VEXAS without vacuoles: Linking genotype to phenotype.

Introduction: VEXAS syndrome is a rare condition characterized by somatic mutations in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene and a constellation of clinical/morphologic findings, including the presence of cytoplasmic vacuoles within bone marrow hematopoietic cells. Methods and objectives: In this report, we present a case of a male patient diagnosed with VEXAS-associated myelodysplastic syndrome following the detection of a non-canonical UBA1 p.Gly477Ala variant whose bone marrow biopsy revealed a conspicuous absence of cytoplasmic vacuolization in hematopoietic cells. This case prompts a comprehensive review of the existing literature on the significance and pathobiology of vacuolization in the context of VEXAS and UBA1 mutations.

Chronic Myelomonocytic Leukemia and Atypical Chronic Myeloid Leukemia: A National Analysis.

BACKGROUND: Myelodysplastic/myeloproliferative overlap syndromes (MDS/MPN) are rare blood cancers characterized by concomitant myeloid hyperplasia and dysplasia. These heterogenous disorders include chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML). METHODS: Using two large national cancer databases to examine a total of 15,704 CMML and 702 aCML patients, we report the largest study to date on the incidence, survival and demographic characteristics of CMML and aCML in the United States. RESULTS: Overall age-adjusted incidence of CMML and aCML was 0.63 per 100,000 Americans per year and 0.03 per 100,000 per year, respectively. CMML incidence in the U.S. was noted to rise steadily in the years between 2001 and 2019. Median patient age was 75 and 72 years for CMML and aCML, and the majority of CMML and aCML patients were male (62.9% and 62.0%) and White (90.1% and 86.3%). Median OS was 17.4 months for CMML, and 15.2 months for aCML. Multivariate Cox regression demonstrated features associated with reduced survival, including increasing age, comorbidities, Medicaid insurance status, and low-income residential zip code, highlighting survival disparities in underinsured and socioeconomically disadvantaged patients. In CMML, Black race was associated with inferior survival, while female sex, management at an academic center, and later calendar-year of diagnosis were associated with improved OS. CONCLUSION: These findings underscore the need to better understand the biological basis for such differences in survival and reflect the importance of access to specialized care for patients with these rare disorders.

Polycythemia vera: past, present and future.

There has been remarkable progress in the development of novel therapeutic approaches for patients with polycythemia vera (PV). Historically, therapy goals in PV were to mitigate thrombotic risks and control blood counts and symptoms. There is now increased focus on disease modification through progressive attrition of JAK2-mutant stem/progenitor cells. The approval of ropeginterferon, a novel monoPEGylated interferon, coupled with findings from LOW-PV and longer-term data from CONTINUATION-PV that strongly support a disease-modifying effect for interferon therapy, have transformed the treatment paradigm for this disorder. Results from MAJIC-PV demonstrate that disease modification can also be induced with JAK inhibitors, suggesting an urgent need to incorporate prospective molecular monitoring into PV trials. Novel agents, such as hepcidin mimetics, aim to help patients with PV restore normal hematocrit levels and become phlebotomy-free. In this review, we will summarize past, current and future approaches to PV management and highlight findings from key clinical studies.

Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms.

Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender (P = 0.026), ≥2 autosomal monosomies (P < 0.001), -17/17p (P = 0.011), multi-hit TP53 allelic state (P < 0.001) and CUX1 co-alterations (P = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies (P = 0.004), TP53 VAF > 25% (P = 0.002), TP53 splice junction mutations (P = 0.007) and antecedent treated myeloid neoplasm (P = 0.001). In addition, mutations/deletions in CUX1, U2AF1, EZH2, TET2, CBL, or KRAS ('EPI6' signature) predicted inferior OS24 (HR = 2.0 [1.5-2.8]; P < 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals (N = 144), TP53 VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including TP53 splice junction mutations, EPI6 and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival (P < 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.

Clonal Hematopoiesis in Patients With Human Immunodeficiency Virus and Cancer.

