Morpho-electric diversity of human hippocampal CA1 pyramidal neurons.

Hippocampal pyramidal neuron activity underlies episodic memory and spatial navigation. Although extensively studied in rodents, extremely little is known about human hippocampal pyramidal neurons, even though the human hippocampus underwent strong evolutionary reorganization and shows lower theta rhythm frequencies. To test whether biophysical properties of human Cornu Amonis subfield 1 (CA1) pyramidal neurons can explain observed rhythms, we map the morpho-electric properties of individual CA1 pyramidal neurons in human, non-pathological hippocampal slices from neurosurgery. Human CA1 pyramidal neurons have much larger dendritic trees than mouse CA1 pyramidal neurons, have a large number of oblique dendrites, and resonate at 2.9 Hz, optimally tuned to human theta frequencies. Morphological and biophysical properties suggest cellular diversity along a multidimensional gradient rather than discrete clustering. Across the population, dendritic architecture and a large number of oblique dendrites consistently boost memory capacity in human CA1 pyramidal neurons by an order of magnitude compared to mouse CA1 pyramidal neurons.

The impact of skin color and tone on histamine iontophoresis and Doppler flowmetry measurements as a pharmacodynamic biomarker.

The phenotypical manifestations of asthma among children are diverse and exhibit varying responses to therapeutic interventions. There is a need to develop objective biomarkers to improve the characterization of allergic and inflammatory responses relevant to asthma to predict therapeutic treatment responses. We have previously investigated histamine iontophoresis with laser Doppler flowmetry (HILD) as a potential surrogate biomarker that characterizes histamine response and may be utilized to guide the treatment of allergic and inflammatory disease. We have identified intra-individual variability of HILD response type among children and adults with asthma and that HILD response type varied in association with racial classification. As laser Doppler flowimetry may be impacted by skin color, we aimed to further validate the HILD method by determining if skin color or tone is associated with observed HILD response type differences. We conducted an observational study utilizing quantification of skin color and tone obtained from photographs of the skin among participants during HILD assessments via the RGB color model. We compared RGB values across racial, ethnic, and HILD response type via the Kruskal-Wallis test and calculated Kendall rank correlation coefficient to evaluate the relationship between RGB composite scores and HILD pharmacodynamic measures. We observed that RGB scores differed among racial groups and histamine response phenotypes (p < 0.05). However, there was a lack of correlation between the RGB composite score and HILD pharmacodynamic measures (r values 0.1, p > 0.05). These findings suggest that skin color may not impact HILD response variations, necessitating further research to understand previously observed differences across identified racial groups.

Renal Tubular Acidosis in the Neonate.

See Bonus NeoBriefs videos and downloadable teaching slides Metabolic acidosis can manifest in the neonatal period and cause significant morbidity and mortality in neonates. Preterm infants are at an even higher risk of developing metabolic acidosis. If the acidosis results from a dysfunction of acid-base homeostasis by the renal system, the disorder is known as renal tubular acidosis (RTA). In this review, we will describe renal development and normal acid-base homeostasis by the renal system. We will also discuss the pathophysiology of the different types of RTA, laboratory findings to aid in diagnosis, and treatment considerations. Understanding RTA will help neonatal clinicians recognize and diagnose an infant affected by RTA and initiate treatment in a timely manner.

Clinically Significant Treatment Delay in Pediatric Scaphoid Fractures.

PURPOSE: Pediatric scaphoid fractures present to treatment in a delayed manner 8% to 29% of the time. The indications for cast immobilization in this population are not clear. The definition of a clinically important treatment delay is based only on anecdotal reports. Successful treatment with a cast may be more desirable than surgical intervention. However, it remains unclear what clinical and radiographic factors may predict success with casting. METHODS: A retrospective analysis of all scaphoid fractures treated at a single pediatric hospital was performed to identify fracture characteristics, the presence of cystic change, treatment method, and healing rate. A cut-point analysis was performed to determine the number of days of treatment delay, predictive of casting failure. Kaplan-Meier assessments were performed to determine the differences in time in cast. Characteristics of the delayed group were described and stratified by treatment success or failure. RESULTS: After review, 254 patients met the inclusion criteria. Cut-point analysis determined that a presentation delay of ≥21 days was associated with failure to unite with casting. The median time in the cast for the acute and delayed groups was not significantly different. The casting union rate of delayed fractures was less than acute fractures (75.0% vs 97.0%). CONCLUSIONS: Delayed presentation of scaphoid fractures 21 days or more after injury predicts a greater risk of casting failure; however, the union rate remains high with comparable time in cast. Cast immobilization for scaphoid fractures presenting 21 days or more after injury is a reasonable option. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognosis IV.

