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ImportanceRespiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections (LRTIs) and infant hospitalization worldwide.ObjectiveTo evaluate the characteristics and outcomes of RSV-related critical illness in US infants during peak 2022 RSV transmission.Design, Setting, and ParticipantsThis cross-sectional study used a public health prospective surveillance registry in 39 pediatric hospitals across 27 US states. Participants were infants admitted for 24 or more hours between October 17 and December 16, 2022, to a unit providing intensive care due to laboratory-confirmed RSV infection.ExposureRespiratory syncytial virus.Main Outcomes and MeasuresData were captured on demographics, clinical characteristics, signs and symptoms, laboratory values, severity measures, and clinical outcomes, including receipt of noninvasive respiratory support, invasive mechanical ventilation, vasopressors or extracorporeal membrane oxygenation, and death. Mixed-effects multivariable log-binomial regression models were used to assess associations between intubation status and demographic factors, gestational age, and underlying conditions, including hospital as a random effect to account for between-site heterogeneity.ResultsThe first 15 to 20 consecutive eligible infants from each site were included for a target sample size of 600. Among the 600 infants, the median (IQR) age was 2.6 (1.4-6.0) months; 361 (60.2%) were male, 169 (28.9%) were born prematurely, and 487 (81.2%) had no underlying medical conditions. Primary reasons for admission included LRTI (594 infants [99.0%]) and apnea or bradycardia (77 infants [12.8%]). Overall, 143 infants (23.8%) received invasive mechanical ventilation (median [IQR], 6.0 [4.0-10.0] days). The highest level of respiratory support for nonintubated infants was high-flow nasal cannula (243 infants [40.5%]), followed by bilevel positive airway pressure (150 infants [25.0%]) and continuous positive airway pressure (52 infants [8.7%]). Infants younger than 3 months, those born prematurely (gestational age <37 weeks), or those publicly insured were at higher risk for intubation. Four infants (0.7%) received extracorporeal membrane oxygenation, and 2 died. The median (IQR) length of hospitalization for survivors was 5 (4-10) days.Conclusions and RelevanceIn this cross-sectional study, most US infants who required intensive care for RSV LRTIs were young, healthy, and born at term. These findings highlight the need for RSV preventive interventions targeting all infants to reduce the burden of severe RSV illness.

Abstract The role of measurable residual disease (MRD) in multiple myeloma patients treated with chimeric antigen receptor (CAR) T cells is uncertain. We analyzed MRD kinetics during the first year after idecabtagene vicleucel (ide-cel) infusion in 125 relapsed/refractory multiple myeloma patients enrolled in KarMMa. At month 1 after ide-cel, there were no differences in progression-free survival (PFS) between patients in less than complete response (CR) versus those in CR; only MRD status was predictive of significantly different PFS at this landmark. In patients with undetectable MRD at 3 months and beyond, PFS was longer in those achieving CR versus <CR. Persistent MRD in the 10−6 logarithmic range and reappearance of normal plasma cells in MRD-negative patients were associated with inferior PFS. This study unveils different prognostic implications of serological and MRD response dynamics after ide-cel and suggests the potential value of studying the reappearance of normal plasma cells as a surrogate of loss of CAR T-cell functionality. Significance: This is one of the first studies evaluating the impact of CR and MRD dynamics after CAR T therapy in relapsed/refractory multiple myeloma. These data help interpret the prognostic significance of serological and MRD responses at early and late time points after CAR T-cell infusion. See related commentary by Landgren and Kazandjian, p. 346 . This article is featured in Selected Articles from This Issue, p. 337

Abstract Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)–like (N = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.