BACKGROUND: Cancer-related deaths for people with human immunodeficiency virus (PWH) are increasing due to longer life expectancies and disparately poor cancer-related outcomes. We hypothesize that advanced biological aging contributes to cancer-related morbidity and mortality for PWH and cancer. We sought to determine the impact of clonal hematopoiesis (CH) on cancer disparities in PWH. METHODS: We conducted a retrospective study to compare the prevalence and clinical outcomes of CH in PWH and people without HIV (PWoH) and cancer. Included in the study were PWH and similar PWoH based on tumor site, age, tumor sequence, and cancer treatment status. Biological aging was also measured using epigenetic methylation clocks. RESULTS: In 136 patients with cancer, PWH had twice the prevalence of CH compared to similar PWoH (23% vs 11%, P = .07). After adjusting for patient characteristics, PWH were 4 times more likely than PWoH to have CH (odds ratio, 4.1 [95% confidence interval, 1.3-13.9]; P = .02). The effect of CH on survival was most pronounced in PWH, who had a 5-year survival rate of 38% if they had CH (vs 59% if no CH), compared to PWoH who had a 5-year survival rate of 75% if they had CH (vs 83% if no CH). CONCLUSIONS: This study provides the first evidence that PWH may have a higher prevalence of CH than PWoH with the same cancers. CH may be an independent biological aging risk factor contributing to inferior survival for PWH and cancer.

JAK2 R683S Mutation Resulting in Dual Diagnoses of Chronic Eosinophilic Leukemia and Myelodysplastic/Myeloproliferative Overlap Syndrome.

A 66-year-old male presented with hypereosinophilia, thrombocytosis, extensive thrombosis refractory to direct oral anticoagulant therapy, and evidence of end-organ damage, including rash, splenic infarcts, and pulmonary infiltrates. Bone marrow biopsy revealed myeloid malignancy consistent with both chronic eosinophilic leukemia and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) with SF3B1 mutation and thrombocytosis. Next-generation sequencing of the patient's eosinophils and neutrophil compartments revealed pathologic variants in EZH2 and SF3B1 in addition to a noncanonical JAK2 R683S mutation that has not been previously described in myeloproliferative disorders or other chronic myeloid neoplasms. These mutations were not present in the patient's lymphoid cell fraction, suggesting that the hematopoietic malignancy arose in a myeloid-committed progenitor cell. Based on this case and previous work from our group, we propose that noncanonical JAK2 mutations may permit signal transduction that biases toward eosinophilic differentiation in chronic myeloid neoplasms. Although the patient's blood counts initially responded to ruxolitinib and hydroxyurea, the response was not durable. Early referral for allogenic bone marrow transplant appears necessary to prevent long-term complications and disease progression in myeloid neoplasms with clonal hypereosinophilia driven by noncanonical JAK2 mutations.

Differences in epigenetic age by HIV status among patients with a non-AIDS defining cancer.

OBJECTIVE: People with HIV (PWH) are living longer and experiencing higher numbers of non-AIDS-defining cancers (NADC). Epigenetic aging biomarkers have been linked to cancer risk, and cancer is now a leading cause of death in PWH, but these biomarkers have not been investigated in PWH and cancer. DESIGN: In order to compare epigenetic age by HIV status, HIV-uninfected participants were matched to PWH by reported age, tumor site, tumor sequence number, and cancer treatment status. METHODS: DNA from blood was assayed using Illumina MethylationEPIC BeadChip, and we estimated immune cell composition and aging from three epigenetic clocks: Horvath, GrimAge, and epiTOC2. Age acceleration by clock was computed as the residual from the expected value, calculated using linear regression, for each study participant. Comparisons across HIV status used the Wilcoxon rank sum test. Hazard ratios and 95% confidence intervals for the association between age acceleration and survival in PWH were estimated with Cox regression. RESULTS: Among 65 NADC participants with HIV and 64 without, biological age from epiTOC2 ( P  < 0.0001) and GrimAge ( P  = 0.017) was significantly higher in PWH. Biological age acceleration was significantly higher in PWH using epiTOC2 ( P  < 0.01) and GrimAge ( P  < 0.0001), with the difference in GrimAge remaining statistically significant after adjustment for immune cell composition. Among PWH, GrimAge acceleration was significantly associated with increased risk of death (hazard ratio 1.11; 95% confidence interval (CI) 1.04-1.18). CONCLUSION: We observed a higher epigenetic age in PWH with a NADC diagnosis compared with their HIV-uninfected counterparts, as well as a significant association between this accelerated biological aging and survival for patients diagnosed with a NADC.

