The Durability of Antibody Responses of Two Doses of High-Dose Relative to Two Doses of Standard-Dose Inactivated Influenza Vaccine in Pediatric Hematopoietic Cell Transplant Recipients: A Multi-Center Randomized Controlled Trial.

BACKGROUND: Our previous study established a 2-dose regimen of high-dose trivalent influenza vaccine (HD-TIV) to be immunogenically superior compared to a 2-dose regimen of standard-dose quadrivalent influenza vaccine (SD-QIV) in pediatric allogeneic hematopoietic cell transplant (HCT) recipients. However, the durability of immunogenicity and the role of time post-HCT at immunization as an effect modifier are unknown. METHODS: This phase II, multi-center, double-blinded, randomized controlled trial compared HD-TIV to SD-QIV in children 3-17 years old who were 3-35 months post-allogeneic HCT, with each formulation administered twice, 28-42 days apart. Hemagglutination inhibition (HAI) titers were measured at baseline, 28-42 days following each dose, and 138-222 days after the second dose. Using linear mixed effects models, we estimated adjusted geometric mean HAI titer ratios (aGMR: HD-TIV/SD-QIV) to influenza antigens. Early and late periods were defined as 3-5 and 6-35 months post-HCT, respectively. RESULTS: During 3 influenza seasons (2016-2019), 170 participants were randomized to receive HD-TIV (n = 85) or SD-QIV (n = 85). HAI titers maintained significant elevations above baseline for both vaccine formulations, although the relative immunogenic benefit of HD-TIV to SD-QIV waned during the study. A 2-dose series of HD-TIV administered late post-HCT was associated with higher GMTs compared to the early post-HCT period (late group: A/H1N1 aGMR = 2.16, 95% confidence interval [CI] = [1.14-4.08]; A/H3N2 aGMR = 3.20, 95% CI = [1.60-6.39]; B/Victoria aGMR = 1.91, 95% CI = [1.01-3.60]; early group: A/H1N1 aGMR = 1.03, 95% CI = [0.59-1.80]; A/H3N2 aGMR = 1.23, 95% CI = [0.68-2.25]; B/Victoria aGMR = 1.06, 95% CI = [0.56-2.03]). CONCLUSIONS: Two doses of HD-TIV were more immunogenic than SD-QIV, especially when administered ≥6 months post-HCT. Both groups maintained higher titers compared to baseline throughout the season. CLINICAL TRIALS REGISTRATION: NCT02860039.

Seasonality, Clinical Characteristics, and Outcomes of Respiratory Syncytial Virus Disease by Subtype Among Children Aged <5 Years: New Vaccine Surveillance Network, United States, 2016-2020.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of acute respiratory illnesses in children. RSV can be broadly categorized into 2 major subtypes: A and B. RSV subtypes have been known to cocirculate with variability in different regions of the world. Clinical associations with viral subtype have been studied among children with conflicting findings such that no conclusive relationships between RSV subtype and severity have been established. METHODS: During 2016-2020, children aged <5 years were enrolled in prospective surveillance in the emergency department or inpatient settings at 7 US pediatric medical centers. Surveillance data collection included parent/guardian interviews, chart reviews, and collection of midturbinate nasal plus/minus throat swabs for RSV (RSV-A, RSV-B, and untyped) using reverse transcription polymerase chain reaction. RESULTS: Among 6398 RSV-positive children aged <5 years, 3424 (54%) had subtype RSV-A infections, 2602 (41%) had subtype RSV-B infections, and 272 (5%) were not typed, inconclusive, or mixed infections. In both adjusted and unadjusted analyses, RSV-A-positive children were more likely to be hospitalized, as well as when restricted to <1 year. By season, RSV-A and RSV-B cocirculated in varying levels, with 1 subtype dominating proportionally. CONCLUSIONS: Findings indicate that RSV-A and RSV-B may only be marginally clinically distinguishable, but both subtypes are associated with medically attended illness in children aged <5 years. Furthermore, circulation of RSV subtypes varies substantially each year, seasonally and geographically. With introduction of new RSV prevention products, this highlights the importance of continued monitoring of RSV-A and RSV-B subtypes.