Ambulatory amoxicillin use for common acute respiratory infections during a national shortage: Results from the SHARPS-OP benchmarking collaborative.

We quantified antibiotic prescribing for ambulatory pediatric acute respiratory illness at 22 institutions in "pre-shortage" (Jan 2019-Sep 2022) and "shortage" (Oct 2022-Mar 2023) periods for amoxicillin. While acute respiratory illness prescribing increased across settings, the proportion of amoxicillin prescriptions decreased. Variation was seen within and between institutions.

Appropriateness of antibiotic prescribing varies by clinical services at United States children's hospitals.

OBJECTIVE: To describe patterns of inappropriate antibiotic prescribing at US children's hospitals and how these patterns vary by clinical service. DESIGN: Serial, cross-sectional study using quarterly surveys. SETTING: Surveys were completed in quarter 1 2019-quarter 3 2020 across 28 children's hospitals in the United States. PARTICIPANTS: Patients at children's hospitals with ≥1 antibiotic order at 8:00 a.m. on institution-selected quarterly survey days. METHODS: Antimicrobial stewardship physicians and pharmacists collected data on antibiotic orders and evaluated appropriateness of prescribing. The primary outcome was percentage of inappropriate antibiotics, stratified by clinical service and antibiotic class. Secondary outcomes included reasons for inappropriate use and association of infectious diseases (ID) consultation with appropriateness. RESULTS: Of 13,344 orders, 1,847 (13.8%) were inappropriate; 17.5% of patients receiving antibiotics had ≥1 inappropriate order. Pediatric intensive care units (PICU) and hospitalists contributed the most inappropriate orders (n = 384 and n = 314, respectively). Surgical subspecialists had the highest percentage of inappropriate orders (22.5%), and 56.8% of these were for prolonged or unnecessary surgical prophylaxis. ID consultation in the previous 7 days was associated with fewer inappropriate orders (15% vs 10%; P < .001); this association was most pronounced for hospitalist, PICU, and surgical and medical subspecialty services. CONCLUSIONS: Inappropriate antibiotic use for hospitalized children persists and varies by clinical service. Across 28 children's hospitals, PICUs and hospitalists contributed the most inappropriate antibiotic orders, and surgical subspecialists' orders were most often judged inappropriate. Understanding service-specific prescribing patterns will enable antimicrobial stewardship programs to better design interventions to optimize antibiotic use.

Morphoelectric and transcriptomic divergence of the layer 1 interneuron repertoire in human versus mouse neocortex.

Neocortical layer 1 (L1) is a site of convergence between pyramidal-neuron dendrites and feedback axons where local inhibitory signaling can profoundly shape cortical processing. Evolutionary expansion of human neocortex is marked by distinctive pyramidal neurons with extensive L1 branching, but whether L1 interneurons are similarly diverse is underexplored. Using Patch-seq recordings from human neurosurgical tissue, we identified four transcriptomic subclasses with mouse L1 homologs, along with distinct subtypes and types unmatched in mouse L1. Subclass and subtype comparisons showed stronger transcriptomic differences in human L1 and were correlated with strong morphoelectric variability along dimensions distinct from mouse L1 variability. Accompanied by greater layer thickness and other cytoarchitecture changes, these findings suggest that L1 has diverged in evolution, reflecting the demands of regulating the expanded human neocortical circuit.

Signature morphoelectric properties of diverse GABAergic interneurons in the human neocortex.

