Department of Pediatrics - Open Access Policy Deposits

Gut microbiota and derived metabolites mediate obstructive sleep apnea induced atherosclerosis.

(2025)

Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia/hypercapnia (IHC), affects predominantly obese individuals, and increases atherosclerosis risk. Since we and others have implicated gut microbiota and metabolites in atherogenesis, we dissected their contributions to OSA-induced atherosclerosis. Atherosclerotic lesions were compared between conventionally-reared specific pathogen free (SPF) and germ-free (GF) Apoe-/- mice following a high fat high cholesterol diet (HFHC), with and without IHC conditions. The fecal microbiota and metabolome were profiled using 16S rRNA gene amplicon sequencing and untargeted tandem mass spectrometry (LC-MS/MS) respectively. Phenotypic data showed that HFHC significantly increased atherosclerosis as compared to regular chow (RC) in both aorta and pulmonary artery (PA) of SPF mice. IHC exacerbated lesions in addition to HFHC. Differential abundance analysis of gut microbiota identified an enrichment of Akkermansiaceae and a depletion of Muribaculaceae (formerly S24-7) family members in the HFHC-IHC group. LC-MS/MS showed a dysregulation of bile acid profiles with taurocholic acid, taurodeoxycholic acid, and 12-ketodeoxycholic acid enriched in the HFHC-IHC group, long-chain N-acyl amides, and phosphatidylcholines. Interestingly, GF Apoe-/- mice markedly reduced atherosclerotic formation relative to SPF Apoe-/- mice in the aorta under HFHC/IHC conditions. In contrast, microbial colonization did not show a significant impact on the atherosclerotic progression in PA. In summary, this research demonstrated that (1) IHC acts cooperatively with HFHC to induce atherosclerosis; (2) gut microbiota modulate atherogenesis, induced by HFHC/IHC, in the aorta not in PA; (3) different analytical methods suggest that a specific imbalance between Akkermansiaceae and Muribaculaceae bacterial families mediate OSA-induced atherosclerosis; and (4) derived bile acids, such as deoxycholic acid and lithocholic acid, regulate atherosclerosis in OSA. The knowledge obtained provides novel insights into the potential therapeutic approaches to prevent and treat OSA-induced atherosclerosis.

Cellular heterogeneity and patterning strategies as revealed by upper respiratory epithelium single cell atlas

(2025)

Colistin exerts potent activity against mcr+ Enterobacteriaceae via synergistic interactions with the host defense

(2025)

Colistin (COL) is a cationic cyclic peptide that disrupts the membranes of Gram-negative bacteria and is often used as a last resort antibiotic against multidrug-resistant strains. The emergence of plasmid-borne mcr genes, which confer transferable COL resistance, has raised serious concerns, particularly in strains also carrying extended-spectrum β-lactamase and carbapenemase genes. Standard antimicrobial susceptibility testing (AST), performed in enriched bacteriological media, indicates no activity of COL against mcr+ strains, leading to its exclusion from treatment regimens. However, these media poorly reflect in vivo physiology and lack host immune components. Here we show that COL retained bactericidal activity against mcr-1+ Escherichia coli, Klebsiella pneumoniae, and Salmonella enterica when tested in tissue culture medium containing physiological bicarbonate. COL enhanced serum complement deposition on bacterial surfaces and synergized with human serum to kill pathogens. At clinically achievable concentrations, COL killed mcr-1+ strains in freshly isolated human blood and was effective as monotherapy in a murine E. coli bacteremia model. These findings suggest that COL, currently dismissed based on conventional AST, may offer clinical benefit against mcr-1+ infections when evaluated under more physiological conditions - warranting reconsideration in clinical microbiology practices and future trials for high-risk patients.

Acceptance and Implementation of Evidence-Based Practices in Delivery Room Resuscitation: A Qualitative Study

(2025)

Phylogeographic and genetic network assessment of COVID-19 mitigation protocols on SARS-CoV-2 transmission in university campus residences

(2025)

Background

Congregate living provides an ideal setting for SARS-CoV-2 transmission in which many outbreaks and superspreading events occurred. To avoid large outbreaks, universities turned to remote operations during the initial COVID-19 pandemic waves in 2020 and 2021. In late-2021, the University of California San Diego (UC San Diego) facilitated the return of students to campus with comprehensive testing, vaccination, masking, wastewater surveillance, and isolation policies.

Methods

We performed molecular epidemiological and phylogeographic analysis of 4418 SARS-CoV-2 genomes sampled from UC San Diego students during the Omicron waves between December 2021 and September 2022, representing 58% of students with confirmed SARS-CoV-2 infection. We overlaid these analyses across on-campus residential information to assess the spread and persistence of SARS-CoV-2 within university residences.

