Patient and Visit Characteristics of Pediatric Patients With High-frequency Low-acuity Emergency Department Visits.

INTRODUCTION: Pediatric patients account for a disproportionate number of low-acuity emergency department (ED) visits. The aim of this study is to describe pediatric patient and visit characteristics for high-frequency users for low-acuity visits. METHODS: This was a retrospective cohort study of children presenting to a tertiary care pediatric ED and an affiliated community ED, over a 2-year period, with at least 10 low-acuity visits. Twenty patients with the highest number of visits were classified as "superusers." We analyzed patient data from the larger sample of high-frequency users and visit specific data from superuser visits. IBM SPSS Statistics 25 (SPSS Inc., Chicago, IL) was used to perform descriptive statistics and to summarize demographic and visit specific variables. RESULTS: We identified 181 high-frequency users with a mean number of visits of 14.3 ± 4.3 and a subpopulation of 20 superusers accounting for 434 visits. The majority of high-frequency users (89%) identified as African American and had public insurance (96.1%). Many patients received primary care affiliated with the home institution. In the first year of the study, 50.3% of high-frequency users were infants younger than 1 year at the index visit and 47.4% of superusers were infants at the index visit.Superuser visits were evenly distributed among seasons and the majority of visits occurred during the weekdays (70.7%). The majority of visits were for medical complaints (86.6%) and almost half (47.6%) resulted in some testing (24.9%) or treatment (30.6%); however, only 1.4% resulted in hospital admission. CONCLUSIONS: In our sample, most high-frequency low-acuity ED patients were infants, African American and have public insurance. Many are seen during clinic hours and are paneled at affiliated clinics. Among superusers, the majority of the visits did not require any testing, intervention, or treatment.

Metabolic dysfunction and immunometabolism in COVID-19 pathophysiology and therapeutics.

The COVID-19 pandemic has emerged as a public health crisis and has placed a significant burden on healthcare systems. Patients with underlying metabolic dysfunction, such as type 2 diabetes mellitus and obesity, are at a higher risk for COVID-19 complications, including multi-organ dysfunction, secondary to a deranged immune response, and cellular energy deprivation. These patients are at a baseline state of chronic inflammation associated with increased susceptibility to the severe immune manifestations of COVID-19, which are triggered by the cellular hypoxic environment and cytokine storm. The altered metabolic profile and energy generation of immune cells affect their activation, exacerbating the imbalanced immune response. Key immunometabolic interactions may inform the development of an efficacious treatment for COVID-19. Novel therapeutic approaches with repurposed drugs, such as PPAR agonists, or newly developed molecules such as the antagomirs, which block microRNA function, have shown promising results. Those treatments, alone or in combination, target both immune and metabolic pathways and are ideal for septic COVID-19 patients with an underlying metabolic condition.

A Prospective Look at Career Aspirations Among Pediatric Emergency Medicine Trainees.

OBJECTIVES: Before delivering a contract negotiation workshop to pediatric emergency medicine fellows in training, we wanted to understand the group's career aspirations. We hypothesized that fellows would be interested in nonclinical skill building in addition to the clinical training. METHODS: A 9-question survey was anonymously administered to fellows registered for the national conference using SurveyMonkey before the conference date. Six questions were quantitative, 2 were qualitative and open ended, and 1 required ranking of elements. RESULTS: Seventy-seven (47%) of the conference attendees responded to the survey, and approximately 80 (48%) attended the workshop session.Of the 77 fellows responding when asked about desired percentage of time per week devoted to the 4 categories of clinical, research, education, and administrative work within a 40-hour week, 76 (99%) chose the clinical category with an average of 58% of total hours devoted, 71 (92%) chose education with an average of 14% of total hours, 69 (90%) chose administration with an average of 8% of total hours, and 62 (81%) chose research with an average of 11% of total hours.Seventy attendees provided 1 sentence with the description of their ideal job. Thematic analysis of these responses revealed the following 5 main themes: academic potential, clinical environment, remuneration, job location, and work-life balance. CONCLUSIONS: Diversification in pediatric emergency medicine training is becoming a growing area of importance. Our study highlights a discrepancy in the expected time dedicated for nonclinical activities from those seen in previous workforce studies.