Human cortex transcriptomic studies have revealed a hierarchical organization of γ-aminobutyric acid-producing (GABAergic) neurons from subclasses to a high diversity of more granular types. Rapid GABAergic neuron viral genetic labeling plus Patch-seq (patch-clamp electrophysiology plus single-cell RNA sequencing) sampling in human brain slices was used to reliably target and analyze GABAergic neuron subclasses and individual transcriptomic types. This characterization elucidated transitions between PVALB and SST subclasses, revealed morphological heterogeneity within an abundant transcriptomic type, identified multiple spatially distinct types of the primate-specialized double bouquet cells (DBCs), and shed light on cellular differences between homologous mouse and human neocortical GABAergic neuron types. These results highlight the importance of multimodal phenotypic characterization for refinement of emerging transcriptomic cell type taxonomies and for understanding conserved and specialized cellular properties of human brain cell types.

Genes associated with cognitive ability and HAR show overlapping expression patterns in human cortical neuron types.

GWAS have identified numerous genes associated with human cognition but their cell type expression profiles in the human brain are unknown. These genes overlap with human accelerated regions (HARs) implicated in human brain evolution and might act on the same biological processes. Here, we investigated whether these gene sets are expressed in adult human cortical neurons, and how their expression relates to neuronal function and structure. We find that these gene sets are preferentially expressed in L3 pyramidal neurons in middle temporal gyrus (MTG). Furthermore, neurons with higher expression had larger total dendritic length (TDL) and faster action potential (AP) kinetics, properties previously linked to intelligence. We identify a subset of genes associated with TDL or AP kinetics with predominantly synaptic functions and high abundance of HARs.

Integrated multimodal cell atlas of Alzheimer's disease.

Alzheimer's disease (AD) is the most common cause of dementia in older adults. Neuropathological and imaging studies have demonstrated a progressive and stereotyped accumulation of protein aggregates, but the underlying molecular and cellular mechanisms driving AD progression and vulnerable cell populations affected by disease remain coarsely understood. The current study harnesses single cell and spatial genomics tools and knowledge from the BRAIN Initiative Cell Census Network to understand the impact of disease progression on middle temporal gyrus cell types. We used image-based quantitative neuropathology to place 84 donors spanning the spectrum of AD pathology along a continuous disease pseudoprogression score and multiomic technologies to profile single nuclei from each donor, mapping their transcriptomes, epigenomes, and spatial coordinates to a common cell type reference with unprecedented resolution. Temporal analysis of cell-type proportions indicated an early reduction of Somatostatin-expressing neuronal subtypes and a late decrease of supragranular intratelencephalic-projecting excitatory and Parvalbumin-expressing neurons, with increases in disease-associated microglial and astrocytic states. We found complex gene expression differences, ranging from global to cell type-specific effects. These effects showed different temporal patterns indicating diverse cellular perturbations as a function of disease progression. A subset of donors showed a particularly severe cellular and molecular phenotype, which correlated with steeper cognitive decline. We have created a freely available public resource to explore these data and to accelerate progress in AD research at SEA-AD.org.

Benchmarking of Outpatient Pediatric Antibiotic Prescribing: Results of a Multicenter Collaborative.

BACKGROUND: Most antibiotic use occurs in ambulatory settings. No benchmarks exist for pediatric institutions to assess their outpatient antibiotic use and compare prescribing rates to peers. We aimed to share pediatric outpatient antibiotic use reports and benchmarking metrics nationally. METHODS: We invited institutions from the Sharing Antimicrobial Reports for Pediatric Stewardship OutPatient (SHARPS-OP) Collaborative to contribute quarterly aggregate reports on antibiotic use from January 2019 to June 2022. Outpatient settings included emergency departments (ED), urgent care centers (UCC), primary care clinics (PCC) and telehealth encounters. Benchmarking metrics included the percentage of: (1) all acute encounters resulting in antibiotic prescriptions; (2) acute respiratory infection (ARI) encounters resulting in antibiotic prescriptions; and among ARI encounters receiving antibiotics, (3) the percentage receiving amoxicillin ("Amoxicillin index"); and (4) the percentage receiving azithromycin ("Azithromycin index"). We collected rates of antibiotic prescriptions with durations ≤7 days and >10 days from institutions able to provide validated duration data. RESULTS: Twenty-one institutions submitted aggregate reports. Percent ARI encounters receiving antibiotics were highest in the UCC (40.2%), and lowest in telehealth (19.1%). Amoxicillin index was highest for the ED (76.2%), and lowest for telehealth (55.8%), while the azithromycin index was similar for ED, UCC, and PCC (3.8%, 3.7%, and 5.0% respectively). Antibiotic duration of ≤7 days varied substantially (46.4% for ED, 27.8% UCC, 23.7% telehealth, and 16.4% PCC). CONCLUSIONS: We developed a benchmarking platform for key pediatric outpatient antibiotic use metrics drawing data from multiple pediatric institutions nationally. These data may serve as a baseline measurement for future improvement work.

