Nephrotic Syndrome Throughout Childhood: Diagnosing Podocytopathies From the Womb to the Dorm.

The etiologies of podocyte dysfunction that lead to pediatric nephrotic syndrome (NS) are vast and vary with age at presentation. The discovery of numerous novel genetic podocytopathies and the evolution of diagnostic technologies has transformed the investigation of steroid-resistant NS while simultaneously promoting the replacement of traditional morphology-based disease classifications with a mechanistic approach. Podocytopathies associated with primary and secondary steroid-resistant NS manifest as diffuse mesangial sclerosis, minimal change disease, focal segmental glomerulosclerosis, and collapsing glomerulopathy. Molecular testing, once an ancillary option, has become a vital component of the clinical investigation and when paired with kidney biopsy findings, provides data that can optimize treatment and prognosis. This review focuses on the causes including selected monogenic defects, clinical phenotypes, histopathologic findings, and age-appropriate differential diagnoses of nephrotic syndrome in the pediatric population with an emphasis on podocytopathies.

Impact of Student Pharmacist State Anxiety on Vasopressor Calculation Accuracy in Advanced Cardiac Life Support Simulations.

OBJECTIVE: To assess the impact of student pharmacist state anxiety on vasopressor calculation accuracy in advanced cardiac life support (ACLS) simulations. METHODS: Third-year professional students participated in 2 ACLS-related simulation laboratory sessions. In week 1, students completed 3 calculations at their workstation with no stressors. Students were then randomized into teams for a bedside simulation where they independently completed 3 additional calculations either with or without stressors. Team assignments were maintained for week 2 where all participants completed a high-fidelity ACLS simulation that included a team vasopressor calculation. At both encounters, calculation accuracy was assessed as well as pre- and post-state anxiety using the Spielberger State-Trait Anxiety Inventory (STAI) survey tool. RESULTS: Students' (N = 145) trait anxiety aligned with normative data for similarly aged professional students. Post-simulation state anxiety in week 1 was found to be higher for those completing the activity with stressors than without (STAI score 44.7 vs 36.9) paired with lower bedside calculation accuracy, despite similar initial workstation calculation accuracy. In week 2, pre-simulation state anxiety score and calculation accuracy were not significantly different between the 2 groups. However, the state anxiety score significantly increased post-simulation for those exposed to stress in the previous week. CONCLUSION: Stress negatively impacted student pharmacist vasopressor calculation accuracy. However, the repeated exposure to a stressed simulation did not result in a significant difference in pre- or post-simulation state anxiety score or calculation accuracy when compared to a non-stressed control. Consideration should be made whether to include more "real-life" simulations in student pharmacist education.

In utero torsion of an accessory hepatic lobe mimicking a congenital tumor.

Accessory hepatic lobes are rare anatomic variants connected to the liver by a fibrous stalk or parenchymal attachments. They are usually detected incidentally, but torsion is a rare complication. Here, we report torsion of an accessory hepatic lobe occurring in utero with a focus on the MRI findings. The lesion mimicked a congenital tumor, and we provide potential clues that may have narrowed the differential diagnosis prior to surgical exploration.

A quality initiative to improve recognition of fluid overload among pediatric ICU patients requiring continuous kidney replacement therapy: preliminary results.

BACKGROUND: Initiation of continuous kidney replacement therapy (CKRT) greater than 20% fluid overload is associated with increased morbidity and mortality. We aimed to reduce the number of patients initiated on CKRT greater than 20% fluid overload by 50% in one year by implementation of a quality improvement initiative. METHODS: This is a prospective quality improvement study set in a pediatric ICU of an urban children's hospital of patients initiated on CKRT over 2 years. The intervention included creation of an electronic health record order for daily calculation of net percent fluid overload, incorporation into daily rounds, and education programs tailored to physicians and bedside nursing. We measured adherence with the new order set, percent fluid overload at CKRT initiation, days on CKRT, timing of first nephrology consultation, and death prior to discharge. RESULTS: A total of 32% of patients were initiated on CKRT greater than 20% fluid overload pre-initiative and 9% post-initiative, a 72% reduction over 13 months. Patients initiated on CKRT greater than 20% fluid overload had median CKRT course of 8 (IQR 4-14) vs. 22 days (IQR 13.5-62). CONCLUSION: Creating a system using EHR with education may reduce initiation of CKRT after development of severe fluid overload. A higher resolution version of the Graphical abstract is available as Supplementary information.

Computer-Based Natural Language Search Applied to the Electronic Medical Record for Tonsil Triage.