Findings

Within campus residences, SARS-CoV-2 transmission was frequent among students residing in the same room or suite. However, a quarter of pairs of suitemates with concurrent infections had distantly related viruses, suggesting separate sources of infection during periods of high incidence in the surrounding community. Students with concurrent infections residing in the same building were not at substantial increased probability of being members of the same transmission cluster. Genetic network and phylogeographic inference indicated that only between 3.1 and 12.4% of infections among students could be associated with transmission within buildings outside of individual suites. The only super-spreading event we detected was related to a large event outside campus residences.

Interpretation

We found little evidence for sustained SARS-CoV-2 transmission within individual buildings, aside from students who resided in the same suite. Even in the face of heightened community transmission during the 2021-2022 Omicron waves, congregate living did not result in a heightened risk for SARS-CoV-2 transmission in the context of the multi-pronged mitigation strategy.

Funding

SEARCH Alliance: Centers for Disease Control and Prevention (CDC) BAA (75D301-22-R-72097) and the Google Cloud Platform Research Credits Program. J.O.W.: NIH-NIAID (R01 AI135992). T.I.V.: Branco Weiss Fellowship and Newkirk Fellowship. L.L.: University of California San Diego.

Identifying wastewater chemicals in coastal aerosols

(2025)

The Tijuana River, at the US-Mexico border, discharges millions of gallons of wastewater daily-sewage, industrial waste, and runoff-into the Pacific Ocean, making it the dominant source of coastal pollution in this region. This study examines how such wastewater influences coastal aerosols by tracking spatial gradients from near the border northward. Using benzoylecgonine (a nonvolatile cocaine metabolite) as a sewage tracer, we find that wastewater compounds-including a mixture of illicit drugs, drug metabolites, and chemicals from tires and personal care products-become aerosolized and are detectable in both water and air. Spatial analyses confirm that most measured chemicals concentrate in aerosols near the Tijuana River, potentially exposing local populations to tens of nanograms per hour (e.g., octinoxate and methamphetamine) via inhalation. This airborne pathway highlights a largely overlooked source of atmospheric pollution, emphasizing the need to reassess health risks in coastal regions as global water contamination continues to escalate.

Addressing population-level cancer data needs in northwestern Mexico: results from a South–South Colombian–Mexican partnership

(2025)

"South-South" partnerships forged between institutions in resource-constrained settings, usually in low- and middle-income countries, provide innovative frameworks for resource, knowledge, and expertise exchanges to address public health challenges in regions sharing similar contexts. Population-based cancer registries (PBCRs) and surveillance systems in low- and middle-income countries are essential for cancer control, yet they are scarce. In response, the authors formed a South-South Colombian-Mexican partnership to implement the first PBCR in Tijuana, northwestern Mexico, and an integrated pediatric cancer real-time clinical outcomes monitoring system, replicated from Colombia's successful model, VIGICANCER. The newly established team assessed local needs in Mexico, adapted VIGICANCER protocols to the local context, and conducted training. In 2017, BajaREG was inaugurated in Tijuana, and, in 2018, joined the newly launched Mexican National Cancer Registry Network. In 2020, the Pediatric and Adolescent Cancer Registry Surveillance System (PACARSS) was integrated into BajaREG. Between 2018 and 2024, BajaREG registered 8 231 adult and 268 pediatric cases. PACARSS currently collects population-level data on pediatric cancer clinical outcomes in Tijuana. Despite multiple challenges, including the COVID-19 pandemic, stakeholder engagement enabled success. The authors showcase how locally tailored South-South partnerships can capitalize on collaborations and facilitate the implementation of sustainable PBCRs and surveillance systems in regions sharing similar challenges, resources, and health care systems.

Severe hepatitis in pediatric patients: The Severe Hepatitis In Pediatric Patients (SHIPP) registry

(2025)

Objectives

Clusters of severe acute hepatitis in children were reported worldwide beginning in October 2021. Although most children recovered, some progressed to liver failure leading to death or liver transplantation. Herein, we characterize the clinical characteristics, and outcomes of this group of children through an international collaborative effort.

Methods

Participation was solicited via a global listserv to pediatric gastroenterologists worldwide. Patients <18 years, alanine aminotransferase >500 U/L, without chronic liver disease or acetaminophen ingestion were eligible. Data were submitted by individual sites into a Research Electronic Data Capture registry created in July 2022.