Pediatric urgent care education: a survey-based needs assessment.

BACKGROUND: There is an increasing number of pediatric urgent care centers that are largely staffed by pediatric residency graduates. It is unclear if pediatric residency adequately prepares a physician to fully and successfully provide care in an urgent care setting. The goal of this study is to conduct an assessment of urgent care directors' perceptions of recent pediatric residency graduates' preparedness to successfully provide pediatric urgent care after graduation. METHODS: This is a 2018 cross-sectional survey of all pediatric emergency medicine division chiefs in the United States and all pediatric urgent care directors who are members of the Society for Pediatric Urgent Care. An electronic survey was distributed consisting of eight multiple choice questions regarding perceived preparedness and knowledge gaps of recent pediatric residency graduates for independent practice in urgent care. Descriptive statistics were used to analyze results and qualitative data were analyzed via an inductive thematic approach. RESULTS: Forty-two percent (65/154) of surveys were completed. No respondents believed that a recent pediatric residency graduate would be adequately prepared to independently practice in a pediatric urgent care and 81% of respondents recommended some additional training. Most respondents described this training as important (46%) or very important (35%). Most respondents recommended between 6 months and 1 year as the appropriate amount of time to achieve competency. CONCLUSIONS: Despite the growing number pediatric residency graduates staffing pediatric urgent care centers, the majority of surveyed pediatric emergency medicine division chiefs and pediatric urgent care directors do not think that pediatric residency adequately prepares graduates to successfully provide urgent care to pediatric patients. We recommend further exploration of gaps in knowledge of recent pediatric residency graduates as a next step towards developing systems for further training for pediatric residency graduates to gain competency in urgent care management.

Comparison of Resource Utilization and Length of Hospitalization Between Overweight and Healthy-Weight Pediatric Trauma Patients Presenting to a Pediatric Emergency Department With Moderate to Severe Injury: A Prospective Study.

OBJECTIVES: Our study aimed to compare overweight and healthy-weight pediatric trauma patient outcomes, specifically with respect to hospital length of stay and resource utilization. We hypothesized that overweight pediatric trauma patients would have increased hospital length of stay and radiographic study use compared with their healthy-weight counterparts. METHODS: This was a prospective, observational, cohort study of pediatric trauma patients aged 2 to 19 years presenting to an urban pediatric emergency department over a period of 1 year. Using measured height and weight values, body mass index (BMI) for age was calculated and plotted on the Centers for Disease Control and Prevention BMI-for-age growth charts. Patients were followed up throughout their hospitalization, and the following items were recorded: trauma alert level, mechanism of injury, age, sex, race, Glasgow Coma Scale score, total number of days in hospital, total number of intensive care unit days, total number of radiographs obtained, total number of computed tomography scans obtained, and mechanism of injury. RESULTS: Our study population included 109 subjects. The mean age of the subjects was 9.7 years. The number of patients meeting the definition of obese (BMI for age ≥95%) was 15, or 14% of the total study population. There was no significant difference between the overweight cohort and the healthy-weight cohort found among any of the variables recorded and analyzed. CONCLUSIONS: Although there are many chronic conditions in children associated with obesity, in the case of trauma, it does not seem to be a strong concern. A continued focus on preventing and reversing childhood obesity for other physical and mental health outcomes may be more important.

The Neurodevelopmental Perspective of Surgical Necrotizing Enterocolitis: The Role of the Gut-Brain Axis.