Sociodemographic Comparison of Children With High-risk Medical Conditions Referred vs Identified Through Screening Plus Outreach for COVID-19 Therapeutics.

Importance: Minoritized groups are less likely to receive COVID-19 therapeutics, but few studies have identified potential methods to reduce disparities. Objective: To determine whether screening plus outreach, when compared with referral alone, increases identification of vulnerable pediatric patients at high risk for severe disease eligible for COVID-19 therapeutics from low-resourced communities. Design, Setting, and Participants: A retrospective cohort study of COVID-19 medication allocation between January 1, 2022, and February 15, 2022, at Lurie Children's Hospital, a quaternary care children's hospital, in Chicago, Illinois. The cohorts were pediatric patients referred for COVID-19 therapeutics or with a positive SARS-CoV-2 polymerase chain reaction within the hospital system followed by outreach. Screening involved daily review of positive cases of SARS-CoV-2, followed by medical record review for high-risk conditions, and communication with clinicians and/or patients and families to offer therapy. Exposures: Diagnosis of COVID-19. Main Outcomes and Measures: The primary measure was difference in child opportunity index (COI) scores between the 2 cohorts. Secondary measures included presence and duration of symptoms at diagnosis, medication uptake, race and ethnicity, insurance type, qualifying medical condition, sex, primary language, and age. Results: Of 145 total patients, the median (IQR) age was 15 (13-17) years, and most were male (87 participants [60.0%]), enrolled in public insurance (83 participants [57.2%]), and members of minoritized racial and ethnic groups (103 participants [71.0%]). The most common qualifying conditions were asthma and/or obesity (71 participants [49.0%]). From 9869 SARS-CoV-2 tests performed, 94 eligible patients were identified via screening for COVID-19 therapeutics. Fifty-one patients were identified via referral. Thirty-two patients received medication, of whom 8 (25%) were identified by screening plus outreach alone. Compared with referred patients, patients in the screening plus outreach group were more likely to have moderate, low, or very low COI composite scores (70 patients [74.5%] vs 27 patients [52.9%]); public insurance (65 patients [69.1%] vs 18 patients [35.3%]); and asthma or obesity (60 patients [63.8%] vs 11 patients [21.6%]). Patients in the referral group were more likely to be non-Hispanic White (23 patients [45.1%] vs 19 patients [20.2%]) and receive medication (24 patients [47.1%] vs 8 patients [8.5%]). Conclusions and Relevance: Compared with referral patients, screening plus outreach patients for COVID-19 medications were more socially vulnerable, with lower COI scores, and more likely to have asthma or obesity. Future studies should investigate communication strategies to improve uptake of these medications after outreach.

Clinical Predictors of Subacute Myocardial Dysfunction in Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19.

Multisystem Inflammatory Syndrome in Children (MIS-C) often involves a post-viral myocarditis and associated left ventricular dysfunction. We aimed to assess myocardial function by strain echocardiography after hospital discharge and to identify risk factors for subacute myocardial dysfunction. We conducted a retrospective single-center study of MIS-C patients admitted between 03/2020 and 03/2021. Global longitudinal strain (GLS), 4-chamber longitudinal strain (4C-LS), mid-ventricular circumferential strain (CS), and left atrial strain (LAS) were measured on echocardiograms performed 3-10 weeks after discharge and compared with controls. Among 60 MIS-C patients, hypotension (65%), ICU admission (57%), and vasopressor support (45%) were common, with no mortality. LVEF was abnormal (< 55%) in 29% during hospitalization but only 4% at follow-up. Follow-up strain abnormalities were prevalent (GLS abnormal in 13%, 4C-LS in 18%, CS in 16%, LAS in 5%). Hypotension, ICU admission, ICU and hospital length of stay, and any LVEF < 55% during hospitalization were factors associated with lower strain at follow-up. Higher peak C-reactive protein (CRP) was associated with hypotension, ICU admission, total ICU days, and with lower follow-up GLS (r = - 0.55; p = 0.01) and CS (r = 0.41; p = 0.02). Peak CRP < 18 mg/dL had negative predictive values of 100% and 88% for normal follow-up GLS and CS, respectively. A subset of MIS-C patients demonstrate subclinical systolic and diastolic function abnormalities at subacute follow-up. Peak CRP during hospitalization may be a useful marker for outpatient cardiac risk stratification. MIS-C patients with hypotension, ICU admission, any LVEF < 55% during hospitalization, or a peak CRP > 18 mg/dL may warrant closer monitoring than those without these risk factors.

