Impact of metagenomic next-generation sequencing on clinical decision-making at an academic medical center, a retrospective study, Iowa, 2020-2022.

We assessed the impact of metagenomic next-generation sequencing (mNGS) on patient care using previously established criteria. Among 37 patients receiving mNGS testing, 16% showed results that had a positive clinical impact. While mNGS results may offer valuable supplementary information, results should be interpreted within the broader clinical context and evaluation.

Infantile Hemangiomas of the Head and Neck: A Single-Center Experience.

Background: Infantile hemangiomas (IHs) are the most common benign vascular tumors of infancy. Methods: We report our experiences with 248 patients with head and neck IHs. Results: The median admission age was 4 months, and the female/male ratio was 2.18. Among the cases, 45% were followed by no treatment. No local complications were observed in any of these patients. Propranolol was provided to all patients who received medical treatment. The median duration of treatment was 12 months (1-30 months), and the median follow-up period of all patients was 14 months (0-118 months). The treatment response was 98%. The complication rate was 17%, and children aged between 3 and 9 months accounted for 60% of the patients who developed complications. Most of the complications were local complications, such as ulceration and bleeding. Conclusions: Although most IHs regress spontaneously, complications may occur. Propranolol alone is an effective treatment option, and early treatment initiation increases the success rate.

Pediatric paravertebral tumors: analysis of 96 patients.

PURPOSE: The most important complication of paravertebral tumors is cord compression (CC), which is an oncologic emergency. Early and appropriate intervention is important in terms of reducing morbidity and mortality. Here, we report our clinical experience with paravertebral tumors. METHODS: The files of patients who were followed up for benign/malignant paravertebral tumors between 1988 and 2022 were evaluated retrospectively. RESULTS: There were 96 patients with paravertebral tumors. The median age at diagnosis was 5 years (1 month-17 years). The male/female ratio was 1.13. The median time to diagnosis was 4 weeks (0-28 weeks). The most common presenting complaint was pain (62.5%). The diagnosis distribution was as follows: sympathetic nervous system (SNS) tumors (n: 38), soft tissue sarcomas (STS) (n: 23), Langerhans cell histiocytosis (LCH) (n: 12), central nervous system (CNS) tumors (n: 9), germ cell tumor (n: 6), lymphomas (n: 4), and benign tumors (n: 4). Sixty-five patients (67.7%) had CC, 40% of whom received chemotherapy as first-line treatment. Decompression surgery was performed in 58.5% of the patients. For patients with CC, 26 patients had advanced disease at admission. Serious neurologic sequelae were observed in seventeen (17.7%) patients. CONCLUSION: Pain and neurological findings in childhood are warning signs for paravertebral tumors and CC. A detailed neurologic examination and radiodiagnostic imaging should be performed, and a definitive diagnosis should be made quickly. Anticancer treatment should be planned multidisciplinary. Decompression surgery should be discussed for patients with severe neurological deficits. Childhood cancers are chemosensitive; if possible, treatment should be initiated with chemotherapy to avoid neurological sequelae.

Safety and Immunogenicity of a Delayed Heterologous Avian Influenza A(H7N9) Vaccine Boost Following Different Priming Regimens: A Randomized Clinical Trial.

BACKGROUND: Influenza A (H7N9) has caused multiple disease waves with evidence of strain diversification. Optimal influenza A (H7N9) prime-boost vaccine strategies are unknown. METHODS: We recruited participants who had received monovalent inactivated A/Shanghai/2/2013 (H7N9) vaccine (MIV) approximately 5 years earlier, as follows: MIV with MF59 (MF59 × 2 group), MIV with AS03 (AS03 × 2 group), unadjuvanted MIV (No Adj group), MIV with MF59 or AS03 followed by unadjuvanted MIV (Adjx1 group), and A/H7-naive (unprimed group). Participants were randomized to receive 1 dose of AS03-adjuvanted or unadjuvanted A/Hong Kong/125/2017 (H7N9) MIV and were followed for safety and immunogenicity using hemagglutination inhibition (HAI) and neutralizing antibody assays. RESULTS: We enrolled 304 participants: 153 received the adjuvanted boost and 151 received the unadjuvanted boost. At 21 days postvaccination, the proportion of participants with HAI antibody titers against the boosting vaccine strain of ≥40 in the adjuvanted and unadjuvanted arms, respectively, were 88% and 49% in MF59 × 2 group, 89% and 75% in AS03 × 2 group, 59% and 20% in No Adj group, 94% and 55% in Adjx1group, and 9% and 11% in unprimed group. CONCLUSIONS: Serologic responses to a heterologous A(H7N9) MIV boost were highest in participants primed and boosted with adjuvant-containing regimens. CLINICAL TRIALS REGISTRATION: NCT03738241.