Socioeconomic differences in antibiotic use for common infections in pediatric urgent-care centers-A quasi-experimental study.

OBJECTIVE: To investigate differences in the rate of firstline antibiotic prescribing for common pediatric infections in relation to different socioeconomic statuses and the impact of an antimicrobial stewardship program (ASP) in pediatric urgent-care clinics (PUCs). DESIGN: Quasi-experimental. SETTING: Three PUCs within a Midwestern pediatric academic center. PATIENTS AND PARTICIPANTS: Patients aged >60 days and <18 years with acute otitis media, group A streptococcal pharyngitis, community-acquired pneumonia, urinary tract infection, or skin and soft-tissue infections who received systemic antibiotics between July 2017 and December 2020. We excluded patients who were transferred, admitted, or had a concomitant diagnosis requiring systemic antibiotics. INTERVENTION: We used national guidelines to determine the appropriateness of antibiotic choice in 2 periods: prior to (July 2017-July 2018) and following ASP implementation (August 2018-December 2020). We used multivariable regression analysis to determine the odds ratios of appropriate firstline agent by age, sex, race and ethnicity, language, and insurance type. RESULTS: The study included 34,603 encounters. Prior to ASP implementation in August 2018, female patients, Black non-Hispanic children, those >2 years of age, and those who self-paid had higher odds of receiving recommended firstline antibiotics for all diagnoses compared to male patients, children of other races and ethnicities, other ages, and other insurance types, respectively. Although improvements in prescribing occurred after implementation of our ASP, the difference within the socioeconomic subsets persisted. CONCLUSIONS: We observed socioeconomic differences in firstline antibiotic prescribing for common pediatric infections in the PUCs setting despite implementation of an ASP. Antimicrobial stewardship leaders should consider drivers of these differences when developing improvement initiatives.

A Comparison of Pathogen Detection and Risk Factors among Symptomatic Children with Gastroenteritis Compared with Asymptomatic Children in the Post-rotavirus Vaccine Era.

OBJECTIVE: To describe demographics, pathogen distribution/seasonality, and risk factors in children seeking care for acute gastroenteritis (AGE) at a midwestern US emergency department during 5 postrotavirus vaccine years (2011-2016), and further, to compare the same data with matched healthy controls (HC). STUDY DESIGN: AGE and HC participants <11 years old enrolled in the New Vaccine Surveillance Network study between December 2011 to June 2016 were included. AGE was defined as ≥3 diarrhea episodes or ≥1 vomiting episode. Each HC's age was similar to an AGE participant's age. Pathogens were analyzed for seasonality effects. Participant risk factors for AGE illness and pathogen detections were compared between HC and a matched subset of AGE cases. RESULTS: One or more organisms was detected in 1159 of 2503 children (46.3%) with AGE compared with 99 of 537 HC (17.3%). Norovirus was detected most frequently among AGE (n = 568 [22.7%]) and second-most frequently in HC (n = 39 [6.8%]). Rotavirus was the second most frequently detected pathogen among AGE (n = 196 [7.8%]). Children with AGE were significantly more likely to have reported a sick contact compared with HC, both outside the home (15.6% vs 1.4%; P < .001) and inside the home (18.6% vs 2.1%; P < .001). Daycare attendance was higher among children with AGE (41.4%) compared with HC (29.5%; P < .001). The Clostridium difficile detection rate was slightly higher among HC (7.0%) than AGE (5.3%). CONCLUSIONS: Norovirus was the most prevalent pathogen among children with AGE. Norovirus was detected in some HC, suggesting potential asymptomatic shedding among HC. The proportion of AGE participants with a sick contact was approximately 10 times greater than that of HC.