Natural Products That Contain Higher Homologated Amino Acids.

This review focuses on discussing natural products (NPs) that contain higher homologated amino acids (homoAAs) in the structure as well as the proposed and characterized biosynthesis of these non-proteinogenic amino acids. Homologation of amino acids includes the insertion of a methylene group into its side chain. It is not a very common modification found in NP biosynthesis as approximately 450 homoAA-containing NPs have been isolated from four bacterial phyla (Cyanobacteria, Actinomycetota, Myxococcota, and Pseudomonadota), two fungal phyla (Ascomycota and Basidiomycota), and one animal phylum (Porifera), except for a few examples. Amino acids that are found to be homologated and incorporated in the NP structures include the following ten amino acids: alanine, arginine, cysteine, isoleucine, glutamic acid, leucine, phenylalanine, proline, serine, and tyrosine, where isoleucine, leucine, phenylalanine, and tyrosine share the comparable enzymatic pathway. Other amino acids have their individual homologation pathway (arginine, proline, and glutamic acid for bacteria), likely utilize the primary metabolic pathway (alanine and glutamic acid for fungi), or have not been reported (cysteine and serine). Despite its possible high potential in the drug discovery field, the biosynthesis of homologated amino acids has a large room to explore for future combinatorial biosynthesis and metabolic engineering purpose.

Characterization of HphA: The First Enzyme in the Homologation Pathway of l-Phenylalanine and l-Tyrosine.

Homologation of amino acids is the insertion or deletion of a methylene group to their side chain, which is a relatively uncommon chemical transformation observed in peptide natural product (NP) structure. Homologated amino acids can potentially make the NP more stable in a biological system, but its biosynthesis is yet to be understood. This study biochemically characterized the first of three unexplored enzymes in the homologation pathway of l-phenylalanine and l-tyrosine. Previously proposed reactions catalyzed by HphA were confirmed by reversed-phase high-performance liquid chromatography and tandem mass spectrometry analysis. The substrate profile and kinetic parameters showed high selectivity for the natural substrates and their close analogs. The comparability of HphA to homologous enzymes in primary metabolic pathways, 2-isopropylmate synthase and homocitrate synthase which are involved in l-leucine and l-lysine biosynthesis, respectively, was validated by bioinformatical and site-directed mutagenesis studies. The knowledge obtained from this study has deepened the understanding of the homologation of amino acids, which can lead to future combinatorial biosynthesis and metabolic engineering studies.

Medical Costs of Respiratory Syncytial Virus-Associated Hospitalizations and Emergency Department Visits in Children Aged Younger Than 5 Years: Observational Findings from the New Vaccine Surveillance Network, 2016-2019.

OBJECTIVE: To assess medical costs of hospitalizations and emergency department (ED) care associated with respiratory syncytial virus (RSV) disease in children enrolled in the New Vaccine Surveillance Network. STUDY DESIGN: We used accounting and prospective surveillance data from 6 pediatric health systems to assess direct medical costs from laboratory-confirmed RSV-associated hospitalizations (n = 2007) and ED visits (n = 1267) from 2016 through 2019 among children aged <5 years. We grouped costs into categories relevant to clinical care and administrative billing practices. We examined RSV-associated medical costs by care setting using descriptive and bivariate analyses. We assessed associations between known RSV risk factors and hospitalization costs and length of stay using χ2 tests of association. RESULTS: The median cost was $7100 (IQR $4006-$13 355) per hospitalized child and $503 (IQR $387-$930) per ED visit. Eighty percent (n = 2628) of our final sample were children aged younger than 2 years. Fewer weeks' gestational age was associated with greater median costs in hospitalized children (P < .001, ≥37 weeks of gestational age: $6840 [$3905-$12 450]; 29-36 weeks of gestational age: $7721 [$4362-$15 274]; <29 weeks of gestational age: $9131 [$4518-$19 924]). Infants born full term accounted for 70% of the total expenditures in our sample. Almost three quarters of the health care dollars spent originated in children younger than 12 months of age, the primary age group targeted by recommended RSV prophylactics. CONCLUSIONS: Reducing the cost burden for RSV-associated medical care in young children will require prevention of RSV in all young children, not just high-risk infants. Newly available maternal vaccine and immunoprophylaxis products could substantially reduce RSV-associated medical costs.