This state-of-the-art review article aims to highlight the most recent evidence about the therapeutic options of surgical necrotizing enterocolitis, focusing on the molecular basis of the gut-brain axis in relevance to the neurodevelopmental outcomes of primary peritoneal drainage and primary laparotomy. Current evidence favors primary laparotomy over primary peritoneal drainage as regards neurodevelopment in the surgical treatment of necrotizing enterocolitis. The added exposure to inhalational anesthesia in infants undergoing primary laparotomy is an additional confounding variable but requires further study. The concept of the gut-brain axis suggests that bowel injury initiates systemic inflammation potentially affecting the developing central nervous system. Signals about microbes in the gut are transduced to the brain and the limbic system via the enteric nervous system, autonomic nervous system, and hypothalamic-pituitary axis. Preterm infants with necrotizing enterocolitis have significant differences in the diversity of the microbiome compared with preterm controls. The gut bacterial flora changes remarkably prior to the onset of necrotizing enterocolitis with a predominance of pathogenic organisms. The type of initial surgical approach correlates with the length of functional gut and microbiome equilibrium influencing brain development and function through the gut-brain axis. Existing data favor patients who were treated with primary laparotomy over those who underwent primary peritoneal drainage in terms of neurodevelopmental outcomes. We propose that this is due to the sustained injurious effect of the remaining diseased and necrotic bowel on the developing newborn brain, in patients treated with primary peritoneal drainage, through the gut-brain axis and probably not due to the procedure itself.

FAK-Src-paxillin system expression and disease outcome in human neuroblastoma.

BACKGROUND: Neuroblastoma (NB) often presents with metastatic disease and poor survival. The need for new prognostic markers remains invaluable. The FAK-Src-Paxillin protein system is associated with aggressive phenotype in adult malignancies but is largely unexplored in pediatric NB. OBJECTIVE: To assess FAK-Src-Paxillin protein expression in human NB cell lines and clinical cytology material and to delineate its association with survival. DESIGN/METHODS: Western blot and immunohistochemistry were applied for FAK-Src-Paxillin expression in NB cell lines and 23 human cytology specimens, respectively. Protein expression in human clinical samples was correlated with clinicopathological parameters, MYCN amplification and survival. RESULTS: FAK, Src and Paxillin proteins are expressed in human NB cells lines, and can be detected in clinical cytology specimens from NB patients, (59%, 32% and 33% respectively). Simultaneous FAK-Src-Paxillin expression was noted in 30% of NB patients. Children with concomitant positivity FAK, Src, and Paxillin tumors, as well as MYCN amplification, had increased mortality compared to those without. CONCLUSIONS: FAK-Src-Paxillin system is a marker of unfavorable prognosis for human NB patients but also a promising therapeutic target.

Effect of Intranasally Delivered rh-VEGF165 on Angiogenesis Following Cerebral Hypoxia-Ischemia in the Cerebral Cortex of Newborn Piglets.

BACKGROUND: Vascular endothelial growth factor (VEGF) stimulates vascular genesis and angiogenesis. Cerebral Hypoxia-Ischemia (HI) leads to the reduction of vasculature in the cerebral cortex of newborn piglets. OBJECTIVE: The present study tests the hypothesis that post-hypoxia intranasal administration of recombinant human VEGF165 (rh-VEGF165) for 3 days increases the vascular density in the cerebral cortex of newborn piglets without promoting neovascularization. DESIGN/METHODS: Ventilated newborn piglets were divided into three groups (n = 5/group): normoxic (Nx), hypoxic-ischemic (HI), and HI treated with intranasal rh-VEGF165rh-VEGF165 (HI-VEGF). HI piglets were exposed to HI (0.05 FiO2) for 30 min. Recombinant h-VEGF165 (100 ng/kg) was administered 15 min after HI and then once daily for 3 days. The animals were perfused transcardially and coronal brains sections were processed for Isolectin, Hoechst, and ki-67 cell proliferation marker staining. To assess the vascular density, 30-35 fields per animal section were manually counted using image J software. RESULTS: The vascular density (vessels/mm²) was 42.0 ± 8.0 in the Nx group, 26.4 ± 4.8 (p < 0.05 vs. Nx) in the HI group, and 46.0 ± 11.9 (p < 0.05 vs. HI) in the HI-VEGF group. When stained for newly formed vessels, via Ki-67 staining, the vascular density was 5.4 ± 3.6 in the Nx group (p < 0.05 vs. HI), 10.2 ± 2.1 in the HI group, and 10.9 ± 2.9 in the HI-VEGF group (p = 0.72 vs. HI). HI resulted in a decrease in vascular density. Intranasal rh-VEGF165rh-VEGF165 resulted in the attenuation of the HI-induced decrease in vascular density. However, rh-VEGF165 did not result in the formation of new vascularity, as evident by ki-67 staining. CONCLUSIONS: Intranasal rh-VEGF165 may prevent the HI-induced decrease in the vascular density of the brain and could serve as a promising adjuvant therapy for hypoxic-ischemic encephalopathy (HIE).

