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Otitis media (OM) is a leading cause of childhood hearing loss. Variants in FUT2 , which encodes alpha-(1,2)-fucosyltransferase, were identified to increase susceptibility to OM, potentially through shifts in the middle ear (ME) or nasopharyngeal (NP) microbiotas as mediated by transcriptional changes. Greater knowledge of differences in relative abundance of otopathogens in carriers of pathogenic variants can help determine risk for OM in patients. In order to determine the downstream effects of FUT2 variation, we examined gene expression in relation to carriage of a common pathogenic FUT2 c.461G>A (p.Trp154*) variant using RNA-sequence data from saliva samples from 28 patients with OM. Differential gene expression was also examined in bulk mRNA and single-cell RNA-sequence data from wildtype mouse ME mucosa after inoculation with non-typeable Haemophilus influenzae (NTHi). In addition, microbiotas were profiled from ME and NP samples of 65 OM patients using 16S rRNA gene sequencing. In human carriers of the FUT2 variant, FN1, KMT2D, MUC16 and NBPF20 were downregulated while MTAP was upregulated. Post-infectious expression in the mouse ME recapitulated these transcriptional differences, with the exception of Fn1 upregulation after NTHi-inoculation. In the NP, Candidate Division TM7 was associated with wildtype genotype (FDR-adj- p =0.009). Overall, the FUT2 c.461G>A variant was associated with transcriptional changes in processes related to response to infection and with increased load of potential otopathogens in the ME and decreased commensals in the NP. These findings provide increased understanding of how FUT2 variants influence gene transcription and the mucosal microbiota, and thus contribute to the pathology of OM.

Otitis media (OM) is common in young children and can cause hearing loss and speech, language, and developmental delays. OM has high heritability; however, little is known about OM-related molecular and genetic processes. CDHR3 was previously identified as a locus for OM susceptibility, but to date, studies have focused on how the CDHR3 p.Cys529Tyr variant increases epithelial binding of rhinovirus-C and risk for lung or sinus pathology. In order to further delineate a role for CDHR3 in OM, we performed the following: exome sequencing using DNA samples from OM-affected individuals from 257 multi-ethnic families; Sanger sequencing, logistic regression and transmission disequilibrium tests for 407 US trios or probands with OM; 16S rRNA sequencing and analysis for middle ear and nasopharyngeal samples; and single-cell RNA sequencing and differential expression analyses for mouse middle ear. From exome sequence data, we identified a novel pathogenic CDHR3 splice variant that co-segregates with OM in US and Finnish families. Additionally, a frameshift and six missense rare or low-frequency variants were identified in Finnish probands. In US probands, the CDHR3 p.Cys529Tyr variant was associated with the absence of middle ear fluid at surgery and also with increased relative abundance of Lysobacter in the nasopharynx and Streptomyces in the middle ear. Consistent with published data on airway epithelial cells and our RNA-sequence data from human middle ear tissues, Cdhr3 expression is restricted to ciliated epithelial cells of the middle ear and is downregulated after acute OM. Overall, these findings suggest a critical role for CDHR3 in OM susceptibility.Key messages• Novel rare or low-frequency CDHR3 variants putatively confer risk for otitis media.• Pathogenic variant CDHR3 c.1653 + 3G > A was found in nine families with otitis media.• CDHR3 p.Cys529Tyr was associated with lack of effusion and bacterial otopathogens.• Cdhr3 expression was limited to ciliated epithelial cells in mouse middle ear.• Cdhr3 was downregulated 3 h after infection of mouse middle ear.