OBJECTIVES We sought to improve utilization of a sepsis care bundle and decrease 3- and 30- day sepsis-attributable mortality, as well as determine which care elements of a sepsis bundle are associated with improved outcomes. METHODS Children’s Hospital Association formed a QI collaborative to Improve Pediatric Sepsis Outcomes (IPSO) (January 2017–March 2020 analyzed here). IPSO Suspected Sepsis (ISS) patients were those without organ dysfunction where the provider “intended to treat” sepsis. IPSO Critical Sepsis (ICS) patients approximated those with septic shock. Process (bundle adherence), outcome (mortality), and balancing measures were quantified over time using statistical process control. An original bundle (recognition method, fluid bolus < 20 min, antibiotics < 60 min) was retrospectively compared with varying bundle time-points, including a modified evidence-based care bundle, (recognition method, fluid bolus < 60 min, antibiotics < 180 min). We compared outcomes using Pearson χ-square and Kruskal Wallis tests and adjusted analysis. RESULTS Reported are 24 518 ISS and 12 821 ICS cases from 40 children’s hospitals (January 2017–March 2020). Modified bundle compliance demonstrated special cause variation (40.1% to 45.8% in ISS; 52.3% to 57.4% in ICS). The ISS cohort’s 30-day, sepsis-attributable mortality dropped from 1.4% to 0.9%, a 35.7% relative reduction over time (P < .001). In the ICS cohort, compliance with the original bundle was not associated with a decrease in 30-day sepsis-attributable mortality, whereas compliance with the modified bundle decreased mortality from 4.75% to 2.4% (P < .01). CONCLUSIONS Timely treatment of pediatric sepsis is associated with reduced mortality. A time-liberalized care bundle was associated with greater mortality reductions.

Abstract Background Multiple anaphylaxis mediators have been demonstrated to provoke migraine‐like attacks following intravascular infusion, suggesting that anaphylaxis could cause headache; however, headache is rarely noted in anaphylaxis and is not included among diagnostic criteria. Objective Our study objectives were to estimate the frequency of headache among prospectively enrolled emergency department (ED) patients with anaphylaxis and assess the association of headache with patient and anaphylaxis characteristics. Methods A cross‐sectional study of ED patients aged ≥5 years who met anaphylaxis diagnostic criteria from January 8, 2020 to September 9, 2022 was conducted. The primary outcome of interest was headache frequency among patients who met at least one anaphylaxis criterion. We explored the association of headache with patient characteristics and anaphylaxis characteristics. Results We included 63 patients with anaphylaxis. In all, 17 (27%, 95% confidence interval [CI] 17%–40%) patients reported the presence of a headache. Female patients had more than a nine times increased odds of having headache (odds ratio [OR] 9.3, 95% CI 1.14–77.1, p = 0.016). Presentation with headache was associated with the presence of dyspnea (OR 5.5, 95% CI 1.56–19.7, p = 0.006). Conclusion Headache in anaphylaxis may be more common than previously recognized, especially in females. Larger prospective studies are needed to characterize headache as a marker of neurological involvement in anaphylaxis.

Abstract Purpose Twenty five percent of practicing physicians in the US are International Medical Graduates (IMGs) – physicians who completed their medical school training outside of the United States and Canada. There are multiple studies demonstrating higher socio-economic background is associated with medical school matriculation in the US. However, despite a substantial prevalence of IMGs in the American healthcare system, studies of the association between demographics, socio-economic background, and securing a residency position in the match are lacking. Methods We created a survey with questions on residency match-related data and information on personal socio-economic background. An invitation to participate in the study was sent to all IMGs that applied to the included residency programs after the conclusion of the 2022 residency match. We used multivariable logistic regression to compare survey responses to the odds of securing a residency match. Results The total number of survey respondents was 744 (response rate 15.1%). We found that younger age, higher United States Medical License Examination (USMLE) scores, higher-income country of origin (including the United States), fewer match attempts, applying to fewer specialties, having parents with college degree or higher, and coming from higher-than-average or lower-than-average family income were associated with increased odds of matching. Gender, personal income, and visa status did not demonstrate significant associations with residency match. Conclusions Residency match is a significant expense for IMGs, especially for those from lower-income countries. International applicants from higher socio-economic backgrounds might have advantages in securing medical residency positions in the United States when controlling for other variables.