Incidence and Clinical Characteristics of Severe Acute Respiratory Syndrome Coronavirus 2 Infection After Vaccination in Children.

The objective of this single-center cohort study was to characterize the frequency, clinical characteristics, and molecular epidemiology of pediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection after vaccination. Between May 15, 2021, and January 1, 2022, 171 children experienced SARS-CoV-2 infection postvaccination, 146 (86%) following the Omicron variant predominance. Outcomes were generally mild and comparable before and after Omicron predominance.

Severity of Illness Caused by Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern in Children: A Single-Center Retrospective Cohort Study.

BACKGROUND: Recent COVID-19 surges are attributed to emergence of more transmissible SARS-CoV-2 variants of concern (VOCs). The relative severity of VOCs in children is unknown. METHODS: We performed a single-center retrospective cohort study of children ≤18 years old diagnosed with COVID-19 from October 2020-February 2022 and whose SARS-CoV-2 isolate underwent Illumina sequencing. We measured the frequency of five markers of COVID-19 severity. Logistic regression models were fitted to estimate the odds of each severity marker with each VOC. RESULTS: Among 714 children, 471 (66.0%) were infected with a VOC: 96 (13.4%) alpha, 38 (5.3%) gamma, 119 (16.7%) delta, and 215 (30.1%) omicron. High-risk medical conditions and increasing age were independently associated with COVID-19 severity. After adjusting for age, race, ethnicity, high-risk medical conditions, and COVID-19 community incidence, neither alpha, delta, nor omicron was associated with severe COVID-19. Gamma was independently associated with hospitalization (OR 6.7, 95% CI 2.0-22.1); pharmacologic treatment (OR 5.7, 95% CI 1.2-26.8); respiratory support (OR 11.9, 95% CI 2.7-62.4); and severe disease per the WHO Clinical Progression Scale (OR 11.7, 95% CI 2.1-90.5). Upon subgroup analyses, omicron was independently associated with ICU admission and severe disease per the WHO Clinical Progression Scale in children without SARS-CoV-2 immunization or prior COVID-19 infection. CONCLUSIONS: Compared to non-VOC COVID-19, the gamma VOC was independently associated with increased COVID-19 severity, as was omicron in children without SARS-CoV-2 immunization or prior COVID-19 infection. SARS-CoV-2 vaccination and prior COVID-19 prevented severe outcomes during the omicron surge.

Intestinal Absorption of Lipids Using a Pancreatic Enzyme-Free Nutritional Supplement in Patients with Cystic Fibrosis: A Randomized, Double-Blind, Crossover Pilot Trial.

Nutritional supplements for patients with exocrine pancreatic insufficiency (EPI) typically utilize pancreatic enzyme replacement therapy (PERT) which is associated with gastrointestinal side effects. We evaluated serum triglyceride levels in patients with cystic fibrosis following consumption of an enzyme-modified oil oral nutritional supplement (EMO-ONS) versus a standard triacylglycerol-based ONS product (TAG-ONS) used concomitantly with PERT and patient tolerability between the two approaches. Ten subjects with CF and EPI taking PERT were enrolled in a single-center, double-blind, cross-over proof of concept trial. Five subjects randomized to Arm 1 were administered a PERT placebo and EMO-ONS and 5 subjects in Arm 2 were administered TAG-ONS+PERT. After 4 to 14 days, subjects received the opposite ONS. Serum triglyceride levels were measured at baseline and hourly for 6 h. Following the above, subjects were randomly assigned to receive 2 daily servings of EMO-ONS+PERT placebo or TAG-ONS+PERT at home for 7-days, self-reporting gastrointestinal symptoms daily. Mean change in peak serum triglyceride levels were similar for both groups (EMO-ONS = 41.9 ± 46.7 mg/dL vs. TAG-ONS+PERT = 46.4 ± 44.1 mg/L; p = 0.85). There was no difference in mean ratio of the serum triglyceride AUC between the two groups (p = 0.58) or self-reported gastrointestinal tolerance. EMO-based products may provide a PERT-free alternative to traditional ONS products in patients with cystic fibrosis.