Unraveling the Mystery: Next Generation Sequencing Sheds Light on Neuroblastoma Pathogenesis and Targeted Therapies.

BACKGROUND: There is considerable interest in the molecular evaluation of solid tumors in pediatric cases. Although clinical trials are in progress for targeted therapies against neuroblastoma (NB), novel therapeutic strategies are needed for high-risk cases that are resistant to therapy. The aim of the present study was to document the specific gene mutations related to targeted therapy in relapsed or refractory NB patients by using next generation sequencing (NGS). METHODS: The study included 57 NB patients from amongst 1965 neuroblastic cases in Turkey who experienced a recurrence after multi-model therapy. The cases were diagnosed, risk-stratified, and treated according to the classification system from the International Neuroblastoma Risk Group. Single nucleotide variations in 60 genes were investigated using the Pillar Onco/Reveal Multicancer v4 panel and Pillar RNA fusion panel on the Illumina Miniseq platform. RESULTS: ERBB2 I655V was the most frequent mutation and was found in 39.65% of cases. Anaplastic Lymphoma Kinase (ALK) mutations (F1174L, R1275Q, and rare mutations in the tyrosine kinase domain) were detected in 29.3% of cases. Fusion mutations in NTRK1, NTRK3, ROS1, RET, FGFR3, ALK and BRAF were observed in 19.6% of cases. CONCLUSIONS: This study presents valuable mutation data for relapsed and refractory NB patients. The high frequency of the ERBB2 I655V mutation may allow further exploration of this mutation as a potential therapeutic target. Rare BRAF mutations may also provide opportunities for targeted therapy. The role of ABL1 mutations in NB should also be explored further.

The association of miR-204 and mir-483 5p expression with clinicopathological features of Wilms tumor: Could this provide foresight?

BACKGROUND: Wilms tumor is the most common cancer of the kidney that occurs during childhood, and histologically, it mimics renal embryogenesis. With the development and improvement of up-to-date treatment protocols, the survival rates of Wilms tumor have increased. However, metastases or local relapses are still observed in 15% of patients. The search for reliable biomarkers to identify at-risk patients is ongoing to predict the variability in treatment success. Currently, the evaluation of clinical, histopathological and genetic features are common diagnostic methods; however, epigenetic features can be examined with microRNA expression analyses and might allow us to comment on the behavior of the tumor and treatment response. METHODS: In this study, we aimed to evaluate the relationship between microRNA-204 and microRNA-483-5p expression with clinicopathological data and the effect on Wilms tumor survival. For this purpose, the expression levels of RNU6B, microRNA-204 and microRNA-483-5p were evaluated in tumor and normal tissue by qreal time-polymerase chain reaction. We also investigated the relationship between microRNA expression levels with the clinicopathological and histological features of Wilms tumor. RESULTS AND CONCLUSION: The results of our study indicate that the relative expression levels of microRNA-204 in Wilms tumor tissues were significantly lower than that in adjacent normal tissues. By contrast, tumor tissue had a higher microRNA-483-5p expression than the corresponding normal tissues. A statistically significant difference between microRNA-204 expression level with age and the presence of anaplasia was observed. The upregulation of microRNA-483-5p was found to have a significant correlation with patients after preoperative chemotherapy and complete tumor necrosis. Taken together, our data suggest that microRNA-204 could play a critical role as a tumor suppressor, whereas microRNA-483-5p acts as an oncogene in Wilms tumor progression. More importantly, microRNA-204 might be a novel predictive biomarker for anaplastic histology and could be useful for developing therapeutic interventions targeting this marker.

