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Anastomotic stricture is the most common complication after esophageal atresia (EA) repair. We sought to determine if postoperative acid suppression is associated with reduced stricture formation.A prospective, multi-institutional cohort study of infants undergoing primary EA repair from 2016 to 2020 was performed. Landmark analysis and multivariate Cox regression were used to explore if initial duration of acid suppression was associated with stricture formation at hospital discharge (DC), 3-, 6-, and 9-months postoperatively.Of 156 patients, 79 (51%) developed strictures and 60 (76%) strictures occurred within three months following repair. Acid suppression was used in 141 patients (90%). Landmark analysis showed acid suppression was not associated with reduction in initial stricture formation at DC, 3-, 6- and 9-months, respectively (p = 0.19-0.95). Multivariate regression demonstrated use of a transanastomotic tube was significantly associated with stricture formation at DC (Hazard Ratio (HR) = 2.21 (95% CI 1.24-3.95, p0.01) and 3-months (HR 5.31, 95% CI 1.65-17.16, p0.01). There was no association between acid suppression duration and stricture formation.No association between the duration of postoperative acid suppression and anastomotic stricture was observed. Transanastomotic tube use increased the risk of anastomotic strictures at hospital discharge and 3 months after repair.

Clinical practice guidelines are a valuable resource aiding medical decision-making based on scientific evidence. In anaesthesia, guidelines are increasing in both number and scope, influencing individual practice and shaping local departmental policy. The aim of this review is to assess the quality of clinical practice guidelines published in high impact anaesthesia journals over the past 5 yr using the internationally validated Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. A literature search was conducted in Scopus to identify all guidelines published in the top 10 anaesthesia journals as per Clarivate Analytics Impact Factor from 2016 and 2020. Fifty-one guidelines were included for analysis by five independent appraisers using AGREE II. Each guideline was assessed across six domains and 23 items. Individual domain scores were calculated with a threshold agreed via consensus to represent high-quality guidelines. There was a significant increase in overall score over time (P=0.041), driven by Domain 3 (Rigour of Development, P=0.046). The raw overall score for Domain 3, however, was low. The other domains performed as expected based on previous studies, with Domains 1, 4, and 6 achieving high scores and Domains 2 and 5 incurring poor ratings. Most guidelines studied involved international collaboration but emerged from a single professional society. Use of an appraisal tool was stated as high but poorly detailed. The improvement in the overall score of guidelines and rigour of development is promising; however, only seven guidelines met high-quality criteria, suggesting room for improvement for the overall integrity of guidelines in anaesthesia.

Despite the popularity of feature importance (FI) measures in interpretable machine learning, the statistical adequacy of these methods is rarely discussed. From a statistical perspective, a major distinction is between analysing a variable’s importance before and after adjusting for covariates—i.e., between marginal and conditional measures. Our work draws attention to this rarely acknowledged, yet crucial distinction and showcases its implications. We find that few methods are available for testing conditional FI and practitioners have hitherto been severely restricted in method application due to mismatched data requirements. Most real-world data exhibits complex feature dependencies and incorporates both continuous and categorical features (i.e., mixed data). Both properties are oftentimes neglected by conditional FI measures. To fill this gap, we propose to combine the conditional predictive impact (CPI) framework with sequential knockoff sampling. The CPI enables conditional FI measurement that controls for any feature dependencies by sampling valid knockoffs—hence, generating synthetic data with similar statistical properties—for the data to be analysed. Sequential knockoffs were deliberately designed to handle mixed data and thus allow us to extend the CPI approach to such datasets. We demonstrate through numerous simulations and a real-world example that our proposed workflow controls type I error, achieves high power, and is in-line with results given by other conditional FI measures, whereas marginal FI metrics can result in misleading interpretations. Our findings highlight the necessity of developing statistically adequate, specialized methods for mixed data.