Appropriateness of Diagnosis and Management for Otitis Media With Effusion in Pediatric Urgent Care Clinics.

BACKGROUND: Otitis media with effusion (OME)'s clinical presentation is often confused with acute otitis media (AOM) by clinicians. Despite OME guidelines recommending watchful waiting with no antibiotics, rates of antibiotic use remain elevated. The aim of this study was to determine the clinician diagnosis validity and the rates of antibiotics prescribed among pediatric OME patients evaluated in 3 urgent care clinics within a pediatric health care system. METHODS: We retrospectively reviewed a random sample of encounters for children aged 0 to 18 years with a billing diagnosis of OME in 2019. We recorded clinical symptoms, antibiotic prescribed, and the clinicians' diagnosis. We used the American Academy of Pediatrics guidelines to assign an AOM diagnosis and compared those with the clinicians' final diagnoses using Pearson χ 2 . RESULTS: Of the 912 eligible charts, clinicians' final diagnoses were as follows: AOM for 271 (29.7%) patients, OME for 638 (70.0%) patients, and no ear pathology for 3 (0.3%) patients. Antibiotics were prescribed for 519 (56.9%) patients; of those, only 242 (46.6%) had a final clinician diagnosis of AOM. Antibiotic prescribing rates were higher when a clinician diagnosed AOM compared with OME (89.3% vs 43.2%; P < 0.001). Per American Academy of Pediatrics guidelines, up to 273 (29.9%) patients qualified for an AOM diagnosis, but those were not the same as those diagnosed with AOM by clinicians ( P < 0.001). CONCLUSIONS: When evaluating children with a billing diagnosis of OME, a third fit a diagnosis of AOM. Clinicians commonly misdiagnosed AOM, but also prescribed antibiotics to almost half of those they diagnose with OME.

Target cell-specific synaptic dynamics of excitatory to inhibitory neuron connections in supragranular layers of human neocortex.

Rodent studies have demonstrated that synaptic dynamics from excitatory to inhibitory neuron types are often dependent on the target cell type. However, these target cell-specific properties have not been well investigated in human cortex, where there are major technical challenges in reliably obtaining healthy tissue, conducting multiple patch-clamp recordings on inhibitory cell types, and identifying those cell types. Here, we take advantage of newly developed methods for human neurosurgical tissue analysis with multiple patch-clamp recordings, post-hoc fluorescent in situ hybridization (FISH), machine learning-based cell type classification and prospective GABAergic AAV-based labeling to investigate synaptic properties between pyramidal neurons and PVALB- vs. SST-positive interneurons. We find that there are robust molecular differences in synapse-associated genes between these neuron types, and that individual presynaptic pyramidal neurons evoke postsynaptic responses with heterogeneous synaptic dynamics in different postsynaptic cell types. Using molecular identification with FISH and classifiers based on transcriptomically identified PVALB neurons analyzed by Patch-seq, we find that PVALB neurons typically show depressing synaptic characteristics, whereas other interneuron types including SST-positive neurons show facilitating characteristics. Together, these data support the existence of target cell-specific synaptic properties in human cortex that are similar to rodent, thereby indicating evolutionary conservation of local circuit connectivity motifs from excitatory to inhibitory neurons and their synaptic dynamics.

Admission Pa o2 and Mortality Among PICU Patients and Select Diagnostic Subgroups.