Bronchoscopy procedures should be tracked for safety, quality improvement, and federal regulations. The aim of this study was to develop and test a method for evaluating flexible bronchoscopy use and outcomes using the electronic medical record (EMR) system in current clinical use at a large children's hospital. We created a custom bronchoscopy procedure note for our EMR system (Epic Systems Corporation) to track demographics, bronchoscopist, coordinated procedures, and outcome. Unplanned outcomes in children were defined as a disposition (admission to the hospital or elevation of care) after flexible bronchoscopy that differed from the preoperative plan. Readmissions to the hospital and emergency visits within our hospital system were also tracked electronically. Unplanned outcomes and readmissions were evaluated by a bronchoscopy quality team. Over 2.5 years, we tracked 1,297 bronchoscopic procedures performed on 1,161 patients (60% male, 78% American Society of Anesthesiologists class 2 or 3, mean age 5.5 yr [range, 0.02-40 yr]). Overall, 27 unplanned outcomes occurred (2.1%). The risk of unplanned outcomes did not appear to be different between procedures performed by a trainee with faculty oversight and those performed by a faculty member alone. Patients with multiple same-day procedures were more likely to have unplanned outcomes (21 of 27 [78%], P = 0.004) than were patients who had flexible bronchoscopy alone. The relative risk (RR) of having an unplanned outcome was not different from flexible bronchoscopy alone in the subset of patients with multiple procedures coordinated through our multidisciplinary aerodigestive clinic (RR 0.7; 95% CI, 0.1-3.4). The risk of unplanned events was significantly elevated in children with coordinated procedures scheduled outside the aerodigestive group (RR, 5.8; 95% CI, 2.4-14.5). Ten patients (<1%) were readmitted or seen urgently within 1 week; three of these unplanned outcomes were attributed to complications of the bronchoscopy. An EMR system may be used to track procedural outcomes. Unplanned outcomes after flexible bronchoscopy were infrequent at our institution. Children who underwent multiple procedures had unplanned outcomes more often; however, the subset of children who underwent coordinated procedures through our multidisciplinary aerodigestive clinic did not demonstrate this increased risk.

Purpose Patients with pediatric congenital heart disease (CHD) have high rates of concomitant airway obstruction most commonly manifesting as tracheobronchomalacia. These patients airways can be difficult to manage and have traditionally been managed by positive pressure and tracheostomy. Options for management have evolved with airway stenting and splinting providing viable treatment options in this population. Recent Findings The field of airway stenting has evolved with time, moving from non-bioabsorbable stents, metal, and silicone to bioabsorbable stents. These bioabsorbable stents have moved into the pediatric population and have offered the ability to treat tracheobronchomalacia in CHD with the goal to get to definitive treatment often. Beyond stenting, a role for external airway reinforcement has been developed with recent advances in bioabsorbable splints. Three-dimensional (3D) printing has played a crucial role in the success of the external airway splints. Summary Evolution in the fields of endoluminal stenting and external airway splinting has improved the treatment of airway obstruction associated with CHD. Advances in materials and 3D printing have allowed for greater success with reduced complications.

Otitis media (OM), a very common disease in young children, can result in hearing loss. In order to potentially replicate previously reported associations between OM and PLG, exome and Sanger sequencing, RNA-sequencing of saliva and middle ear samples, 16S rRNA sequencing, molecular modeling, and statistical analyses including transmission disequilibrium tests (TDT) were performed in a multi-ethnic cohort of 718 families and simplex cases with OM. We identified four rare PLG variants c.112A > G (p.Lys38Glu), c.782G > A (p.Arg261His), c.1481C > T (p.Ala494Val) and c.2045 T > A (p.Ile682Asn), and one common variant c.1414G > A (p.Asp472Asn). However TDT analyses for these PLG variants did not demonstrate association with OM in 314 families. Additionally PLG expression is very low or absent in normal or diseased middle ear in mouse and human, and salivary expression and microbial α-diversity were non-significant in c.1414G > A (p.Asp472Asn) carriers. Based on molecular modeling, the novel rare variants particularly c.782G > A (p.Arg261His) and c.2045 T > A (p.Ile682Asn) were predicted to affect protein structure. Exploration of other potential disease mechanisms will help elucidate how PLG contributes to OM susceptibility in humans. Our results underline the importance of following up findings from genome-wide association through replication studies, preferably using multi-omic datasets.

We present a case report of a 28-year-old primigravida with a singleton pregnancy complicated by a fetal bronchogenic cyst compressing the left mainstem bronchus with resultant hyperinflation of the entire left lung and rightward mediastinal shift. An ex utero intrapartum treatment to resection of the fetal bronchogenic cyst via a fetal thoracotomy was performed at 36 weeks' gestational age, circumventing a potentially complicated neonatal airway emergency at birth.

Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three DNA methylation groups with distinct clinical outcomes, biological drivers and therapeutic vulnerabilities. Merlin-intact meningiomas (34%) have the best outcomes and are distinguished by NF2 /Merlin regulation of susceptibility to cytotoxic therapy. Immune-enriched meningiomas (38%) have intermediate outcomes and are distinguished by immune infiltration, HLA expression and lymphatic vessels. Hypermitotic meningiomas (28%) have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. To translate these findings into clinical practice, we show cytostatic cell cycle inhibitors attenuate meningioma growth in cell culture, organoids, xenografts and patients. DNA methylation profiling of 565 meningiomas highlights three groups associated with distinct molecular, clinical and therapeutic features.

Glioblastoma (GBM) displays marked cellular and metabolic heterogeneity that varies among cellular microenvironments within a tumor. Metabolic targeting has long been advocated as a therapy against many tumors including GBM, but how lipid metabolism is altered to suit different microenvironmental conditions and whether cancer stem cells (CSCs) have altered lipid metabolism are outstanding questions in the field. We interrogated gene expression in separate microenvironments of GBM organoid models that mimic the transition between nutrient-rich and nutrient-poor pseudopalisading/perinecrotic tumor zones using spatial-capture RNA-sequencing. We revealed a striking difference in lipid processing gene expression and total lipid content between diverse cell populations from the same patient, with lipid enrichment in hypoxic organoid cores and also in perinecrotic and pseudopalisading regions of primary patient tumors. This was accompanied by regionally restricted upregulation of hypoxia-inducible lipid droplet-associated (HILPDA) gene expression in organoid cores and pseudopalisading regions of clinical GBM specimens, but not lower-grade brain tumors. CSCs have low lipid droplet accumulation compared to non-CSCs in organoid models and xenograft tumors, and prospectively sorted lipid-low GBM cells are functionally enriched for stem cell activity. Targeted lipidomic analysis of multiple patient-derived models revealed a significant shift in lipid metabolism between GBM CSCs and non-CSCs, suggesting that lipid levels may not be simply a product of the microenvironment but also may be a reflection of cellular state. CSCs had decreased levels of major classes of neutral lipids compared to non-CSCs, but had significantly increased polyunsaturated fatty acid production due to high fatty acid desaturase (FADS1/2) expression which was essential to maintain CSC viability and self-renewal. Our data demonstrate spatially and hierarchically distinct lipid metabolism phenotypes occur clinically in the majority of patients, can be recapitulated in laboratory models, and may represent therapeutic targets for GBM.

Nuclear matrix‐associated proteins (NMPs) play critical roles in regulating chromatin organization and gene transcription by binding to the matrix attachment regions (MARs) of DNA. However, the functional significance of NMPs in glioblastoma (GBM) progression remains unclear. Here, we show that the Special AT‐rich Binding Protein‐2 (SATB2), one of crucial NMPs, recruits histone acetyltransferase CBP to promote the FOXM1‐mediated cell proliferation and tumor growth of GBM. SATB2 is preferentially expressed by glioma stem cells (GSCs) in GBM. Disrupting SATB2 markedly inhibited GSC proliferation and GBM malignant growth by down‐regulating expression of key genes involved in cell proliferation program. SATB2 activates FOXM1 expression to promote GSC proliferation through binding to the MAR sequence of FOXM1 gene locus and recruiting CBP to the MAR. Importantly, pharmacological inhibition of SATB2/CBP transcriptional activity by the CBP inhibitor C646 suppressed GSC proliferation in vitro and GBM growth in vivo . Our study uncovers a crucial role of the SATB2/CBP‐mediated transcriptional regulation in GBM growth, indicating that targeting SATB2/CBP may effectively improve GBM treatment. SYNOPSIS Aberrant expression of nuclear matrix‐associated proteins (NMPs) has been shown to associate with tumor growth in various human cancers. This study shows that SATB2, a key NMP, and its coactivator CBP critically contribute to glioblastoma (GBM) growth, suggesting SATB2/CBP is a therapeutic target. SATB2 and CBP are preferentially expressed by glioma stem cells (GSCs) in GBMs. SATB2 recruits CBP to activate FOXM1 transcription, promoting GSC proliferation and GBM tumor growth. Inhibition of SATB2/CBP transcriptional activity by the CBP inhibitor C646 suppressed GBM growth. Graphical Abstract Aberrant expression of nuclear matrix‐associated proteins (NMPs) has been shown to associate with tumor growth in various human cancers. This study shows that SATB2, a key NMP, and its coactivator CBP critically contribute to glioblastoma (GBM) growth, suggesting SATB2/CBP is a therapeutic target.