Results

Two hundred and seven cases were collected, with a peak incidence of 28 in April 2022. The median age was 40 months, 52.7% were male, 63.3% were white, and 44% were Hispanic. At presentation, 80% reported gastrointestinal symptoms followed by fever (27.7%). The median duration of hospitalization was 5.5 days with 51 patients requiring intensive care. Adenovirus serum/whole blood DNA was detected in 28/133 (21%) and seven patients were treated with cidofovir. Liver biopsies, performed in 76 patients revealed portal and lobular inflammation with none identifying a viral etiology. Eleven patients underwent liver transplantation, four were adenovirus positive, all of whom survived. There were four reported deaths.

Conclusions

In this large data set of pediatric patients with severe acute hepatitis, the majority did not have a singular definitive etiology but did recover spontaneously. Continued community surveillance and close cooperation are critical toward understanding the etiology of such clusters in pediatrics.

Parenting Training Plus Behavioral Treatment for Children With Obesity

(2025)

Importance

Family-based behavioral treatment (FBT) is recommended for childhood obesity treatment; however, it is not effective for all families. Since parenting training (PT) has been associated with healthy weight and eating behaviors, intensive PT may augment delivery of behavior change strategies and improve child weight loss outcomes.

Objective

To compare the efficacy of child overweight or obesity treatment that adds intensive PT to standard FBT with the efficacy of FBT alone.

Design, setting, and participants

This 2-arm randomized clinical trial (Reinforced, Enhanced, Families, Responsibility, Education, Support, and Health [ReFRESH]) conducted from April 2017 to November 2022 at an academic center in San Diego, California, included children aged 7 to 12 years with overweight or obesity (body mass index [BMI]≥85th to <99.9th percentile) and one of their parents.

Interventions

Parent-child dyads were randomized 1:1 to the intervention group, which received FBT plus PT, or the control group, which received FBT alone. Both groups received twenty 60-minute sessions over 6 months with separate parent and child groups led by staff and nine 20-minute behavior change coaching sessions. The FBT plus PT group sessions incorporated additional intensive parenting skills training in an interactive format.

Main outcomes and measures

The primary outcome was change from baseline in child BMI z score and BMI as a percentage of the 95th BMI percentile (BMIp95) after treatment (month 6) and at 6- and 12-month follow-up. Secondary outcomes included the proportion of children who attained clinically meaningful weight loss (ie, reduction of ≥0.20 BMI z score units) and intervention dropout rates. Intention-to-treat analysis was conducted using linear mixed models and logistic regression.

Results

A total of 140 parent-child dyads were included, with 70 in each treatment arm. Mean (SD) child age was 9.91 (1.54) years, and baseline BMI z score was 2.28 (0.80); 71 children (50.7%) were female. There were no significant between-group differences in BMI z score or BMIp95 after treatment or at the follow-up time points. Both groups had significant decreases in weight status after treatment (combined BMI z score: β, -0.14 [95% CI, -0.21 to -0.07]; P < .001; combined BMIp95: β, -3.46 [95% CI, -5.41 to -1.51]; P < .001). More children in the FBT plus PT arm compared with the FBT arm had a reduction of at least 0.20 BMI z score units (34 [48.6%] vs 22 [31.4%]; P = .01) after treatment (adjusted odds ratio, 2.10 [95% CI, 1.01-4.47]). Both treatments were well accepted, with no between-group differences in risk of dropout (hazard ratio, 1.01 [95% CI, 0.72-1.43]).

Conclusions and relevance

In this randomized clinical trial examining the effect of parenting training on child weight status, there were no significant differences in weight status between groups; children in both groups had a significant reduction in weight status. However, more children had clinically meaningful weight loss in the FBT plus PT group. Further work is needed to determine factors associated with treatment response and changes in parenting skills.

Trial registration

ClinicalTrials.gov Identifier: NCT02976636.

Model of metabolism and gene expression predicts proteome allocation in Pseudomonas putida

(2025)

The genome-scale model of metabolism and gene expression (ME-model) for Pseudomonas putida KT2440, iPpu1676-ME, provides a comprehensive representation of biosynthetic costs and proteome allocation. Compared to a metabolic-only model, iPpu1676-ME significantly expands on gene expression, macromolecular assembly, and cofactor utilization, enabling accurate growth predictions without additional constraints. Multi-omics analysis using RNA sequencing and ribosomal profiling data revealed translational prioritization in P. putida, with core pathways, such as nicotinamide biosynthesis and queuosine metabolism, exhibiting higher translational efficiency, while secondary pathways displayed lower priority. Notably, the ME-model significantly outperformed the M-model in alignment with multi-omics data, thereby validating its predictive capacity. Thus, iPpu1676-ME offers valuable insights into P. putida's proteome allocation and presents a powerful tool for understanding resource allocation in this industrially relevant microorganism.

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