Early Estimate of Nirsevimab Effectiveness for Prevention of Respiratory Syncytial Virus-Associated Hospitalization Among Infants Entering Their First Respiratory Syncytial Virus Season - New Vaccine Surveillance Network, October 2023-February 2024.

Respiratory syncytial virus (RSV) is the leading cause of hospitalization among infants in the United States. In August 2023, CDC's Advisory Committee on Immunization Practices recommended nirsevimab, a long-acting monoclonal antibody, for infants aged <8 months to protect against RSV-associated lower respiratory tract infection during their first RSV season and for children aged 8-19 months at increased risk for severe RSV disease. In phase 3 clinical trials, nirsevimab efficacy against RSV-associated lower respiratory tract infection with hospitalization was 81% (95% CI = 62%-90%) through 150 days after receipt; post-introduction effectiveness has not been assessed in the United States. In this analysis, the New Vaccine Surveillance Network evaluated nirsevimab effectiveness against RSV-associated hospitalization among infants in their first RSV season during October 1, 2023-February 29, 2024. Among 699 infants hospitalized with acute respiratory illness, 59 (8%) received nirsevimab ≥7 days before symptom onset. Nirsevimab effectiveness was 90% (95% CI = 75%-96%) against RSV-associated hospitalization with a median time from receipt to symptom onset of 45 days (IQR = 19-76 days). The number of infants who received nirsevimab was too low to stratify by duration from receipt; however, nirsevimab effectiveness is expected to decrease with increasing time after receipt because of antibody decay. Although nirsevimab uptake and the interval from receipt of nirsevimab were limited in this analysis, this early estimate supports the current nirsevimab recommendation for the prevention of severe RSV disease in infants. Infants should be protected by maternal RSV vaccination or infant receipt of nirsevimab.

The effect of long-term soccer training on left ventricular structure and function in elite male youth soccer players.

AIMS: Cardiac adaptations in elite, male adolescent youth soccer players have been demonstrated in relation to training status. The time course of these adaptations and the delineation of the influence of volatile growth phases from the training effect on these adaptations remain unclear. Consequently, the aims of the study were to evaluate the impact of 3 years of elite-level soccer training on changes in left ventricular (LV) structure and function in a group of highly trained elite youth male soccer players (SP) as they transitioned through the pre-to-adolescent phase of their growth. METHODS: Twenty-two male youth SP from the highest Level of English Premier League Academy U-12 teams were evaluated once a year for three soccer seasons as the players progressed from the U-12 to U-14 teams. Fifteen recreationally active control participants (CON) were also evaluated over the same 3-year period. Two-dimensional transthoracic echocardiography was used to quantify LV structure and function. RESULTS: After adjusting for the influence of growth and maturation, training-induced increases in Years 2 and 3 were noted for: LV end diastolic volume (LVEDV; p = 0.02) and LV end systolic volume (LVESV; p = 0.02) in the SP compared to CON. Training-induced decrements were noted for LV ejection fraction (LVEF; p = 0.006) and TDI-S' (p < 0.001). CONCLUSIONS: An increase in training volume (Years 2 and 3) were aligned with LV volumetric adaptations and decrements in systolic function in the SP that were independent from the influence of rapid somatic growth. Decrements in systolic function were suggestive of a functional reserve for exercise.

Sustained Within-season Vaccine Effectiveness Against Influenza-associated Hospitalization in Children: Evidence From the New Vaccine Surveillance Network, 2015-2016 Through 2019-2020.