OBJECTIVES: Evaluate the relationship between admission Pa o2 and mortality in a large multicenter dataset and among diagnostic subgroups. DESIGN: Retrospective cohort study. SETTING: North American PICUs participating in Virtual Pediatric Systems, LLC (VPS), 2015-2019. PATIENTS: Noncardiac patients 18 years or younger admitted to a VPS PICU with admission Pa o2 . INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Thirteen thousand seventy-one patient encounters were included with an overall mortality of 13.52%. Age categories were equally distributed among survivors and nonsurvivors with the exception of small differences among neonates and adolescents. Importantly, there was a tightly fitting quadratic relationship between admission Pa o2 and mortality, with the highest mortality rates seen among hypoxemic and hyperoxemic patients (likelihood-ratio test p < 0.001). This relationship persisted after adjustment for illness severity using modified Pediatric Index of Mortality 3 scores. A similar U-shaped relationship was demonstrated among patients with diagnoses of trauma, head trauma, sepsis, renal failure, hemorrhagic shock, and drowning. However, among the 1,500 patients admitted following cardiac arrest, there was no clear relationship between admission Pa o2 and mortality. CONCLUSIONS: In a large multicenter pediatric cohort, admission Pa o2 demonstrates a tightly fitting quadratic relationship with mortality. The persistence of this relationship among some but not all diagnostic subgroups suggests the pathophysiology of certain disease states may modify the hyperoxemia association.

Disruption of seasonal enterovirus and parechovirus detections in the CSF and plasma of children during the COVID-19 pandemic.

BACKGROUND: Enteroviruses (EV) and parechovirus (PeV) are a common cause of CNS infection in children. Both viruses demonstrate consistent seasonal patterns, with detections mainly in the summer-fall months. While research has shown COVID-19 pandemic-related disruption of traditional seasonality of respiratory pathogens, the pandemic's impact on non-respiratory pathogens is less understood. The aim of this study was to quantify the EV/PeV seasonal variations during pre-COVID years compared to variations observed during the COVID pandemic. METHODS: Patients with EV/PeV testing of CSF/plasma between January 2012 through September 2022 were identified. Restricted cubic spline methods were used to model the detections. Poisson models were utilized to model pre-COVID (2012-2019) EV/PeV detections. The expected seasonal trends from these models were then compared to the observed EV/PeV detections during the COVID pandemic (2020-2022). RESULTS: A total of 5199 patients were included. The annual pre-pandemic proportion of EV detections ranged between 7.5%-20.3%. PeV exhibited a biennial pattern with peak proportions between 8.0%-16.3%. EV/PeV detections during the COVID pandemic period, especially during 2020 and 2021, were considerably lower than would have been expected based on pre-pandemic modeling. However, PeV detections from January through September 2022 nearly reached the pre-pandemic modeled expectation, including instances of exceeded expectations. CONCLUSIONS: A significant disruption in expected seasonal EV/PeV detections was observed during the early phases of the COVID-19 pandemic. However, testing that occurred during summer-fall of 2022, when social mitigation initiatives were relaxed, showed a rapid increase in detections. Additional data are needed to further understand which public health initiatives are effective at decreasing EV/PeV transmission.

Impact of an antibiotic stewardship program on antibiotic choice, dosing, and duration in pediatric urgent cares.

BACKGROUND: Many antimicrobial stewardship programs (ASPs) focus on decreasing unnecessary antibiotics. We describe the impact of an outpatient ASP on choice, dose, and duration of antibiotics when used for common infections in pediatric urgent care (PUC) centers. METHODS: We reviewed encounters at 4 PUC centers within our organization for patients 6 months to 18 years old with acute otitis media, group A streptococcal pharyngitis, community-acquired pneumonia, urinary tract infection, and skin and soft tissue infections who received systemic antibiotics. We determined appropriate antibiotic choice, dose, and duration for each diagnosis. Pearson's χ² test compared appropriate prescribing before ASP implementation (July 2017-July 2018) and postimplementation (August 2018-December 2020). Control charts trended improvement over time. RESULTS: Our study included 35,917 encounters. The percentage of prescriptions with the recommend agent at the appropriate dose and duration increased from a mean of 32.7% to 52.4%. The center lines for appropriate agent, dose, and duration all underwent upward shifts. The most substantial changes were seen in antibiotic duration (63.2%-80.5%), and appropriate dose (64.6%-77%). CONCLUSIONS: Implementation of an outpatient ASP improved prescribing patterns for choosing the appropriate agent, duration, and dose for many common infections in our PUCs.