Abstract Background: The genotoxin colibactin, produced by Escherichia coli containing the pks island, is associated with a tumor single base substitution (SBS) mutational signature SBS88. It is unknown whether lifestyle and environmental factors related to gut dysbiosis impact colorectal cancer (CRC) risk and survival differently by colibactin signature status. Methods: Utilizing the resources of the Genetic Epidemiology of Colorectal cancer Consortium and Colon Cancer Family Registry (GECCO-CCFR), a consortium including both case-control and cohort study designs, SBS88 tumor mutational signature was measured in 4308 CRC cases who were microsatellite stable (MSS) and had at least five somatic single nucleotide variants for signature decomposition. Associations of 13 lifestyle and environmental factors with CRC risk by colibactin signature status were assessed using logistic and multinomial regression; associations with CRC survival were assessed using Cox proportional hazards regression. Results: 392 (9%) of the 4308 MSS tumors were positive for SBS88. Having a BMI ≥30 kg/m2 (versus a BMI 18.5-24.9 kg/m2) was strongly associated with worse CRC-specific survival among those with the SBS88 signature, but not among those with SBS88 negative CRC [further adjusted hazard ratio (HR) = 3.40 95% confidence interval (CI) 1.47, 7.84, and HR = 0.97 95% CI 0.78, 1.21, respectively, P for heterogeneity = 0.066]. Associations of fruit intake with CRC risk may be differential by SBS88 status. In minimally adjusted models, those in the highest quartile of fruit intake (versus the first quartile) had 0.53 (95% CI 0.37, 0.76) times the risk of SBS88 positive CRC, as opposed to 0.75 (95% CI 0.66, 0.85) times the risk of SBS88 negative CRC (P for heterogeneity = 0.047). Among cohort studies specifically, associations between CRC risk and BMI, alcohol, and fruit intake also differed by SBS88 status (P for heterogeneity ranging 0.02-0.05). Conclusions: Higher BMI may be associated with worse CRC-specific survival among those with SBS88 positive tumors. BMI, alcohol, and dietary factors may be differentially associated with CRC risk based on SBS88 status. Citation Format: Claire Elizabeth Thomas, Peter Georgeson, Conghui Qu, Robert S. Steinfelder, Daniel D. Buchanan, Mark A. Jenkins, Andrea Gsur, Jane C. Figueiredo, Polly A. Newcomb, Peter T. Campbell, Christina Newton, Caroline Y. Um, Lisa Boardman, Victor Moreno, Jenny Chang-Claude, Michael Hoffmeister, Marc J. Gunter, Andrew T. Chan, Shuji Ogino, Ellen L. Goode, Brigid Lynch, Yohannes A. Melaku, Steven Gallinger, Sonja I. Berndt, Wen-Yi Huang, Ulrike Peters, Amanda I. Phipps. Lifestyle and environmental factors in relation to colorectal cancer risk and survival by colibactin tumor mutational signature status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6453.

e20005 Background: iAEs such as cytokine release syndrome (CRS) and neurotoxicity (NT) are common with CAR T cell therapies such as ide-cel; CRS and NT observed with ide-cel are generally low grade and manageable with tocilizumab (toci) and corticosteroids. Identifying iAE risk with sensitivity and specificity is challenging, suggesting multifactorial etiology and limitations evaluating dynamic processes at specific timepoints. Macrophage activation syndrome (MAS; per CTCAE) has a specific molecular profile representing a homogeneous subgroup within CRS, tending to be more severe/refractory to front-line management. Using longitudinal data on post-infusion soluble factors we aimed to develop a candidate post-infusion inflammatory risk score based on MAS molecular signature and determine associations with pt baseline characteristics. Methods: Statistical learning tools were applied to the longitudinal profile of 34 factors measured over 28 d after ide-cel infusion in 291 pts from KarMMa (NCT03361748) and KarMMa-2 (NCT03601078) to extract features describing the profiles. Unsupervised machine learning-based clustering was applied to these features and enrichment for MAS cases within each cluster was assessed. A metric describing membership in a cluster of interest was used as a candidate post-infusion inflammatory risk score for further correlative analyses. Results: Pts with MAS had cytokine profiles consistent with high levels of pro-inflammatory signalling across multiple inflammatory cell types. Cytokine profiles of MAS were qualitatively similar to those of CRS/NT; however, unsupervised clustering showed a distinct group of pts with MAS. A metric of similarity to the MAS-enriched cluster was defined as a candidate post-infusion inflammatory risk score, posited to identify pts more likely to have more severe/refractory iAEs. This inflammatory risk score positively correlated with CRS and NT grades and frequency of toci usage (Kruskal-Wallis test; all P < 0.001). A prototype predictive model based on baseline pt and clinical characteristics strongly correlated with post-infusion inflammatory risk score (Pearson; ρ = 0.88). Low blood counts, higher tumor burden, and elevated levels of inflammatory markers on the day of ide-cel infusion were associated with a higher inflammatory risk score. Conclusions: A molecular profile of severe/refractory iAEs was preliminarily identified in ide-cel treated pts with MM. This profile enabled derivation of a candidate post-infusion inflammatory risk score and a prototype predictive model of this risk score based on pt baseline characteristics was developed. These results may help identify pts at risk for severe/refractory iAEs, who may be potential candidates for closer monitoring or novel interventions, and warrant further study. Clinical trial information: NCT03361748 , NCT03601078 .