BACKGROUND: Adult studies have demonstrated within-season declines in influenza vaccine effectiveness (VE); data in children are limited. METHODS: We conducted a prospective, test-negative study of children 6 months through 17 years hospitalized with acute respiratory illness at 7 pediatric medical centers during the 2015-2016 through 2019-2020 influenza seasons. Case-patients were children with an influenza-positive molecular test matched by illness onset to influenza-negative control-patients. We estimated VE [100% × (1 - odds ratio)] by comparing the odds of receipt of ≥1 dose of influenza vaccine ≥14 days before illness onset among influenza-positive children to influenza-negative children. Changes in VE over time between vaccination date and illness onset date were estimated using multivariable logistic regression. RESULTS: Of 8430 children, 4653 (55%) received ≥1 dose of influenza vaccine. On average, 48% were vaccinated through October and 85% through December each season. Influenza vaccine receipt was lower in case-patients than control-patients (39% vs 57%, P < .001); overall VE against hospitalization was 53% (95% confidence interval [CI]: 46, 60%). Pooling data across 5 seasons, the odds of influenza-associated hospitalization increased 4.2% (-3.2%, 12.2%) per month since vaccination, with an average VE decrease of 1.9% per month (n = 4000, P = .275). Odds of hospitalization increased 2.9% (95% CI: -5.4%, 11.8%) and 9.6% (95% CI: -7.0%, 29.1%) per month in children ≤8 years (n = 3084) and 9-17 years (n = 916), respectively. These findings were not statistically significant. CONCLUSIONS: We observed minimal, not statistically significant within-season declines in VE. Vaccination following current Advisory Committee on Immunization Practices (ACIP) guidelines for timing of vaccine receipt remains the best strategy for preventing influenza-associated hospitalizations in children.

SARS-CoV-2 Epidemiology and COVID-19 mRNA Vaccine Effectiveness Among Infants and Children Aged 6 Months-4 Years - New Vaccine Surveillance Network, United States, July 2022-September 2023.

SARS-CoV-2 infection in young children is often mild or asymptomatic; however, some children are at risk for severe disease. Data describing the protective effectiveness of COVID-19 mRNA vaccines against COVID-19-associated emergency department (ED) visits and hospitalization in this population are limited. Data from the New Vaccine Surveillance Network, a prospective population-based surveillance system, were used to estimate vaccine effectiveness using a test-negative, case-control design and describe the epidemiology of SARS-CoV-2 in infants and children aged 6 months-4 years during July 1, 2022-September 30, 2023. Among 7,434 children included, 5% received a positive SARS-CoV-2 test result, and 95% received a negative test result; 86% were unvaccinated, 4% had received 1 dose of any vaccine product, and 10% had received ≥2 doses. When compared with receipt of no vaccines among children, receipt of ≥2 COVID-19 mRNA vaccine doses was 40% effective (95% CI = 8%-60%) in preventing ED visits and hospitalization. These findings support existing recommendations for COVID-19 vaccination of young children to reduce COVID-19-associated ED visits and hospitalization.

Clinical characteristics and outcomes of children with single or co-detected rhinovirus-associated acute respiratory infection in Middle Tennessee.

BACKGROUND: Rhinovirus (RV) is one of the most common etiologic agents of acute respiratory infection (ARI), which is a leading cause of morbidity and mortality in young children. The clinical significance of RV co-detection with other respiratory viruses, including respiratory syncytial virus (RSV), remains unclear. We aimed to compare the clinical characteristics and outcomes of children with ARI-associated RV-only detection and those with RV co-detection-with an emphasis on RV/RSV co-detection. METHODS: We conducted a prospective viral surveillance study (11/2015-7/2016) in Nashville, Tennessee. Children < 18 years old who presented to the emergency department (ED) or were hospitalized with fever and/or respiratory symptoms of < 14 days duration were eligible if they resided in one of nine counties in Middle Tennessee. Demographics and clinical characteristics were collected by parental interviews and medical chart abstractions. Nasal and/or throat specimens were collected and tested for RV, RSV, metapneumovirus, adenovirus, parainfluenza 1-4, and influenza A-C using reverse transcription quantitative polymerase chain reaction assays. We compared the clinical characteristics and outcomes of children with RV-only detection and those with RV co-detection using Pearson's χ2 test for categorical variables and the two-sample t-test with unequal variances for continuous variables. RESULTS: Of 1250 children, 904 (72.3%) were virus-positive. RV was the most common virus (n = 406; 44.9%), followed by RSV (n = 207; 19.3%). Of 406 children with RV, 289 (71.2%) had RV-only detection, and 117 (28.8%) had RV co-detection. The most common virus co-detected with RV was RSV (n = 43; 36.8%). Children with RV co-detection were less likely than those with RV-only detection to be diagnosed with asthma or reactive airway disease both in the ED and in-hospital. We did not identify differences in hospitalization, intensive care unit admission, supplemental oxygen use, or length of stay between children with RV-only detection and those with RV co-detection. CONCLUSION: We found no evidence that RV co-detection was associated with poorer outcomes. However, the clinical significance of RV co-detection is heterogeneous and varies by virus pair and age group. Future studies of RV co-detection should incorporate analyses of RV/non-RV pairs and include age as a key covariate of RV contribution to clinical manifestations and infection outcomes.