Infantile Tubercular Meningitis With Brain Infarct.

A previously healthy 6-month-old Asian girl presented to the emergency department (ED) after 7 to 10 days of fever of 101 to 102°F, cough, and intermittent vomiting. Pneumonia was diagnosed and successfully treated, and the patient was discharged. She returned to the ED after her mother noticed mild facial asymmetry, left upper extremity weakness, and an episode of jerkiness. The mother then revealed that both she and the child's maternal grandmother, who also lived with the patient, had suffered chronic coughs in recent months. The mother's previous chest radiograph showed pulmonary tuberculosis. The patient's magnetic resonance imaging findings were consistent with a cerebrovascular event. Positive results on cerebrospinal fluid analysis, the mother's suspicious tuberculosis-like history, and the patient's clinical symptoms pointed heavily toward a diagnosis of tuberculous meningitis. A 4-drug antituberculosis regimen with dexamethasone was instituted and scheduled to continue for 12 months. However, the patient returned to the ED 2 months later after developing an obstructive hydrocephalus.

Atopic dermatitis is more severe in children over the age of two who have an increased body mass index.

AIM: Childhood obesity increases the risk of developing atopic dermatitis, but no objective measuring tool has been used to determine whether it also affects the severity. Our aim was to determine whether an association existed between increased body mass index (BMI) or weight for length and severity of atopic dermatitis, as measured by the SCORing Atopic Dermatitis (SCORAD) index. METHODS: Children with atopic dermatitis who presented to the emergency department at an urban children's hospital (n = 104) were assessed using the SCORAD index. We assessed the relationship between BMI percentile or weight for length percentile, based on age, and atopic dermatitis severity, using single-variable multinomial logistic regression with odds ratios. RESULTS: A significant association was found between BMI >24 and atopic dermatitis severity for children older than 2 years. When analysed separately, a significant association between BMI percentile and SCORAD severity was found in boys but not in girls. CONCLUSION: These data suggest that the severity of atopic dermatitis is associated with increased BMI percentile in children older than 2 years, although this association was not apparent in younger ages using weight for length. Our results indicate the need for new avenues in the prevention and treatment of these entities.

Hypercapnia Causes Injury of the Cerebral Cortex and Cognitive Deficits in Newborn Piglets.

In critically ill newborns, exposure to hypercapnia (HC) is common and often accepted in neonatal intensive care units to prevent severe lung injury. However, as a "safe" range of arterial partial pressure of carbon dioxide levels in neonates has not been established, the potential impact of HC on the neurodevelopmental outcomes in these newborns remains a matter of concern. Here, in a newborn Yorkshire piglet model of either sex, we show that acute exposure to HC induced persistent cortical neuronal injury, associated cognitive and learning deficits, and long-term suppression of cortical electroencephalogram frequencies. HC induced a transient energy failure in cortical neurons, a persistent dysregulation of calcium-dependent proapoptotic signaling in the cerebral cortex, and activation of the apoptotic cascade, leading to nuclear deoxyribonucleic acid fragmentation. While neither 1 h of HC nor the rapid normalization of HC was associated with changes in cortical bioenergetics, rapid resuscitation resulted in a delayed onset of synaptosomal membrane lipid peroxidation, suggesting a dissociation between energy failure and the occurrence of synaptosomal lipid peroxidation. Even short durations of HC triggered biochemical responses at the subcellular level of the cortical neurons resulting in altered cortical activity and impaired neurobehavior. The deleterious effects of HC on the developing brain should be carefully considered as crucial elements of clinical decisions in the neonatal intensive care unit.