OBJECTIVES: To determine significant histologic findings in tonsils and categorize clinical settings in which they occur to identify cases benefiting from histopathologic examination using a computer-based natural language search (NLS) applied to the electronic medical record. METHODS: The pathology database was queried for tonsillectomy cases accessioned between 2002 and 2018. Tonsils with microscopic examination were reviewed, and indication for examination and diagnoses were tallied. Clinical risk of malignancy was correlated with findings. A NLS was used to interrogate preoperative clinical records of the same group of patients. The search identified cases at risk of significant histologic findings and was implemented as part of standard practice. RESULTS: Of the 18,733 bilateral tonsillectomies identified in the pathology database, 494 were palatine tonsils that underwent microscopic examination, 134 had indications concerning for malignancy, and 14 had significant findings on histologic examination. When the NLS was applied to the medical record of the same group, 223 cases were identified as having risk of malignancy, including all flagged by surgeons and pathologists and 89 additional cases. Clinical implementation resulted in identification of all cases benefiting from examination. CONCLUSIONS: A NLS applied to the electronic medical record to select tonsils for examination was superior to relying on surgeons and pathologists.

Improvement of Refractory Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease with Single-Agent Blockade of IL-1ß and IL-18.

Systemic juvenile idiopathic arthritis associated with interstitial lung disease (SJIA-LD) represents a highly morbid subset of SJIA for which effective therapies are lacking. We report the case of a patient with refractory SJIA-LD who underwent treatment with MAS-825, an investigational bispecific monoclonal antibody targeting IL-1ß and IL-18. MAS-825 treatment was associated with a marked reduction in total IL-18 and free IL-18 in both serum and bronchoalveolar lavage fluid (BAL). Baseline oxygen saturation, exercise tolerance, and quality of life metrics improved after treatment with MAS-825, while pulmonary function testing remained stable. Following treatment, the BAL showed no evidence of pulmonary alveolar proteinosis and inflammatory infiltrates were markedly reduced, reflected by decreased numbers of CD4 T-cells, CD8 T-cells, and macrophages. The patient was able to wean entirely off systemic corticosteroids and other biologics after 10 months of treatment with MAS-825 and experienced no side effects of the drug. This case demonstrates improvement in pulmonary symptoms, lung inflammation, and burden of immunomodulatory therapy after treatment with MAS-825 and suggests that simultaneous targeting of both IL-1ß and IL-18 may be a safe and effective treatment strategy in SJIA-LD.

Multifocal Kaposiform Hemangioendothelioma in a Newborn With Confirmatory Histopathology.

Kaposiform hemangioendothelioma is classified as a locally aggressive vascular tumor of childhood resulting from abnormal angiogenesis and lymphangiogenesis. Most commonly, KHE presents as a single tissue mass, ranging from an erythematous papule to a violaceous indurated tumor. Definitive diagnosis requires tissue sampling with the demonstration of ill-defined nodules and fascicles of spindle-shaped D2-40 positive endothelial cells, forming slit-like vascular channels. This newborn presented with multifocal cutaneous Kaposiform hemangioendothelioma associated with Kasabach-Merritt phenomenon confirmed on histopathology with immunostaining.

The cnf1 gene is associated with an expanding Escherichia coli ST131 H30Rx/C2 subclade and confers a competitive advantage for gut colonization.

Epidemiological projections point to acquisition of ever-expanding multidrug resistance (MDR) by Escherichia coli, a commensal of the digestive tract and a source of urinary tract pathogens. Bioinformatics analyses of a large collection of E. coli genomes from EnteroBase, enriched in clinical isolates of worldwide origins, suggest the Cytotoxic Necrotizing Factor 1 (CNF1)-toxin encoding gene, cnf1, is preferentially distributed in four common sequence types (ST) encompassing the pandemic E. coli MDR lineage ST131. This lineage is responsible for a majority of extraintestinal infections that escape first-line antibiotic treatment, with known enhanced capacities to colonize the gastrointestinal tract. Statistical projections based on this dataset point to a global expansion of cnf1-positive multidrug-resistant ST131 strains from subclade H30Rx/C2, accounting for a rising prevalence of cnf1-positive strains in ST131. Despite the absence of phylogeographical signals, cnf1-positive isolates segregated into clusters in the ST131-H30Rx/C2 phylogeny, sharing a similar profile of virulence factors and the same cnf1 allele. The suggested dominant expansion of cnf1-positive strains in ST131-H30Rx/C2 led us to uncover the competitive advantage conferred by cnf1 for gut colonization to the clinical strain EC131GY ST131-H30Rx/C2 versus cnf1-deleted isogenic strain. Complementation experiments showed that colon tissue invasion was compromised in the absence of deamidase activity on Rho GTPases by CNF1. Hence, gut colonization factor function of cnf1 was confirmed for another clinical strain ST131-H30Rx/C2. In addition, functional analysis of the cnf1-positive clinical strain EC131GY ST131-H30Rx/C2 and a cnf1-deleted isogenic strain showed no detectable impact of the CNF1 gene on bacterial fitness and inflammation during the acute phase of bladder monoinfection. Together these data argue for an absence of role of CNF1 in virulence during UTI, while enhancing gut colonization capacities of ST131-H30Rx/C2 and suggested expansion of cnf1-positive MDR isolates in subclade ST131-H30Rx/C2.