Abstract Background Antimicrobial resistance (AMR) is undermining modern medicine, a problem compounded by bacterial adaptation to antibiotic pressures. Phages are viruses that infect bacteria. Their diversity and evolvability offer the prospect of their use as a therapeutic solution. Reported are outcomes of customized phage therapy for patients with difficult-to-treat antimicrobial resistant infections. Methods We retrospectively assessed 12 cases of customized phage therapy from a phage production center. Phages were screened, purified, sequenced, characterized, and Food and Drug Administration–approved via the IND (investigational new drug) compassionate-care route. Outcomes were assessed as favorable or unfavorable by microbiologic and clinical standards. Infections were device-related or systemic. Other experiences such as time to treatment, antibiotic synergy, and immune responses were recorded. Results Fifty requests for phage therapy were received. Customized phages were generated for 12 patients. After treatment, 42% (5/12) of cases showed bacterial eradication and 58% (7/12) showed clinical improvement, with two-thirds of all cases (66%) showing favorable responses. No major adverse reactions were observed. Antibiotic-phage synergy in vitro was observed in most cases. Immunological neutralization of phages was reported in 5 cases. Several cases were complicated by secondary infections. Complete characterization of the phages (morphology, genomics, and activity) and their production (methods, sterility, and endotoxin tests) are reported. Conclusions Customized phage production and therapy was safe and yielded favorable clinical or microbiological outcomes in two-thirds of cases. A center or pipeline dedicated to tailoring the phages against a patient's specific AMR bacterial infection may be a viable option where standard treatment has failed.

AbstractObjectivesPatients with limited English proficiency (LEP) have been shown to experience disparities in emergency department (ED) care. The objectives of this study were to examine the associations between LEP and irregular ED departures and return ED visits.MethodsWe conducted a multicenter cross‐sectional analysis of 18 EDs within an integrated health system in the upper Midwest from January 1, 2018, to December 31, 2021. ED visits of pediatric and adult patients who were discharged on the index visit were included for analysis. We analyzed the association of LEP with irregular departures, 72‐h and 7‐day return visits, and ED disposition at the time of that return visit. Multivariable model associations were calculated using generalized estimating equations and reported as odds ratios (OR) with 95% confidence intervals (CIs).ResultsA total of 745,464 total ED visits were analyzed, including 27,906 (3.7%) visits among patients with LEP. The most common preferred languages among patients with LEP were Spanish (12,759; 45.7%), Somali (4978; 17.8%), and Arabic (3185; 11.4%). After multivariable adjustment there were no differences in proportions of irregular departures (OR 1.09, 95% CI 0.99–1.21), 72‐h returns (OR 0.99, 95% CI 0.92–1.06), or 7‐day returns (OR 0.99, 95% CI 0.93–1.05) between patients with LEP or English proficiency. Patients with LEP returning within 72 h (OR 1.19, 95% CI 1.01–1.40) and 7 days (OR 1.15, 95% CI 1.01–1.33) were more likely to be admitted to the hospital.ConclusionsAfter multivariable adjustment, we did not find an increased frequency of irregular ED departures or 72‐h or 7‐day returns among patients with LEP compared with people proficient in English. However, we did find that higher proportions of patients with LEP were admitted to the hospital at the time of the return ED visit.