Chronic cannabis use is associated with altered monocyte phenotype, immune response, and depression in physically active individuals.

Introduction: This study evaluated depression, monocyte phenotype, and immune function in physically active cannabis users. Methods: Participants (N = 23) were classified as either cannabis users (CU, n = 11) or non-users (NU, n = 12). White blood cells isolated from blood were analyzed for co-expression of cluster of differentiation 14 and 16 using flow cytometry. Lipopolysaccharide (LPS) was cultured with whole blood and assessed for interleukin-6 and tumor necrosis factor-α (TNF-α) release. Results: The percentage of white blood cells classified as monocytes was not different between groups; however, CU had a significantly greater percentage of monocytes classified as intermediate (p = 0.02). When standardized per milliliter of blood, CU had significantly greater numbers of total monocytes (p = 0.01), classical monocytes (p = 0.02), and intermediate monocytes (p = 0.01). Intermediate monocytes per milliliter of blood were positively correlated to the number of times CU used cannabis per day (r = 0.864, p < 0.01) and Beck Depression Inventory-II (BDI-II) score (r = 0.475, p = 0.03), which was significantly greater in CU (5.1 ± 4.8) compared with NU (0.8 ± 1.0; p < 0.01). CU released significantly less TNF-α per monocyte in response to LPS. Conclusions: CU had altered monocyte phenotypes and functions compared with NU. Elevations in intermediate monocytes were positively correlated with measures of cannabis use and BDI-II score.

Regular Use of Cannabis in Female Athletes Is Associated With a Reduction in Early Anaerobic Power Production.

ABSTRACT: Lisano, JK, Flores, VA, Kisiolek, JN, and Stewart, LK. Regular use of cannabis in female athletes is associated with a reduction in early anaerobic power production. J Strength Cond Res 37(3): 616-622, 2023-Despite a growing number of claims related to the ability of cannabis use to affect health and performance, there is limited research available, especially in female athletes. This cross-sectional study aimed to determine whether chronic cannabis use in physically active female athletes is related to altered health and performance. Healthy, physically active, female cannabis users (CU: n = 12) and noncannabis users (NU: n = 12) with an average age of 23.8 ± 3.7 years and 19.3 ± 4.2% body fat completed athletic performance and health assessments. Significance was set at alpha = 0.05. The age of onset of regular cannabis use was 20.1 ± 2.8 years in CU with an average duration of cannabis use of 5.8 ± 3.1 years. There were no differences between groups with respect to body size, body composition, pulmonary function, cardiorespiratory function, or muscular strength. Cannabis users produced significantly less power in the first 2 stages of the Wingate assessment, but CU experienced significantly less anaerobic fatigue. Although body composition and cardiovascular fitness were comparable, average C-reactive protein concentration classified CU with higher risk for cardiovascular disease (CVD). Athletes and coaches who rely heavily on anaerobic performance should consider these findings because they indicate that regular cannabis use may affect early power production and CVD risk.

Vaccine Effectiveness Against Influenza Hospitalization and Emergency Department Visits in 2 A(H3N2) Dominant Influenza Seasons Among Children <18 Years Old-New Vaccine Surveillance Network 2016-2017 and 2017-2018.

Studies have shown egg-adaptive mutations in influenza vaccine strains that might have impaired protection against circulating A(H3N2) influenza viruses during the 2016-2017 and 2017-2018 seasons. We used the test-negative design and multivariable models to assess vaccine effectiveness against influenza-associated hospitalization and emergency department visits among children (<18 years old) during the 2016-2017 and 2017-2018 seasons. Effectiveness was 71% (95% confidence interval, 59%-79%), 46% (35%-55%), and 45% (33%-55%) against A(H1N1)pdm09, A(H3N2), and B viruses respectively, across both seasons. During high-severity seasons with concerns for vaccine mismatch, vaccination offered substantial protection against severe influenza outcomes requiring hospitalization or emergency department visits among children.