Pathology findings in pediatric patients with COVID-19 and kidney dysfunction.

BACKGROUND: Acute kidney injury (AKI) is seen in one-fifth of pediatric patients with COVID-19 requiring hospital admission, and is associated with increased morbidity, mortality, and residual kidney impairment. The majority of kidney pathology data in patients with COVID-19 is derived from adult case series and there is an overall lack of histologic data for most pediatric patients with COVID-19. METHODS: We assembled a multi-institutional cohort of five unvaccinated pediatric patients with COVID-19 and associated kidney dysfunction with available histology. RESULTS: Three complex patients with current or prior SARS-CoV-2 infection had multifactorial thrombotic microangiopathy with clinical features of hemolytic uremic syndrome (in two) or disseminated intravascular coagulation (in one); one died and another developed chronic kidney disease stage 5. Two with recently preceding SARS-CoV-2 infection presented with nephrotic syndrome; one had IgA vasculitis and one had minimal change disease. Within a short follow-up time, none has returned to baseline kidney function. CONCLUSION: Although uncommon, COVID-19-associated kidney injury can have significant morbidity in the unvaccinated pediatric and adolescent population. A higher resolution version of the Graphical abstract is available as Supplementary information.

Cerebrofacial vascular metameric syndrome is caused by somatic pathogenic variants in PIK3CA.

Disorganized morphogenesis of arteries, veins, capillaries, and lymphatic vessels results in vascular malformations. Most individuals with isolated vascular malformations have postzygotic (mosaic), activating pathogenic variants in a handful of oncogenes within the PI3K-RAS-MAPK pathway (Padia et al., Laryngoscope Investig Otolaryngol 4: 170-173 [2019]). Activating pathogenic variants in the gene PIK3CA, which encodes for the catalytic subunit of phosphatidylinositol 3-kinase, are present in both lymphatic and venous malformations as well as arteriovenous malformations in other complex disorders such as CLOVES syndrome (congenital, lipomatous, overgrowth, vascular malformations, epidermal anevi, scoliosis) (Luks et al., Pediatr Dev Pathol 16: 51 [2013]; Luks et al., J Pediatr 166: 1048-1054.e1-5 [2015]; Al-Olabi et al., J Clin Invest 128: 1496-1508 [2018]). These vascular malformations are part of the PIK3CA-related overgrowth spectrum, a spectrum of entities that have regionalized disordered growth due to the presence of tissue-restricted postzygotic PIK3CA pathogenic variants (Keppler-Noreuil et al., Am J Med Genet A 167A: 287-295 [2015]). Cerebrofacial vascular metameric syndrome (CVMS; also described as cerebrofacial arteriovenous metameric syndrome, Bonnet-Dechaume-Blanc syndrome, and Wyburn-Mason syndrome) is the association of retinal, facial, and cerebral vascular malformations (Bhattacharya et al., Interv Neuroradiol 7: 5-17 [2001]; Krings et al., Neuroimaging Clin N Am 17: 245-258 [2007]). The segmental distribution, the presence of tissue overgrowth, and the absence of familial recurrence are all consistent with CVMS being caused by a postzygotic mutation, which has been hypothesized by previous authors (Brinjiki et al., Am J Neuroradiol 39: 2103-2107 [2018]). However, the genetic cause of CVMS has not yet been described. Here, we present three individuals with CVMS and mosaic activating pathogenic variants within the gene PIK3CA We propose that CVMS be recognized as part of the PIK3CA-related overgrowth spectrum, providing justification for future trials using pharmacologic PIK3CA inhibitors (e.g., alpelisib) for these difficult-to-treat patients.

Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis.

