mean age, 58.4 years; 61 [37.9%] female), 145 (90%) completed the trial. In the primary analysis comparing the combined CNM-Au8 dosage groups vs the combined placebo groups, the primary end point (DRR, 0.97 [95% credible interval, 0.783-1.175]; posterior probability of DRR <1, 0.65) and the 3 secondary end points suggested no benefit or harm of CNM-Au8. In the active (n = 120) vs placebo (n = 163) groups, the most common adverse events were diarrhea (23 [19%] vs 12 [7%]), nausea (17 [14.2%] vs 14 [8.6%]), fatigue (12 [10.8%] vs 30 [18.4%]), and muscular weakness (24 [20%] vs 45 [27.6%]). Conclusions and Relevance No benefit of CNM-Au8 on ALS disease progression was observed at 24 weeks. Trial Registration ClinicalTrials.gov Identifiers: NCT04297683 , NCT04414345

ABSTRACTImportanceHighlighting the global disparities in otolaryngology training and, ultimately, service delivery, emphasizing the need for equitable access to training resources and programs.ObjectiveTo describe the relationship between the quality, content, and location of otolaryngology–head and neck surgery training and education and the resulting impact on the delivery of otolaryngology care globally.DesignAn online cross‐sectional survey to otolaryngologists, gathering information on their training and education experiences, and factors influencing their choice of training location and practice.SettingThe online survey was available in multiple languages, distributed via national and international professional otolaryngology societies, snowballing and social media.ParticipantsThe respondents were practicing otolaryngologists representing all seven World Health Organization regions.ExposuresWorld Bank income groups classification.Main Outcomes and MeasuresOur expected outcome was that subspecialty training and access to educational resources were significantly readily available to respondents from high‐income countries, leading to more confidence in performing complex procedures post training.ResultsA total of 91 participants were included in the analysis, with 47 (52%) practicing in high‐income countries and 44 (48%) in low‐ and middle‐income countries. Sixty‐one participants (67%) were male. Subspecialty training and access to educational resources were significantly less available in low‐ and middle‐income countries, leading to lower confidence among low‐ and middle‐income countries physicians in performing complex procedures. High‐income country respondents reported better access to diverse training resources and felt more prepared for a broader range of procedures.Conclusion and RelevanceSignificant disparities exist in OHNS training resources and subspecialty training opportunities between high‐ and low‐middle‐income countries. There is a critical need to integrate complementary training and educational modalities into local systems. Addressing the shortage of educational resources and promoting open‐access initiatives in low‐middle‐income countries are essential steps toward enhancing surgical education and improving global otolaryngology healthcare outcomes.

ABSTRACT Objective Availability of surgical equipment and access to essential clinical services remains an important barrier to surgical care delivery, particularly in low‐ and middle‐income countries (LMICs). This study aims to characterize the relative availability of essential equipment for otolaryngology‐head and neck surgery (OHNS) care across World Bank income groups. Methods We conducted a cross‐sectional survey on otolaryngologists' perceptions on the availability of surgical equipment and ancillary services in their respective practice settings per a 5‐point Likert scale ranging from never to always available. The study was disseminated online via professional societies, personal contacts, and social media. Eligible participants included otolaryngologists from 194 WHO‐recognized countries, which were grouped by World Bank income group classification and WHO region. Results The study involved 146 otolaryngologists, 69 (47%) from high‐income countries (HICs), and 77 (53%) from LMICs. LMIC respondents were predominantly from the African and South‐East Asian regions, which comprised 48% and 7.8% of all LMIC respondents, respectively. Results revealed significant differences in the availability of otologic, rhinologic, and endoscopic airway equipment between HICs and LMICs. Differences existed among commonly used equipment such as tympanomastoidectomy equipment and rigid bronchoscopy, to subspecialized equipment such as functional endoscopic sinus surgery equipment and cochlear implants ( p < 0.05 each). Conclusions The study highlighted key disparities in the availability of essential equipment for baseline OHNS care, especially for pediatric airway and otologic conditions. These results can be used to guide investment and advocacy efforts to improve specialty‐specific surgical infrastructure relative to the global burden of OHNS diseases in low‐resource settings. Level of Evidence 3

Dividing the interpretation of concurrently acquired chest and abdominal CT images between two radiologists has advantages, and the potential problems can be mitigated by awareness, defined expectations, and communication.