Practice patterns and perceptions of influenza testing amongst pediatric urgent care providers.

INTRODUCTION: Despite a sensitivity of 50% to 70% the rapid influenza diagnostic test (RIDT) continues to play an important role in clinical decision-making due to its quick turn-around time, high specificity, relative simplicity of use, and low cost. METHODS: A quantitative study using a web-based survey was distributed to 110 members of the Society of Pediatric Urgent Care aimed to assess RIDT use for diagnosis and management of influenza in outpatient pediatric patients. RESULTS: Responses from 61 providers were received. Forty-two percent (95% CI 29.5-54.5%) of respondents report higher confidence in their diagnosis of influenza with the aid of a positive RIDT. 28% of respondents (95% CI 16.6-39.4%) report a higher likelihood of prescribing antiviral medications to low-risk patients if an RIDT is positive than without laboratory confirmation. CONCLUSION: Most pediatric urgent care respondents reported higher confidence in their diagnosis and higher likelihood of prescribing antivirals with a positive RIDT rather than by clinical symptoms alone.

Identification and Prediction of Clinical Phenotypes in Hospitalized Patients With COVID-19: Machine Learning From Medical Records.

BACKGROUND: There is significant heterogeneity in disease progression among hospitalized patients with COVID-19. The pathogenesis of SARS-CoV-2 infection is attributed to a complex interplay between virus and host immune response that in some patients unpredictably and rapidly leads to "hyperinflammation" associated with increased risk of mortality. The early identification of patients at risk of progression to hyperinflammation may help inform timely therapeutic decisions and lead to improved outcomes. OBJECTIVE: The primary objective of this study was to use machine learning to reproducibly identify specific risk-stratifying clinical phenotypes across hospitalized patients with COVID-19 and compare treatment response characteristics and outcomes. A secondary objective was to derive a predictive phenotype classification model using routinely available early encounter data that may be useful in informing optimal COVID-19 bedside clinical management. METHODS: This was a retrospective analysis of electronic health record data of adult patients (N=4379) who were admitted to a Johns Hopkins Health System hospital for COVID-19 treatment from 2020 to 2021. Phenotypes were identified by clustering 38 routine clinical observations recorded during inpatient care. To examine the reproducibility and validity of the derived phenotypes, patient data were randomly divided into 2 cohorts, and clustering analysis was performed independently for each cohort. A predictive phenotype classifier using the gradient-boosting machine method was derived using routine clinical observations recorded during the first 6 hours following admission. RESULTS: A total of 2 phenotypes (designated as phenotype 1 and phenotype 2) were identified in patients admitted for COVID-19 in both the training and validation cohorts with similar distributions of features, correlations with biomarkers, treatments, comorbidities, and outcomes. In both the training and validation cohorts, phenotype-2 patients were older; had elevated markers of inflammation; and were at an increased risk of requiring intensive care unit-level care, developing sepsis, and mortality compared with phenotype-1 patients. The gradient-boosting machine phenotype prediction model yielded an area under the curve of 0.89 and a positive predictive value of 0.83. CONCLUSIONS: Using machine learning clustering, we identified and internally validated 2 clinical COVID-19 phenotypes with distinct treatment or response characteristics consistent with similar 2-phenotype models derived from other hospitalized populations with COVID-19, supporting the reliability and generalizability of these findings. COVID-19 phenotypes can be accurately identified using machine learning models based on readily available early encounter clinical data. A phenotype prediction model based on early encounter data may be clinically useful for timely bedside risk stratification and treatment personalization.

Computational analysis of cortical neuronal excitotoxicity in a large animal model of neonatal brain injury.