Viral whole-genome sequencing to assess impact of universal masking on SARS-CoV-2 transmission among pediatric healthcare workers.

OBJECTIVE: To identify the impact of universal masking on COVID-19 incidence and putative SARS-CoV-2 transmissions events among children's hospital healthcare workers (HCWs). DESIGN: Quasi-experimental study. SETTING: Single academic free-standing children's hospital. METHODS: We performed whole-genome sequencing of SARS-CoV-2- PCR-positive samples collected from HCWs 3 weeks before and 6 weeks after implementing a universal masking policy. Phylogenetic analyses were performed to identify clusters of clonally related SARS-CoV-2 indicative of putative transmission events. We measured COVID-19 incidence, SARS-CoV-2 test positivity rates, and frequency of putative transmission events before and after the masking policy was implemented. RESULTS: HCW COVID-19 incidence and test positivity declined from 14.3 to 4.3 cases per week, and from 18.4% to 9.0%, respectively. Putative transmission events were only identified prior to universal masking. CONCLUSIONS: A universal masking policy was associated with reductions in HCW COVID-19 infections and occupational acquisition of SARS-CoV-2.

Severity of Illness Caused by Severe Acute Respiratory Syndrome Coronavirus 2 Variants of Concern in Children: A Single-Center Retrospective Cohort Study.

BACKGROUND: Recent surges in coronavirus 2019 disease (COVID-19) is attributed to the emergence of more transmissible severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs). However, the relative severity of SARS-CoV-2 VOCs in children is unknown. METHODS: This retrospective single-center cohort study was performed at the Ann & Robert H. Lurie Children's Hospital of Chicago, academic free-standing children's hospital. We included all children ≤ 18 years-old diagnosed with COVID-19 between October 15 th , 2020 and August 31 st , 2021 and whose SARS-CoV-2 isolate was sequenced using the Illumina platform. For each patient sample, we identified the SARS-CoV-2 lineage, which was assigned to one of the following groups: Non-VOC, alpha VOC, beta VOC, gamma VOC, or delta VOC. We measured frequency of 5 markers of COVID-19 severity: hospitalization; COVID-19 pharmacologic treatment; respiratory support; intensive care unit admission; and severe disease as classified by the COVID-19 World Health Organization (WHO) Clinical Progression Scale (severe disease; score ≥ 6). A series of logistic regression models were fitted to estimate odds of each severity marker with each VOC (in comparison to non-VOCs), adjusting for COVID-19 community incidence and demographic and clinical co-variates. RESULTS: During the study period, 2,025 patients tested positive for SARS-CoV-2; 1,422 (70.2%) had sufficient viral load to permit sequencing. Among the 499 (35.1%) patients whose isolate was sequenced, median (inter-quartile range) age was 7 (1,12) years; 256 (51.3%) isolates were a VOC: 96 (37.5%) alpha, 38 (14.8%) gamma, and 119 (46.5%) delta. After adjusting for age, Black race, Hispanic ethnicity, high-risk medical conditions, and COVID-19 community incidence, neither alpha nor delta was associated with severe COVID-19. Gamma was independently associated with hospitalization (OR 5.9, 95% CI 1.6-21.5, p =0.007), respiratory support (OR 8.3, 95% CI 1.5-56.3, p =0.02), and severe disease as classified by the WHO Clinical Progression Scale (OR 7.7, 95% CI 1.0-78.1, p =0.05). CONCLUSIONS: Compared to non-VOC COVID-19 infections, the gamma VOC, but not the alpha or delta VOCs, was associated with increased severity. These data suggest that recent increased in pediatric COVID-19 hospitalizations are related to increased delta COVID-19 incidence rather than increased delta virulence in children.

Cardiovascular magnetic resonance imaging in children after recovery from symptomatic COVID-19 or MIS-C: a prospective study.