Abstract Background Infective endocarditis (IE) is a life-threatening infection often challenging to diagnose, particularly in culture-negative cases. Plasma microbial cell-free DNA (mcfDNA) sequencing has shown potential for detecting pathogens in IE. However, its clinical utility, diagnostic impact, and limitations remain debated. This study evaluates its use in diagnosing and managing IE in a tertiary care setting. Methods This single-center retrospective cohort study included adult patients (≥18 years) who underwent mcfDNA sequencing via the Karius test for suspected IE at Mayo Clinic Rochester between December 2019 and February 2024. Diagnostic classification followed the 2023 Duke–International Society of Cardiovascular Infectious Diseases criteria. Data on demographics, clinical features, routine microbiologic workup, and mcfDNA sequencing results were collected. Statistical analysis was conducted to evaluate diagnostic utility and treatment impact. Results Among 141 patients, 66 had a diagnosis of IE, with mcfDNA sequencing identifying pathogens in 60.6% of them, compared with 39.4% with routine workup. mcfDNA sequencing was the sole microbiologic test with positive results in 33.3% of patients, leading to antimicrobial adjustments in 50.0% of that group. Clinically insignificant mcfDNA sequence detection occurred in 28.6% of patients without a diagnosis of IE. Conclusions mcfDNA sequencing is a valuable adjunctive tool for diagnosing culture-negative IE and guiding antimicrobial therapy when clinical suspicion is high. However, its utility depends on appropriate clinical context, highlighting the need for careful test interpretation and further prospective studies to assess patient-centered outcomes and cost-effectiveness.

OBJECTIVE Sepsis is associated with significant morbidity and mortality in pediatric hematology, oncology, and transplant (PHOT) patients. This study characterized PHOT patients who developed hospital-onset sepsis more than 12 hours after admission and identified risk factors for 30-day sepsis-attributable (SA) mortality. PATIENTS AND METHODS We analyzed an existing multicenter database of sepsis collected prospectively over 5 years (2017–2021) as part of the Improving Pediatric Sepsis Outcomes Collaborative. Sepsis was defined using operational elements documented in the health records based on International Classification of Diseases, Tenth Revision codes, treatment, diagnostic tests, and sepsis screen, huddle, or order set use. RESULTS A total of 9604 sepsis episodes in PHOT patients from 49 hospitals were analyzed: 70.5% were identified in the emergency department (ED), 10.9% in inpatient settings less than or equal to 12 hours from admission, and 18.6% were hospital onset. Only 52.5% of patients with hospital-onset sepsis were identified using a sepsis recognition method compared with 87.2% in the ED (P &lt; .001). The overall 30-day SA mortality was 2.2%, with a higher rate (6.9%) among those with hospital-onset sepsis compared with those who developed sepsis at presentation or less than or equal to 12 hours (1.1%, P &lt; .001). CONCLUSIONS Although the difference in SA mortality between hospitalized and nonhospitalized patients may be impacted by nonmeasurable confounders inherent to the type of patients presenting in the different care settings, we reported system-based improvements that may reduce mortality. The 30-day SA mortality was lower in hospitalized PHOT patients when sepsis was detected by early recognition methods, supporting the need for efforts to implement sepsis recognition tools in the inpatient setting.