BACKGROUND: Neonatal hypoxic brain injury is a major cause of intellectual and developmental disability. Hypoxia causes neuronal dysfunction and death in the developing cerebral cortex due to excitotoxic Ca2+-influx. In the translational piglet model of hypoxic encephalopathy, we have previously shown that hypoxia overactivates Ca2+/Calmodulin (CaM) signaling via Sarcoma (Src) kinase in cortical neurons, resulting in overexpression of proapoptotic genes. However, identifying the exact relationship between alterations in neuronal Ca2+-influx, molecular determinants of cell death, and the degree of hypoxia in a dynamic system represents a significant challenge. METHODS: We used experimental and computational methods to identify molecular events critical to the onset of excitotoxicity-induced apoptosis in the cerebral cortex of newborn piglets. We used 2-3-day-old piglets (normoxic [Nx], hypoxic [Hx], and hypoxic + Src-inhibitor-treatment [Hx+PP2] groups) for biochemical analysis of ATP production, Ca2+-influx, and Ca2+/CaM-dependent protein kinase kinase 2 (CaMKK2) expression. We then used SimBiology to build a computational model of the Ca2+/CaM-Src-kinase signaling cascade, simulating Nx, Hx, and Hx+PP2 conditions. To evaluate our model, we used Sobol variance decomposition, multiparametric global sensitivity analysis, and parameter scanning. RESULTS: Our model captures important molecular trends caused by hypoxia in the piglet brain. Incorporating the action of Src kinase inhibitor PP2 further validated our model and enabled predictive analysis of the effect of hypoxia on CaMKK2. We determined the impact of a feedback loop related to Src phosphorylation of NMDA receptors and activation kinetics of CaMKII. We also identified distinct modes of signaling wherein Ca2+ level alterations following Src kinase inhibition may not be a linear predictor of changes in Bax expression. Importantly, our model indicates that while pharmacological pre-treatment significantly reduces the onset of abnormal Ca2+-influx, there exists a window of intervention after hypoxia during which targeted modulation of Src-NMDAR interaction kinetics in combination with PP2 administration can reduce Ca2+-influx and Bax expression to similar levels as pre-treatment. CONCLUSIONS: Our model identifies new dynamics of critical components in the Ca2+/CaM-Src signaling pathway leading to neuronal injury and provides a feasible framework for drug efficacy studies in translational models of neonatal brain injury for the prevention of intellectual and developmental disabilities.

Neuroprotective effect of Src kinase in hypoxia-ischemia: A systematic review.

Background: Hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal morbidity and mortality worldwide. While the application of therapeutic hypothermia has improved neurodevelopmental outcomes for some survivors of HIE, this lone treatment option is only available to a subset of affected neonates. Src kinase, an enzyme central to the apoptotic cascade, is a potential pharmacologic target to preserve typical brain development after HIE. Here, we present evidence of the neuroprotective effects of targeting Src kinase in preclinical models of HIE. Methods: We performed a comprehensive literature search using the National Library of Medicine's MEDLINE database to compile studies examining the impact of Src kinase regulation on neurodevelopment in animal models. Each eligible study was assessed for bias. Results: Twenty studies met the inclusion criteria, and most studies had an intermediate risk for bias. Together, these studies showed that targeting Src kinase resulted in a neuroprotective effect as assessed by neuropathology, enzymatic activity, and neurobehavioral outcomes. Conclusion: Src kinase is an effective neuroprotective target in the setting of acute hypoxic injury. Src kinase inhibition triggers multiple signaling pathways of the sub-membranous focal adhesions and the nucleus, resulting in modulation of calcium signaling and prevention of cell death. Despite the significant heterogeneity of the research studies that we examined, the available evidence can serve as proof-of-concept for further studies on this promising therapeutic strategy.

Pediatric sepsis phenotypes for enhanced therapeutics: An application of clustering to electronic health records.

