for comments on earlier versions of this paper. We also thank the children and parents who participated. Portions of this research were supported by the Graduate School and by a Summer Faculty Fellowship from Illinois State University.

Bacterial infections continue to be a leading cause of mortality and morbidity in patients who undergo blood and marrow transplantations (BMTs). The relative importance of different clinical features (donor type, graft cell source, and conditioning regimen) on the incidence and timing of posttransplantation bacterial infections is uncertain, but a detailed analysis could better guide prevention and therapy. We retrospectively analyzed the incidence and risk factors for early bacterial infections, as well as patterns of antibiotic resistance. We observed 613 bacteremic events among 349 of 834 patients who underwent BMT treated at the University of Minnesota from 2005 to 2010 (cumulative incidence 42%; 95% confidence interval [CI], 38-45). Donor type (allogeneic vs autologous) had the greatest impact on the incidence of bacteremia within 100 days posttransplantation. Among allogeneic transplantations, myeloablative (MA), compared to reduced-intensity conditioning (RIC) was associated with a significantly greater risk of bacteremia, as was the development of acute graft-versus-host disease (aGVHD). Additionally, patients who underwent BMT, compared to the contemporaneous hospital population, developed infections with more frequent resistance to antibiotics used in the treatment against commonly isolated bacterial organisms. These findings have important clinical implications regarding the use and selection of both prophylactic and empiric antibiotic regimens.

Inherited predisposition to myeloid malignancies is more common than previously appreciated. We analyzed the whole-exome sequencing data of paired leukemia and skin biopsy samples from 391 adult patients from the Beat AML 1.0 consortium. Using the 2015 ACMG guidelines for variant interpretation, we curated 1,547 unique variants from 228 genes. The pathogenic/likely pathogenic (P/LP) germline variants were identified in 53 AML patients (13.6%) in 34 genes. 41% of variants were in DNA damage response genes, and the most frequently mutated genes were CHEK2 (8 patients) and DDX41 (7 patients). 44% of the pathogenic germline variants were in genes considered clinically actionable (tier 1). Pathogenic germline variants were also found in new candidate genes (DNAH5, DNAH9, DNMT3A, SUZ12). No strong correlation was found between the germline mutational rate and age of AML onset. Among 49 patients who have a reported history of at least one family member affected with hematological malignancies, six patients harbored known P/LP germline variants and the remaining patients had at least one variant of uncertain significance, suggesting a need for further functional validation studies. Using CHEK2 as an example, we show that three-dimensional protein modeling can be one of the effective methodologies to prioritize variants of unknown significance for functional studies. Further, we evaluated an in-silico approach that applies ACMG/AMP curation in an automated manner using the tool for assessment and prioritization in exome studies (TAPES), which can minimize manual curation time for variants. Overall, our findings suggest a need to comprehensively understand the predisposition potential of many germline variants in order to enable closer monitoring for disease management and treatment interventions for affected patients and families.

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