ABSTRACT Genes involved in the regulation of chromatin structure are frequently disrupted in cancer, contributing to an aberrant transcriptome and phenotypic plasticity. Yet, therapeutics targeting mutant forms of chromatin-modifying enzymes have yielded only modest clinical utility, underscoring the difficulty of targeting the epigenomic underpinnings of aberrant gene regulatory networks. Here, we sought to identify novel epigenetic vulnerabilities in diffuse large B-cell lymphoma (DLBCL). Through phenotypic screens and biochemical analysis, we demonstrated that inhibition of the H3K9 demethylases KDM4A and KDM4C elicits potent, subtype-agnostic cytotoxicity by antagonizing transcriptional networks associated with B-cell identity and epigenetically rewiring heterochromatin. KDM4 demethylases associated with the KRAB zinc finger ZNF587, and their enzymatic inhibition led to DNA replication stress and DNA damage-induced cGAS-STING activation. Broad surveys of transcriptional data from patients also revealed KDM4 family dysregulation in several other cancer types. To explore this potential therapeutic avenue, we performed high-throughput small molecule screens with H3K9me3 nucleosome substrates and identified novel KDM4 demethylase inhibitors. AI-guided protein-ligand binding predictions suggested diverse modes of action for various small molecule hits. Our findings underscore the relevance of targeting fundamental transcriptional and epigenetic mechanisms for anti-cancer therapy. HIGHLIGHTS Phenotypic screens identified JIB-04 as a potent anti-cancer agent for multiple subtypes of diffuse large B-cell lymphoma JIB-04 binds and inhibits KDM4 demethylases resulting in epigenomic rewiring of heterochromatin KDM4 demethylases cooperate with KRAB zinc fingers to limit DNA replication stress, and KDM4 inhibition instigates DNA-damage and cGAS-STING activation in several human cancers High-throughput small molecule screens with semi-synthetic nucleosome substrates and AI-guided molecular docking simulations identify novel KDM4 inhibitors

Abstract Background Plasma microbial cell-free DNA (mcfDNA) sequencing, commercially available from Karius® (Redwood City, CA), has been increasingly utilized in diagnosing endovascular infections. The 2023 updated Duke criteria incorporated detection of pathogen via metagenomic sequencing in its microbiologic criteria. We analyzed the clinical impact of mcfDNA sequencing in the diagnosis and treatment of suspected infective endocarditis (IE) cases. Methods We performed retrospective review of patients with suspected IE who underwent Karius® test at Mayo Clinic, MN, between 2017 to 2023. Results We preformed preliminary analysis of 25 patients. Analysis of baseline characteristics (table 1) revealed that these patients had significant predisposing factors for IE. Before accounting for mcfDNA sequencing, 3 (12%) met criteria for definite IE, 10 (40%) met criteria for possible IE, and 12 (48%) were rejected per 2023 Duke criteria. After incorporating mcfDNA sequencing result, 1 patient who was classified as possible IE was escalated to definite IE. This patient had previous infection of implantable cardioverter-defibrillator (ICD) with Streptococcus dysgalactiae. ICD was removed. She had development of endophthalmitis and stroke, 1 week and 2 weeks after the completion of IV antibiotics, respectively, with echocardiogram showing new tricuspid valve vegetation. Routine work-up was negative despite that she was not on any systemic antibiotics at the time of blood culture collection. mcfDNA sequencing detected Streptococcus dysgalactiae, making definite diagnosis of IE, leading to the physician’s decision to extend the IV antibiotic treatment (treatment escalation). Overall, after mcfDNA sequencing result, treatment decision was not impacted in 14 (56%), ongoing treatment was escalated in 4 (16%), de-escalated in 5 (20%), and antimicrobials was newly initiated in 2 (8%) (figure 1). Positive mcfDNA sequencing result often led to treatment escalation or initiation; negative result often led to treatment de-escalation (figure 2). Conclusion In challenging cases of suspected IE, mcfDNA sequencing led to alteration of antimicrobial treatment in 44% of cases. Further data collection and final analysis will include larger number of patients. Disclosures All Authors: No reported disclosures