Epidemiology of Gram-Negative Bloodstream Infections in the United States: Results From a Cohort of 24 Hospitals.

Background: To address knowledge gaps in management of Gram-negative bloodstream infection, the Antibiotic Stewardship Implementation Collaborative was established consisting of programs from 24 academic and community hospitals across the United States. Methods: A retrospective cohort study was conducted of unique adult patients with Gram-negative bloodstream infection hospitalized at participating hospitals from January to December 2019. Patient level and microbiologic data were collected via electronic medical record review with a standardized data collection form and data dictionary. Data analysis was largely descriptive. The Pearson χ2 test to compare categorical variables and the Wilcoxon rank sum test for continuous variables were used. Results: In total, 4851 bacterial isolates from 3710 eligible unique patients were included in the cohort. Most common source of infection was the urinary tract (47.9%). Source control was achieved in 84% of cases. Escherichia coli (2471, 51.0%) was the most common Gram-negative organism recovered. Antibiogram combining isolates from all participating centers with species-level susceptibilities and source specific antibiograms for isolates from urinary, respiratory, and intraabdominal source were created. Northeast sites contributed the most extended spectrum beta-lactamase (ESBL) producing organisms (73%), but West sites had the highest percentage of ESBL producers of total isolates (16%). A statistically significant difference in percentage of ESBL-producing organisms in Whites vs. non-Whites (14.6 % and 9.5 %, respectively, P<0.01) was observed. Conclusions: While the present study was conducted pre-pandemic, it highlights the need for stewardship data collaboratives to enhance our understanding of the antimicrobial resistance patterns.

Evaluating Demographic Representation in Clinical Trials: Use of the Adaptive Coronavirus Disease 2019 Treatment Trial (ACTT) as a Test Case.

Background: Clinical trials initiated during emerging infectious disease outbreaks must quickly enroll participants to identify treatments to reduce morbidity and mortality. This may be at odds with enrolling a representative study population, especially when the population affected is undefined. Methods: We evaluated the utility of the Centers for Disease Control and Prevention's COVID-19-Associated Hospitalization Surveillance Network (COVID-NET), the COVID-19 Case Surveillance System (CCSS), and 2020 United States (US) Census data to determine demographic representation in the 4 stages of the Adaptive COVID-19 Treatment Trial (ACTT). We compared the cumulative proportion of participants by sex, race, ethnicity, and age enrolled at US ACTT sites, with respective 95% confidence intervals, to the reference data in forest plots. Results: US ACTT sites enrolled 3509 adults hospitalized with COVID-19. When compared with COVID-NET, ACTT enrolled a similar or higher proportion of Hispanic/Latino and White participants depending on the stage, and a similar proportion of African American participants in all stages. In contrast, ACTT enrolled a higher proportion of these groups when compared with US Census and CCSS. The proportion of participants aged ≥65 years was either similar or lower than COVID-NET and higher than CCSS and the US Census. The proportion of females enrolled in ACTT was lower than the proportion of females in the reference datasets. Conclusions: Although surveillance data of hospitalized cases may not be available early in an outbreak, they are a better comparator than US Census data and surveillance of all cases, which may not reflect the population affected and at higher risk of severe disease.

Transplantid.net: A Pilot Crowdsourced, Living, Online Library of Resources for the Teaching and Practice of Transplant Infectious Diseases.

The field of transplant infectious diseases is rapidly evolving, presenting a challenge for clinical practice and trainee education. Here we describe the construction of transplantid.net, a free online library, crowdsourced and continuously updated for the dual purpose of point-of-care evidence-based management and teaching.

Model-Informed Clinical Practice - Determining an Appropriate Ampicillin-Sulbactam Redosing Regimen in Surgical Patients by Utilizing Population Pharmacokinetics and Target Attainment Analysis.