Locoregional delivery of chimeric antigen receptor (CAR) T cells has resulted in objective responses in adults with glioblastoma, but the feasibility and tolerability of this approach is yet to be evaluated for pediatric central nervous system (CNS) tumors. Here we show that engineering of a medium-length CAR spacer enhances the therapeutic efficacy of human erb-b2 receptor tyrosine kinase 2 (HER2)-specific CAR T cells in an orthotopic xenograft medulloblastoma model. We translated these findings into BrainChild-01 ( NCT03500991 ), an ongoing phase 1 clinical trial at Seattle Children's evaluating repetitive locoregional dosing of these HER2-specific CAR T cells to children and young adults with recurrent/refractory CNS tumors, including diffuse midline glioma. Primary objectives are assessing feasibility, safety and tolerability; secondary objectives include assessing CAR T cell distribution and disease response. In the outpatient setting, patients receive infusions via CNS catheter into either the tumor cavity or the ventricular system. The initial three patients experienced no dose-limiting toxicity and exhibited clinical, as well as correlative laboratory, evidence of local CNS immune activation, including high concentrations of CXCL10 and CCL2 in the cerebrospinal fluid. This interim report supports the feasibility of generating HER2-specific CAR T cells for repeated dosing regimens and suggests that their repeated intra-CNS delivery might be well tolerated and activate a localized immune response in pediatric and young adult patients.

New Drug Update 2020.

Five new drugs marketed within the last year that are used for medical problems often experienced by older people have been selected for consideration in this review. The uses and most important properties of these agents are discussed, and a rating for each new drug is determined using the New Drug Comparison Rating (NDCR) system developed by the author (DAH). Advantages, disadvantages, and other important information regarding each new drug are identified and used as the basis for determining the rating. The drugs considered include new agents indicated for the treatment of patients with hypercholesterolemia, Parkinson's disease, insomnia, schizophrenia, and age-related macular degeneration.

Germline SAMD9L truncation variants trigger global translational repression.

SAMD9L is an interferon-induced tumor suppressor implicated in a spectrum of multisystem disorders, including risk for myeloid malignancies and immune deficiency. We identified a heterozygous de novo frameshift variant in SAMD9L in an infant with B cell aplasia and clinical autoinflammatory features who died from respiratory failure with chronic rhinovirus infection. Autopsy demonstrated absent bone marrow and peripheral B cells as well as selective loss of Langerhans and Purkinje cells. The frameshift variant led to expression of a truncated protein with interferon treatment. This protein exhibited a gain-of-function phenotype, resulting in interference in global protein synthesis via inhibition of translational elongation. Using a mutational scan, we identified a region within SAMD9L where stop-gain variants trigger a similar translational arrest. SAMD9L variants that globally suppress translation had no effect or increased mRNA transcription. The complex-reported phenotype likely reflects lineage-dominant sensitivities to this translation block. Taken together, our findings indicate that interferon-triggered SAMD9L gain-of-function variants globally suppress translation.

Hepatopulmonary Syndrome in an Adolescent With Insidious Hypoxia and Small Intrahepatic Portal Venous Shunts: Posttransplant Benefit From Sildenafil.

We report a patient without known preexisting liver disease who presented with hepatopulmonary syndrome (HPS) due to aberrant intrahepatic portal venous development leading to portosystemic shunting. Liver transplantation resulted in resolution of portal hypertension and HPS and sildenafil was safely tolerated in the treatment of persistent fatigue and hypoxemia. Twelve months later, patient has normal allograft function and has returned to normal activity.

Advanced cardiac life support certification for student pharmacists improves simulated patient survival.

BACKGROUND AND PURPOSE: Basic life support (BLS) and advanced cardiac life support (ACLS) skills performance, as well as simulated patient survival, were compared for student pharmacist teams with and without at least one member with American Heart Association (AHA) ACLS certification. EDUCATIONAL ACTIVITY AND SETTING: Doctor of pharmacy students in their third professional year completed a high-fidelity mannequin simulation. Within the previous year, 30 of 184 students (16%) completed ACLS certification. Rapid response teams (n = 31) of five to six members were formed through random student assignment. Two AHA instructors recorded and assessed performance using a checklist adapted from the AHA's standardized forms for BLS and ACLS assessment. Teams with and without ACLS certified members were compared for skills performance and simulated patient survival (i.e. correct performance of all BLS and ACLS skills). FINDINGS: Teams with ACLS certified members (n = 21) were superior to teams without certified members (n = 10) for correct performance of all observed BLS and ACLS skills, including pulse assessment and medication selection for cardiovascular support. For teams who had ACLS certified members, simulated patient survival was 86% higher. The study groups did not differ in their ability to calculate a correct vasopressor infusion rate if warranted. SUMMARY: BLS and ACLS skills performance were improved by AHA ACLS certification. Additionally, simulated patient survival was improved for teams with students who had at least one ACLS certified member.