Vaccine Effectiveness Against Life-Threatening Influenza Illness in US Children.

BACKGROUND: Predominance of 2 antigenically drifted influenza viruses during the 2019-2020 season offered an opportunity to assess vaccine effectiveness against life-threatening pediatric influenza disease from vaccine-mismatched viruses in the United States. METHODS: We enrolled children aged <18 years admitted to the intensive care unit with acute respiratory infection across 17 hospitals. Respiratory specimens were tested using reverse-transcription polymerase chain reaction for influenza viruses and sequenced. Using a test-negative design, we estimated vaccine effectiveness comparing odds of vaccination in test-positive case patients vs test-negative controls, stratifying by age, virus type, and severity. Life-threating influenza included death or invasive mechanical ventilation, vasopressors, cardiopulmonary resuscitation, dialysis, or extracorporeal membrane oxygenation. RESULTS: We enrolled 159 critically ill influenza case-patients (70% ≤8 years; 51% A/H1N1pdm09 and 25% B-Victoria viruses) and 132 controls (69% were aged ≤8 years). Among 56 sequenced A/H1N1pdm09 viruses, 29 (52%) were vaccine-mismatched (A/H1N1pdm09/5A+156K) and 23 (41%) were vaccine-matched (A/H1N1pdm09/5A+187A,189E). Among sequenced B-lineage viruses, majority (30 of 31) were vaccine-mismatched. Effectiveness against critical influenza was 63% (95% confidence interval [CI], 38% to 78%) and similar by age. Effectiveness was 75% (95% CI, 49% to 88%) against life-threatening influenza vs 57% (95% CI, 24% to 76%) against non-life-threating influenza. Effectiveness was 78% (95% CI, 41% to 92%) against matched A(H1N1)pdm09 viruses, 47% (95% CI, -21% to 77%) against mismatched A(H1N1)pdm09 viruses, and 75% (95% CI, 37% to 90%) against mismatched B-Victoria viruses. CONCLUSIONS: During a season when vaccine-mismatched influenza viruses predominated, vaccination was associated with a reduced risk of critical and life-threatening influenza illness in children.

Understanding Variation in Rotavirus Vaccine Effectiveness Estimates in the United States: The Role of Rotavirus Activity and Diagnostic Misclassification.

BACKGROUND: Estimates of rotavirus vaccine effectiveness (VE) in the United States appear higher in years with more rotavirus activity. We hypothesized rotavirus VE is constant over time but appears to vary as a function of temporal variation in local rotavirus cases and/or misclassified diagnoses. METHODS: We analyzed 6 years of data from eight US surveillance sites on 8- to 59-month olds with acute gastroenteritis symptoms. Children's stool samples were tested via enzyme immunoassay (EIA); rotavirus-positive results were confirmed with molecular testing at the US Centers for Disease Control and Prevention. We defined rotavirus gastroenteritis cases by either positive on-site EIA results alone or positive EIA with Centers for Disease Control and Prevention confirmation. For each case definition, we estimated VE against any rotavirus gastroenteritis, moderate-to-severe disease, and hospitalization using two mixed-effect regression models: the first including year plus a year-vaccination interaction, and the second including the annual percent of rotavirus-positive tests plus a percent positive-vaccination interaction. We used multiple overimputation to bias-adjust for misclassification of cases defined by positive EIA alone. RESULTS: Estimates of annual rotavirus VE against all outcomes fluctuated temporally, particularly when we defined cases by on-site EIA alone and used a year-vaccination interaction. Use of confirmatory testing to define cases reduced, but did not eliminate, fluctuations. Temporal fluctuations in VE estimates further attenuated when we used a percent positive-vaccination interaction. Fluctuations persisted until bias-adjustment for diagnostic misclassification. CONCLUSIONS: Both controlling for time-varying rotavirus activity and bias-adjusting for diagnostic misclassification are critical for estimating the most valid annual rotavirus VE.