In the current study, population pharmacokinetic (PK) of ampicillin-sulbactam was performed based on the clinical pharmacokinetics data collected from a prospective study conducted in 40 surgical patients undergoing prolonged surgery where antibiotic redosing was implemented. A population PK model was successfully developed to characterize the disposition of ampicillin and sulbactam. The final models were two-compartment models for both drugs, with creatinine clearance and heart failure affecting clearance and body surface area having an impact on the central volume of distribution of both ampicillin and sulbactam. Comprehensive Monte Carlo simulations were performed to evaluate the probability of target attainment (PTA) of 24 different redosing scenarios. Simulation results indicated that the ampicillin-sulbactam 2-h redosing scheme recommended by ASHP guidelines is likely too conservative given that 3-g dose (2-g ampicillin/1-g sulbactam) with 4-h redosing interval can reach the breakpoint of 2 mg/L for ampicillin in all populations even with the aggressive pharmacokinetic/pharmacodynamic (PK/PD) target of 100% fT > MIC. With the target 50% fT > MIC, all redosing schemes evaluated, including the 8-h redosing scenario, are predicted to be able to reach the breakpoint of 64 mg/L in all patients. According to our findings, redosing of ampicillin-sulbactam should be every 4 h instead of the currently recommended 2-h redosing schedule. Our PTA results should inform future updates to existing general antibiotic redosing guidelines; and, when used in combination with the availability of institution- and/or unit-specific ampicillin susceptibility patterns, our PTA results may be used to customize SSI prophylaxis redosing recommendations for ampicillin-sulbactam at individual hospitals.

Impact on time to active antimicrobial therapy with 24-hour pharmacist review of Accelerate Pheno BC Kit results.

The Accelerate Pheno platform provides rapid identification and susceptibility data. We demonstrate successful incorporation of 24-hour pharmacist review of Accelerate Pheno results that reduced the number of patients going >3 hours from result without an order for active antimicrobial therapy from 29 (2.8%) of 1,043 to 9 (0.85%) of 1,053 (P < .001).

The clinical follow-up and management of COVID-19 in children and adolescents with an immunocompromised state or a malignancy.

BACKGROUND: It is still not known how an immunosuppressive state affects the response to coronavirus disease 2019 (COVID-19) in children and adolescents. The aim of this study was to evaluate clinical characteristics, outcomes, and follow-up results of COVID-19 in pediatric patients with a history of immunocompromise or malignancy, retrospectively. METHODS: Patients with a diagnosis of COVID-19 who were under 18 years of age and had a history of immunosuppressive chronic disease or under immunosuppressant treatment were included in the study. Patients were applied to our outpatient clinic or consulted to our department in a tertiary center during the first year of the pandemic. RESULTS: We evaluated 18 patients with a median age of 15.0 (0.6-17.8) years. Twelve patients (66.6%) were tested because of a symptom and the most common symptom was fever (44.4%, n = 8). Ten of the symptomatic patients (55.5% of all cohort) had a mild disease, the remaining two patients (11.1%) with an end-stage malignancy had critical diseases. Twelve patients (66.7%) were managed on an outpatient basis and were followed up at home, while the remaining six (33.3%) required hospitalization. One patient, who had Ewing sarcoma, died during the follow-up in the intensive care unit, and others were recovered without any morbidities. Lymphocyte (LYM) counts were significantly lower, C-reactive protein (CRP), and ferritin levels were higher in the individuals that needed hospitalization (p = 0.039, 0.027, and 0.039, respectively). DISCUSSION: Immunocompromised children and adolescents with COVID-19 should be monitored closely, especially those with an end-stage malignancy, low LYM count, or high CRP and ferritin levels.

Outpatient and peri-operative antibiotic stewardship in solid organ transplantation.