OBJECTIVE: The heterogeneity of pediatric sepsis patients suggests the potential benefits of clustering analytics to derive phenotypes with distinct host response patterns that may help guide personalized therapeutics. We evaluate the relative performance of latent class analysis (LCA) and K-means, 2 commonly used clustering methods toward the derivation of clinically useful pediatric sepsis phenotypes. METHODS: Data were extracted from anonymized medical records of 6446 pediatric patients that presented to 1 of 6 emergency departments (EDs) between 2013 and 2018 and were thereafter admitted. Using International Classification of Diseases (ICD)-9 and ICD-10 discharge codes, 151 patients were identified with a sepsis continuum diagnosis that included septicemia, sepsis, severe sepsis, and septic shock. Using feature sets used in related clustering studies, LCA and K-means algorithms were used to derive 4 distinct phenotypic pediatric sepsis segmentations. Each segmentation was evaluated for phenotypic homogeneity, separation, and clinical use. RESULTS: Using the 2 feature sets, LCA clustering resulted in 2 similar segmentations of 4 clinically distinct phenotypes, while K-means clustering resulted in segmentations of 3 and 4 phenotypes. All 4 segmentations identified at least 1 high severity phenotype, but LCA-identified phenotypes reflected superior stratification, high entropy approaching 1 (eg, 0.994) indicating excellent separation between estimated phenotypes, and differential treatment/treatment response, and outcomes that were non-randomly distributed across phenotypes (P < 0.001). CONCLUSION: Compared to K-means, which is commonly used in clustering studies, LCA appears to be a more robust, clinically useful statistical tool in analyzing a heterogeneous pediatric sepsis cohort toward informing targeted therapies. Additional prospective studies are needed to validate clinical utility of predictive models that target derived pediatric sepsis phenotypes in emergency department settings.

Solithromycin in Children and Adolescents With Community-acquired Bacterial Pneumonia.

BACKGROUND: Solithromycin is a new macrolide-ketolide antibiotic with potential effectiveness in pediatric community-acquired bacterial pneumonia (CABP). Our objective was to evaluate its safety and effectiveness in children with CABP. METHODS: This phase 2/3, randomized, open-label, active-control, multicenter study randomly assigned solithromycin (capsules, suspension or intravenous) or an appropriate comparator antibiotic in a 3:1 ratio (planned n = 400) to children 2 months to 17 years of age with CABP. Primary safety endpoints included treatment-emergent adverse events (AEs) and AE-related drug discontinuations. Secondary effectiveness endpoints included clinical improvement following treatment without additional antimicrobial therapy. RESULTS: Unrelated to safety, the sponsor stopped the trial prior to completion. Before discontinuation, 97 participants were randomly assigned to solithromycin (n = 73) or comparator (n = 24). There were 24 participants (34%, 95% CI, 23%-47%) with a treatment-emergent AE in the solithromycin group and 7 (29%, 95% CI, 13%-51%) in the comparator group. Infusion site pain and elevated liver enzymes were the most common related AEs with solithromycin. Study drug was discontinued due to AEs in 3 subjects (4.3%) in the solithromycin group and 1 (4.2%) in the comparator group. Forty participants (65%, 95% CI, 51%-76%) in the solithromycin group achieved clinical improvement on the last day of treatment versus 17 (81%, 95% CI, 58%-95%) in the comparator group. The proportion achieving clinical cure was 60% (95% CI, 47%-72%) and 68% (95% CI, 43%-87%) for the solithromycin and comparator groups, respectively. CONCLUSIONS: Intravenous and oral solithromycin were generally well-tolerated and associated with clinical improvement in the majority of participants treated for CABP.

Exosomes in Nephropathies: A Rich Source of Novel Biomarkers.

The biomarkers commonly utilized in diagnostic evaluations of kidney disease suffer from low sensitivity, especially in the early stages of renal damage. On the other hand, obtaining a renal biopsy to augment clinical decision making can lead to potentially serious complications. In order to overcome the shortcomings of currently available diagnostic tools, recent studies suggest that exosomes, cell-secreted extracellular vesicles containing a large array of active molecules to facilitate cell-to-cell communication, may represent a rich source of novel disease biomarkers. Because of their endocytic origin, exosomes carry markers typical for their parent cells, which could permit the localization of biochemical cellular alterations in specific kidney compartments. Different types of exosomes can be isolated from noninvasively obtained biofluids; however, in the context of kidney disease, evidence has emerged on the role of urinary exosomes in the diagnostic and predictive modeling of renal pathology. The current review summarizes the potential application of exosomes in the detection of acute and chronic inflammatory, metabolic, degenerative, and genetic renal diseases.