Respiratory Virus Surveillance Among Children with Acute Respiratory Illnesses - New Vaccine Surveillance Network, United States, 2016-2021.

The New Vaccine Surveillance Network (NVSN) is a prospective, active, population-based surveillance platform that enrolls children with acute respiratory illnesses (ARIs) at seven pediatric medical centers. ARIs are caused by respiratory viruses including influenza virus, respiratory syncytial virus (RSV), human metapneumovirus (HMPV), human parainfluenza viruses (HPIVs), and most recently SARS-CoV-2 (the virus that causes COVID-19), which result in morbidity among infants and young children (1-6). NVSN estimates the incidence of pathogen-specific pediatric ARIs and collects clinical data (e.g., underlying medical conditions and vaccination status) to assess risk factors for severe disease and calculate influenza and COVID-19 vaccine effectiveness. Current NVSN inpatient (i.e., hospital) surveillance began in 2015, expanded to emergency departments (EDs) in 2016, and to outpatient clinics in 2018. This report describes demographic characteristics of enrolled children who received care in these settings, and yearly circulation of influenza, RSV, HMPV, HPIV1-3, adenovirus, human rhinovirus and enterovirus (RV/EV),* and SARS-CoV-2 during December 2016-August 2021. Among 90,085 eligible infants, children, and adolescents (children) aged <18 years† with ARI, 51,441 (57%) were enrolled, nearly 75% of whom were aged <5 years; 43% were hospitalized. Infants aged <1 year accounted for the largest proportion (38%) of those hospitalized. The most common pathogens detected were RV/EV and RSV. Before the emergence of SARS-CoV-2, detected respiratory viruses followed previously described seasonal trends, with annual peaks of influenza and RSV in late fall and winter (7,8). After the emergence of SARS-CoV-2 and implementation of associated pandemic nonpharmaceutical interventions and community mitigation measures, many respiratory viruses circulated at lower-than-expected levels during April 2020-May 2021. Beginning in summer 2021, NVSN detected higher than anticipated enrollment of hospitalized children as well as atypical interseasonal circulation of RSV. Further analyses of NVSN data and continued surveillance are vital in highlighting risk factors for severe disease and health disparities, measuring the effectiveness of vaccines and monoclonal antibody-based prophylactics, and guiding policies to protect young children from pathogens such as SARS-CoV-2, influenza, and RSV.

Modified Curcumins as Potential Drug Candidates for Breast Cancer: An Overview.

Breast cancer (BC), the most common malignancy in women, results from significant alterations in genetic and epigenetic mechanisms that alter multiple signaling pathways in growth and malignant progression, leading to limited long-term survival. Current studies with numerous drug therapies have shown that BC is a complex disease with tumor heterogeneity, rapidity, and dynamics of the tumor microenvironment that result in resistance to existing therapy. Targeting a single cell-signaling pathway is unlikely to treat or prevent BC. Curcumin (a natural yellow pigment), the principal ingredient in the spice turmeric, is well-documented for its diverse pharmacological properties including anti-cancer activity. However, its clinical application has been limited because of its low solubility, stability, and bioavailability. To overcome the limitation of curcumin, several modified curcumin conjugates and curcumin mimics were developed and studied for their anti-cancer properties. In this review, we have focused on the application of curcumin mimics and their conjugates for breast cancer.

Respiratory Syncytial Virus Disease Severity in Young Children.

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of acute respiratory infections (ARIs) in hospitalized children. Although prematurity and underlying medical conditions are known risk factors, most of these children are healthy, and factors including RSV load and subgroups may contribute to severity. Therefore, we aimed to evaluate the role of RSV in ARI severity and determine factors associated with increased RSV-ARI severity in young children. METHODS: Children aged <5 years with fever and/or ARI symptoms were recruited from the emergency department (ED) or inpatient settings at Vanderbilt Children's Hospital. Nasal and/or throat swabs were tested using quantitative reverse-transcription polymerase chain reaction for common respiratory viruses, including RSV. A severity score was calculated for RSV-positive children. RESULTS: From November 2015 through July 2016, 898 participants were enrolled, and 681 (76%) had at least 1 virus detected, with 191 (28%) testing positive for RSV. RSV-positive children were more likely to be hospitalized, require intensive care unit admission, and receive oxygen compared with children positive for other viruses. Higher viral load, White race, younger age, and higher severity score were independently associated with hospitalization in RSV-positive children. No differences in disease severity were noted between RSV A and RSV B. CONCLUSIONS: RSV was associated with increased ARI severity in young children enrolled from the ED and inpatient settings, but no differences in disease severity were noted between RSV A and RSV B. These findings emphasize the need for antiviral therapy and/or preventive measures such as vaccines against RSV in young children.