BACKGROUND: The consequences of inappropriate antimicrobial use including resistance are increasingly recognized as a global public health threat and many steps have been taken over the last few decades to advance antimicrobial stewardship initiatives with most organ transplant centers currently part of institutions with active antimicrobial stewardship programs. METHODS: A review of the literature was conducted and articles were categorized according to the topic and relevance in the judgment of the two authors. RESULTS: A summary review of the currently available literature was created with a focus on periprocedural and outpatient antimicrobial stewardship. Limitations in the data were significant and discussed in the review. CONCLUSION: The principles of antimicrobial stewardship remain important throughout all phases starting with periprocedural prophylactic antimicrobial selection all the way through to discharge and subsequent healthcare encounters. Despite the broad advances in stewardship initiatives and the rapidly progressing supportive data overall there continue to be significant opportunities for additional research within various special patient populations including recipients of solid organ transplantation (SOT). The recent white paper published in the American Journal of Transplantation called to action the transplant and stewardship communities to have an increased focus and awareness of the issues that antimicrobial overuse can present in the SOT patient population. This is an important step that will hopefully generate more data in this group of patients that arguably faces the greatest vulnerability to the consequences of increased antimicrobial resistance.

Expression Profile of Selected Antitumor Immune Response Genes in Pediatric Classic Hodgkin Lymphoma.

Classic Hodgkin lymphoma (cHL) is one of the most common pediatric solid tumors and is responsible for cancer-related deaths in children. Therefore, to modulate the active antitumor T-cell immune response in cHL can be a treatment strategy. In the present study, we aimed to investigate the expression profiles of selected antitumor immune response genes in pediatric cHL and their relationships with clinical and prognostic parameters to determine their significance in precision medicine. Thirty-nine pediatric nodal cHL patients were enrolled in the study. We analyzed mRNA expression of selected immune response regulatory genes such as PD-L1, CSF2, CTLA4, CXCL5, IDO1, CXCL8, MIF, NOS2, PDCD1, PTGS2, and TGFß1 using real-time quantitative polymerase chain reaction. Only PD-L1 overexpression was statistically related to bulky disease, advanced tumor stage, and high-risk disease category and seen significantly in Epstein-Barr virus-negative pediatric cHL. No expression profiles were correlated with relapse or survival. We conclude that PD-L1 overexpression in pediatric cHL cases is a strong predictor of high-risk categorization. In addition to being a prognostic biomarker, PD-L1 blockade is also a druggable marker for the targeted therapy in Epstein-Barr virus-negative pediatric Hodgkin lymphoma.

PD-L1 and PD-L2 Mutations in Pediatric Hodgkin Lymphoma: Do They Have Any Prognostic Significance?

Background: Reed-Sternberg cells can escape from the immune system by enhancement of the expression of PD-L1 and PD-L2. Objectives: The aim of the present study was to investigate the significance PD-L1 and PD-L2 gene mutations in childhood Hodgkin Lymphoma's (HL). Methods: The study included 39 pediatric classical HL cases. PD-L1 and PD-L2 mutations were determined by Sanger sequencing. Clinicopathological parameters were obtained from patients' records. Results: Eight cases (20.5%) showed p.R260C mutations, and three (7.7%) p.R234L in the exome 5 of PD-L1 gene. None of the cases had PD-L2 mutations. p.R260C mutation exhibited a significant relationship with older age and nodular sclerosing (NS) histology and was associated with longer event free survival. Conclusions: Although PD-L1 mutational status did not show statistically significance with well-established prognostic factors, our preliminary data indicate that p.R260C mutation of PD-L1 gene may be associated with longer event free survival in older patients and NS histology in pediatric HL.

Evaluation of the Infectious Diseases Society of America's Core Antimicrobial Stewardship Curriculum for Infectious Diseases Fellows.