BACKGROUND: Cardiac evaluations, including cardiovascular magnetic resonance (CMR) imaging and biomarker results, are needed in children during mid-term recovery after infection with SARS-CoV-2. The incidence of CMR abnormalities 1-3 months after recovery is over 50% in older adults and has ranged between 1 and 15% in college athletes. Abnormal cardiac biomarkers are common in adults, even during recovery. METHODS: We performed CMR imaging in a prospectively-recruited pediatric cohort recovered from COVID-19 and multisystem inflammatory syndrome in children (MIS-C). We obtained CMR data and serum biomarkers. We compared these results to age-matched control patients, imaged prior to the SARS-CoV-2 pandemic. RESULTS: CMR was performed in 17 children (13.9 years, all ≤ 18 years) and 29 age-matched control patients without SARS-CoV-2 infection. Cases were recruited with symptomatic COVID-19 (11/17, 65%) or MIS-C (6/17, 35%) and studied an average of 2 months after diagnosis. All COVID-19 patients had been symptomatic with fever (73%), vomiting/diarrhea (64%), or breathing difficulty (55%) during infection. Left ventricular and right ventricular ejection fractions were indistinguishable between cases and controls (p = 0.66 and 0.70, respectively). Mean native global T1, global T2 values and segmental T2 maximum values were also not statistically different from control patients (p ≥ 0.06 for each). NT-proBNP and troponin levels were normal in all children. CONCLUSIONS: Children prospectively recruited following SARS-CoV-2 infection had normal CMR and cardiac biomarker evaluations during mid-term recovery. Trial Registration Not applicable.

Surveillance Cultures and Infection in 230 Pacemaker and Defibrillator Generator Changes in Pediatric and Adult Congenital Patients.

BACKGROUND: Postoperative infections can occur during surgical replacement of pulse generators for pacemakers and implantable cardioverter-defibrillators. The incidence of infection is poorly documented in children and patients with adult congenital heart disease. The utility of surveillance cultures obtained from device pocket swabs is unknown in this group. METHODS: We reviewed surgical replacements of cardiovascular implantable pulse generators from 2010 to 2017. Two cohorts were defined. In a surveillance cohort (123 patients), aerobic and anaerobic culture swabs of the device pocket were obtained at the time of generator change. In a nonsurveillance cohort (107 patients), generator change occurred without obtaining cultures. RESULTS: During 230 generator changes (mean patient age 19 years; 77% with structural congenital heart disease), two clinical infections occurred at the surgical site (0.9% incidence). Neither infection occurred in the surveillance cohort. Cultures were positive in 12 (9.8%) of 123 patients in the surveillance cohort, but 11 of 12 were likely contaminants and none were subsequently associated with clinical disease. There was no association between clinical infection or positive surveillance cultures and the location of pulse generator, the presence of other concurrent surgeries, or a history of prior pocket infection. CONCLUSIONS: Clinical infection was rare after pulse generator change in children and young adults. No cases required reintervention on the pocket. Surveillance cultures did not improve clinical care. These data extend current recommendations that surveillance cultures are not required during generator change to the pediatric and young adult population.

SIRT5 IS A DRUGGABLE METABOLIC VULNERABILITY IN ACUTE MYELOID LEUKEMIA.

We discovered that the survival and growth of many primary acute myeloid leukemia (AML) samples and cell lines, but not normal CD34+ cells, are dependent on SIRT5, a lysine deacylase implicated in regulating multiple metabolic pathways. Dependence on SIRT5 is genotype-agnostic and extends to RAS- and p53-mutated AML. Results were comparable between SIRT5 knockdown and SIRT5 inhibition using NRD167, a potent and selective SIRT5 inhibitor. Apoptosis induced by SIRT5 disruption is preceded by reductions in oxidative phosphorylation and glutamine utilization, and an increase in mitochondrial superoxide that is attenuated by ectopic superoxide dismutase 2. These data indicate that SIRT5 controls and coordinates several key metabolic pathways in AML and implicate SIRT5 as a vulnerability in AML.

Retapamulin Activity Against Pediatric Strains of Mupirocin-resistant Methicillin-resistant Staphylococcus aureus.

Retapamulin activity against 53 isolates obtained from a mupirocin-resistant community-acquired methicillin-resistant Staphylococcus aureus pediatric disease cluster was evaluated using broth microdilution. All strains were susceptible to retapamulin with minimum inhibitory concentrations ≤ 0.5 µg/mL. DNA sequence analysis of rplC and cfr identified one rplC strain variant that did not demonstrate reduced phenotypic susceptibility to retapamulin. These results demonstrate that retapamulin may be a useful alternative therapy for mupirocin-resistant community-acquired methicillin-resistant S. aureus, especially in disease clusters.