Abstract Background RSV is a common respiratory infection that causes significant morbidity in SOTR. However, risk factors for complications such as hypoxic respiratory failure, mechanical ventilation, and secondary infections have not been well described. Methods This retrospective, international, multicenter cohort study is actively recruiting SOTR hospitalized with RSV. Here, we analyzed data from Mayo Clinic (Rochester, Florida, Arizona), Miami Transplant Institute, Cleveland Clinic, and Royal Melbourne Hospital between 2016 and 2019. Secondary infection was defined as culture positive infection within 90 days of RSV diagnosis. Whenever appropriate, logistic and Cox regression analysis were conducted to identify risk factors. Survival functions were estimated using the Kaplan-Meier method.Figure 1:Forest plots of multivariable logistic regression models for risk factors for A) hypoxia, B) secondary infections, C) mechanical ventilation. Note: all variables included are the ones statistically significant on univariate analysis. Abbreviations: CI, confidence interval; OR, Odds ratio; LRTI: lower respiratory tract infection. Results 233 SOTRs (58.8% male; median, 61 years), including 77 (49.1%) kidney, 23 (9.9%) liver, 79 (33.9%) lung, and 38 (16.3%) heart transplants (Table). Hypoxic respiratory failure, mechanical ventilation, and secondary infection were seen in 98 (42.1%), 23 (9.9%), and 58 (24.9%) patients, respectively. After multivariate analysis, age &gt;60 years, symptoms and imaging evidence of lower respiratory tract infection (LRTI) were associated with oxygen requirement (Figure 1A); similar results were observed in an analysis of the lung transplant cohort only. Risk factors on multivariate analysis for secondary infection include a history of rejection within six months and mechanical ventilation (Figure 1B). Risk factors for mechanical ventilation included age &gt;60 years and LRTI on imaging (Figure 1C) after multivariate analysis. Seventeen (7.3%) patients died within 90 days of diagnosis. Cox univariate analysis identified age &gt;60 years and LRTI on imaging, secondary infections, mechanical ventilation and hypoxia on admission were associated with higher mortality (Figure 2 and 3).Figure 2:Forest plot with Cox proportional hazards models. Note: only univariate results shown, multivariate not done due to low number of events. Conclusion This multicenter study of SOTR hospitalized with RSV identified older age ( &gt;60 years old) as a risk factor for hypoxic respiratory failure, mechanical ventilation and death. Mechanical ventilation and a history if rejection within six months of RSV were associated with increased risk of secondary infections, identifying them as high-risk that needs close surveillance for this complication.Figure 3:Effects of A) Age older than 60 years old and B) mechanical ventilation on 90 day probability of survival after RSV infection Disclosures Michelle Yong, MBBS, FRACP, MPH, PhD, MSD: Grant/Research Support|MSD: Honoraria|Takeda: Advisor/Consultant Yoichiro Natori, MD, Eurofin/Viracor: Honoraria|Nobel Pharma: Advisor/Consultant

ABSTRACT Background Existing risk scores assessing geriatric vulnerability in the emergency department (ED) have shown limited predictive power, especially in diverse populations. We investigated the relationship of a quick and easy‐to‐administer geriatric vulnerability scoring system with functional decline and mortality in older patients admitted to multiple hospitals through the ED in the United States (US) and Brazil (BR). Method Federated, international, multicenter observational study of hospitalized ED patients aged ≥ 65 from US and BR. The six criteria from the PRO‐AGE score (Physical impairment, Recent hospitalization, Older age [≥ 90], Acute mental alteration, Getting thinner, and Exhaustion; 0–8; higher scores = greater vulnerability) were assessed on admission. We used proportional hazards models to investigate the relationships between PRO‐AGE score groups and 90‐day mortality and functional decline, defined as new dependence in activities of daily living (ADL) and instrumental ADL (IADL), after adjusting for age, sex, race and ethnicity, education, Charlson comorbidity score, and study site. Death was considered a competing event for the functional decline outcome. Results A total of 1390 patients were included (US = 560; Brazil = 830). The 90‐day risk of death was higher for the upper compared with the lower (reference) PRO‐AGE group in both cohorts (US: HR = 11.76; 95% confidence interval [CI] = 2.56–54.04; BR: HR = 12.29; 95% CI = 3.54–42.59), whereas the risk of new 90‐day ADL disability was higher for upper (HR = 2.08; 95% CI = 1.21–3.56) and middle groups (HR = 2.10; 95% CI = 1.35–3.27) in the US but only the upper group in BR (HR = 1.70; 95% CI = 1.02–2.85). Conclusion A higher PRO‐AGE score was associated with mortality and functional decline in older ED patients admitted to hospitals in the US and BR, demonstrating its generalizability as a geriatric vulnerability risk score.