Diffuse intrinsic pontine glioma (DIPG) remains a fatal brainstem tumor demanding innovative therapies. As B7-H3 (CD276) is expressed on central nervous system (CNS) tumors, we designed B7-H3–specific chimeric antigen receptor (CAR) T cells, confirmed their preclinical efficacy, and opened BrainChild-03 (NCT04185038), a first-in-human phase I trial administering repeated locoregional B7-H3 CAR T cells to children with recurrent/refractory CNS tumors and DIPG. Here, we report the results of the first three evaluable patients with DIPG (including two who enrolled after progression), who received 40 infusions with no dose-limiting toxicities. One patient had sustained clinical and radiographic improvement through 12 months on study. Patients exhibited correlative evidence of local immune activation and persistent cerebrospinal fluid (CSF) B7-H3 CAR T cells. Targeted mass spectrometry of CSF biospecimens revealed modulation of B7-H3 and critical immune analytes (CD14, CD163, CSF-1, CXCL13, and VCAM-1). Our data suggest the feasibility of repeated intracranial B7-H3 CAR T-cell dosing and that intracranial delivery may induce local immune activation.Significance:This is the first report of repeatedly dosed intracranial B7-H3 CAR T cells for patients with DIPG and includes preliminary tolerability, the detection of CAR T cells in the CSF, CSF cytokine elevations supporting locoregional immune activation, and the feasibility of serial mass spectrometry from both serum and CSF.This article is highlighted in the In This Issue feature, p. 1

Supplementary Data from Intraventricular B7-H3 CAR T Cells for Diffuse Intrinsic Pontine Glioma: Preliminary First-in-Human Bioactivity and Safety

Purpose Function and anatomy of the visual system were evaluated in children with abusive head trauma (AHT). The relationships between retinal hemorrhages at presentation were examined with outcome measures. Methods Retrospective review of data in children with AHT for 1) visual acuity at last follow-up, 2) visual evoked potentials (VEP) after recovery, 3) diffusion metrics of white matter tracts and grey matter within the occipital lobe on diffusion tensor imaging (DTI), and 4) patterns of retinal hemorrhages at presentation. Visual acuity was converted into logarithm of minimum angle of resolution (logMAR) after correction for age. VEPs were also scored by objective signal-to-noise ratio (SNR). Results Of 202 AHT victims reviewed, 45 met inclusion criteria. Median logMAR was reduced to 0.8 (approximately 20/125 Snellen equivalent), with 27% having no measurable vision. Thirty-two percent of subjects had no detectable VEP signal. VEPs were significantly reduced in subjects initially presenting with traumatic retinoschisis or hemorrhages involving the macula (p p Discussion Mechanisms causing traumatic retinoschisis, or traumatic abnormalities of the macula, are associated with significant long-term visual pathway dysfunction. AHT associated abnormalities of the macula, and visual cortical pathways were more fully captured by VEPs than visual acuity or DTI metrics.

Hearing loss is one of the most common indications for temporal bone imaging in children. Hearing loss may be congenital or acquired, and it may be conductive, sensorineural, or mixed audiologically. Temporal bone imaging plays an important role in the assessment and management of this condition. An understanding of the embryology of ear structures better enables the radiologist to interpret abnormalities on imaging of the temporal bone. Here, we provide a general review of ear development and a description of known genetic defects that contribute to congenital ear anomalies associated with hearing loss. We provide appropriate imaging techniques for the temporal bone depending on the clinical presentation and a systematic approach to imaging for children with hearing loss. Diagnostic imaging for developmental anomalies of the ear and cholesteatoma will be discussed.

Food insecurity (FI) causes worse health and education outcomes for children. Screening for FI is feasible and acceptable during well-child visits. Standard protocols, upon positive screen, refer families to community resources, such as food pantries, but followthrough rates are low. Good Apple (GA) was developed to deliver fresh produce and pantry staples to the homes of families facing FI, as identified by pediatricians. Good Apple uses a two-sided, self-sustaining business model: a subscription-based produce delivery service generates revenue from paying customers, which funds free grocery delivery services for families facing FI. The program works with (1) local farmers to rescue and redistribute unsold fruits and vegetables; (2) local food pantries to supplement deliveries with proteins, grains, and dairy; and (3) pediatricians who prescribe GA to families facing FI. Good Apple helps food pantries reach more clients; empowers pediatricians with closed-loop referrals; and delivers healthy food to families facing FI and transportation barriers.