Characteristics of GII.4 Norovirus Versus Other Genotypes in Sporadic Pediatric Infections in Davidson County, Tennessee, USA.

BACKGROUND: Norovirus is a leading cause of epidemic acute gastroenteritis (AGE), with most outbreaks occurring during winter. The majority of outbreaks are caused by GII.4 noroviruses; however, data to support whether this is true for sporadic medically attended AGE are limited. Therefore, we sought to compare the clinical characteristics and seasonality of GII.4 vs non-GII.4 viruses. METHODS: Children aged 15 days -17 years with AGE symptoms were recruited from the outpatient, emergency department, and inpatient settings at Vanderbilt Children's Hospital, Davidson County, Nashville, Tennessee, from December 2012 -November 2015. Stool specimens were tested using qRT-PCR for GI and GII noroviruses and subsequently genotyped by sequencing a partial region of the capsid gene. RESULTS: A total of 3705 patients were enrolled, and stool specimens were collected and tested from 2885 (78%) enrollees. Overall, 636 (22%) samples were norovirus-positive, of which 567 (89%) were GII. Of the 460 (81%) genotyped GII-positive samples, 233 (51%) were typed as GII.4 and 227 (49%) as non-GII.4. Compared with children with non-GII.4 infections, children with GII.4 infections were younger, more likely to have diarrhea, and more likely to receive oral rehydration fluids. Norovirus was detected year-round and peaked during winter. CONCLUSIONS: Approximately 40% of sporadic pediatric norovirus AGE cases were caused by GII.4 norovirus. Children infected with GII.4 had more severe symptoms that required more medical care. Seasonal variations were noticed among different genotypes. These data highlight the importance of continuous norovirus surveillance and provide important information on which strains pediatric norovirus vaccines should protect against.

The Changing Landscape of Pediatric Viral Enteropathogens in the Post-Rotavirus Vaccine Era.

BACKGROUND: Acute gastroenteritis (AGE) is a common reason for children to receive medical care. However, the viral etiology of AGE illness is not well described in the post-rotavirus vaccine era, particularly in the outpatient (OP) setting. METHODS: Between 2012 and 2015, children 15 days through 17 years old presenting to Vanderbilt Children's Hospital, Nashville, Tennessee, with AGE were enrolled prospectively from the inpatient, emergency department, and OP settings, and stool specimens were collected. Healthy controls (HCs) were enrolled and frequency matched for period, age group, race, and ethnicity. Stool specimens were tested by means of reverse-transcription real-time quantitative polymerase chain reaction for norovirus, sapovirus, and astrovirus RNA and by Rotaclone enzyme immunoassay for rotavirus antigen, followed by polymerase chain reaction verification of antigen detection. RESULTS: A total of 3705 AGE case patients and 1563 HCs were enrolled, among whom 2885 case patients (78%) and 1110 HCs (71%) provided stool specimens that were tested. All 4 viruses were more frequently detected in AGE case patients than in HCs (norovirus, 22% vs 8%, respectively; rotavirus, 10% vs 1%; sapovirus, 10% vs 5%; and astrovirus, 5% vs 2%; P < .001 for each virus). In the OP setting, rates of AGE due to norovirus were higher than rate for the other 3 viruses. Children <5 years old had higher OP AGE rates than older children for all viruses. CONCLUSIONS: Norovirus remains the most common virus detected in all settings, occurring nearly twice as frequently as the next most common pathogens, sapovirus and rotavirus. Combined, norovirus, sapovirus, rotavirus, and astrovirus were associated with almost half of all AGE visits and therefore are an important reason for children to receive medical care.