BACKGROUND: Antimicrobial stewardship (AS) programs are required by Centers for Medicare and Medicaid Services and should ideally have infectious diseases (ID) physician involvement; however, only 50% of ID fellowship programs have formal AS curricula. The Infectious Diseases Society of America (IDSA) formed a workgroup to develop a core AS curriculum for ID fellows. Here we study its impact. METHODS: ID program directors and fellows in 56 fellowship programs were surveyed regarding the content and effectiveness of their AS training before and after implementation of the IDSA curriculum. Fellows' knowledge was assessed using multiple-choice questions. Fellows completing their first year of fellowship were surveyed before curriculum implementation ("pre-curriculum") and compared to first-year fellows who complete the curriculum the following year ("post-curriculum"). RESULTS: Forty-nine (88%) program directors and 105 (67%) fellows completed the pre-curriculum surveys; 35 (64%) program directors and 79 (50%) fellows completed the post-curriculum surveys. Prior to IDSA curriculum implementation, only 51% of programs had a "formal" curriculum. After implementation, satisfaction with AS training increased among program directors (16% to 68%) and fellows (51% to 68%). Fellows' confidence increased in 7/10 AS content areas. Knowledge scores improved from a mean of 4.6 to 5.1 correct answers of 9 questions (P = .028). The major hurdle to curriculum implementation was time, both for formal teaching and for e-learning. CONCLUSIONS: Effective AS training is a critical component of ID fellowship training. The IDSA Core AS Curriculum can enhance AS training, increase fellow confidence, and improve overall satisfaction of fellows and program directors.

Real-World Impact of the Accelerate PhenoTest BC Kit on Patients With Bloodstream Infections in the Improving Outcomes and Antimicrobial Stewardship Study: A Quasiexperimental Multicenter Study.

BACKGROUND: Bloodstream infections (BSIs) are a leading cause of morbidity and mortality. The Improving Outcomes and Antimicrobial Stewardship study seeks to evaluate the impact of the Accelerate PhenoTest BC Kit (AXDX) on antimicrobial use and clinical outcomes in BSIs. METHODS: This multicenter, quasiexperimental study compared clinical and antimicrobial stewardship metrics, prior to and after implementation of AXDX, to evaluate the impact this technology has on patients with BSIs. Laboratory and clinical data from hospitalized patients with BSIs (excluding contaminants) were compared between 2 arms, 1 that underwent testing on AXDX (post-AXDX) and 1 that underwent alternative organism identification and susceptibility testing (pre-AXDX). The primary outcomes were time to optimal therapy (TTOT) and 30-day mortality. RESULTS: A total of 854 patients with BSIs (435 pre-AXDX, 419 post-AXDX) were included. Median TTOT was 17.2 hours shorter in the post-AXDX arm (23.7 hours) compared with the pre-AXDX arm (40.9 hours; P<.0001). Compared with pre-AXDX, median time to first antimicrobial modification (24.2 vs 13.9 hours; P<.0001) and first antimicrobial deescalation (36.0 vs 27.2 hours; P=.0004) were shorter in the post-AXDX arm. Mortality (8.7% pre-AXDX vs 6.0% post-AXDX), length of stay (7.0 pre-AXDX vs 6.5 days post-AXDX), and adverse drug events were not significantly different between arms. Length of stay was shorter in the post-AXDX arm (5.4 vs 6.4 days; P=.03) among patients with gram-negative bacteremia. CONCLUSIONS: For BSIs, use of AXDX was associated with significant decreases in TTOT, first antimicrobial modification, and time to antimicrobial deescalation.

Gene-Specific DNA Methylation Profiles in Pediatric Medulloblastomas.

INTRODUCTION: Medulloblastoma is the most common pediatric central nervous tumor of high malignancy that has been classified into both histological subtypes and molecular subgroups by the 2016 World Health Organization classification. However, there is a still need to understand the genomic characteristics and predict the clinical course. The aim of the study is to investigate the significance of the methylation profiles in molecular subclassification and precision medicine of the disease. METHODS: The study enrolled 47 pediatric medulloblastoma patients. DNA methylation levels of KLF4, SPINT2, RASSF1A, EZH2, ZIC2, and PTCH1 genes were analyzed using methylation-specific pyrosequencing. The significance of the statistical relationship between methylation profiles and clinicopathological parameters including molecular subgroups and histological subtypes, the status of metastasis, and event-free survival were analyzed. RESULTS: DNA methylation analysis demonstrated that KLF4, PTCH1, and ZIC2 hypermethylation were associated with the SHH-activated subgroup, whereas both SPINT2 and RASSF1A hypermethylation were associated with metastatic disease. EZH2 gene was not methylated in any of the samples. CONCLUSION: We think that customized DNA methylation profiling may be a useful tool in the molecular subclassification of pediatric medulloblastoma and a potential technical approach in precision medicine.