Peer reviewed: True, Insects are under pressure from agricultural intensification. To protect pollinators, conservation measures such as the EU agri-environment schemes (AES) promote planting wildflowers along fields. However, this can potentially alter disease ecology by serving as transmission hubs or by diluting infections. We tested this by measuring plant-pollinator interactions and virus infections (DWV-A, DWV-B and ABPV) across pollinator communities in agricultural landscapes over a year. AES had a direct effect on DWV-B, reducing prevalence and load in honeybees, with a tentative general dilution effect on load in early summer. DWV-A prevalence was reduced both under AES and with increasing niche overlap between competent hosts, likely via a dilution effect. By contrast, AES had no impact on ABPV, its prevalence driven by the proportion of bumblebees in the community. Epidemiological differences were also reflected in the virus phylogenies, with DWV-B showing recent rapid expansion, while DWV-A and ABPV showed slower growth rates and geographical population structure. Phylogenies indicate that all three viruses freely circulate across their host populations. Our study illustrates how complex interactions between environmental, ecological and evolutionary factors may influence wildlife disease dynamics. Supporting pollinator nutrition can mitigate the transmission of important bee diseases, providing an unexpected boost to pollinator conservation. This article is part of the theme issue 'Infectious disease ecology and evolution in a changing world'.

In 1999–2001, Guagua Pichincha volcano, Ecuador, produced a series of cyclic explosive and effusive eruptions. Rock samples, including dense blocks and pumiceous clasts collected during the eruption sequence, and ballistic bombs later collected from the crater floor, provide information about magma storage, ascent, decompression, degassing, repressurization, and regassing prior to eruption. Pairs of Fe-Ti oxides indicate equilibrium within 1.2–1.5 log units above the NNO oxidation buffer and equilibrium temperatures from 805 to 905 °C. Melt inclusions record H2O contents of 2.7–4.6 wt% and CO2 contents (uncorrected for CO2 segregation into bubbles) from 19 to 310 ppm. Minimum melt inclusion saturation pressures fall between 69 and 168 MPa, or equilibration depths of 2.8 and 6.8 km, the lower end of which is coincident with the maximum inferred equilibration depths for the most vesicular breadcrust bombs sampled. Amphibole phenocrysts lack breakdown rims (except for one sample) and plagioclase phenocrysts have abundant oscillatory compositional zones. Plagioclase areal microlite number densities (Na) range over less than one order of magnitude (8.9×103–8.7×104 mm-2) among all samples, with the exception of a dense, low crystallinity sample (Na = 3.0×103 mm−2) and a pumiceous sample erupted on 17 December 1999 (Na = 1.7×103 mm−2). Plagioclase microlite shapes include tabular, hopper, and swallowtail forms. Taken together, the relatively high plagioclase microlite number densities, the high number of oscillatory zones in plagioclase phenocrysts, the presence of CO2 in groundmass glass, seismicity, and time-varying tilt cycles provide a picture of sudden evacuation of magma residing at different levels in the shallow conduit. Explosive eruptions punctuate inter-eruptive repose periods marked by time-varying rates of degassing (volatile fluxing) and re-pressurization. Shallow residence time in the conduit was sufficient to allow precipitation of silica-phase in the groundmass, but insufficient to allow breakdown of hornblende phenocrysts, with the one exception of the final dome sample from 2000, which has the longest preceding repose time. These results support a model of cyclic pressure cycling, volatile exsolution and regassing, and magma decompression decoupled from ascent.

A longstanding goal of biomedicine is to understand how alterations in molecular and cellular networks give rise to the spectrum of human diseases. For diseases with shared etiology, understanding the common causes allows for improved diagnosis of each disease, development of new therapies and more comprehensive identification of disease genes. Accordingly, this protocol describes how to evaluate the extent to which two diseases, each characterized by a set of mapped genes, are colocalized in a reference gene interaction network. This procedure uses network propagation to measure the network “distance” between gene sets. For colocalized diseases, the network can be further analyzed to extract common gene communities at progressive granularities. In particular, we show how to: (i) obtain input gene sets and a reference gene interaction network, (ii) identify common subnetworks of genes that encompass or are in close proximity to all gene sets, (iii) use multiscale community detection to identify systems and pathways represented by each common subnetwork to generate a network colocalized systems map, (iv) validate identified genes and systems using a mouse variant database, and (v) visualize and further investigate select genes, interactions and systems for relevance to phenotype(s) of interest. We demonstrate the utility of this approach by identifying shared biological mechanisms underlying autism and congenital heart disease. However, this protocol is general and can be applied to any gene sets attributed to diseases or other phenotypes with suspected joint association. A typical NetColoc run takes less than an hour. Software and documentation are available at https://github.com/ucsd-ccbb/NetColoc.

Background: Circulating heat-inducible, heat-shock protein 72 [HSP72] responses to exercise-heat stress have been well studied as a potential biomarker of exertional heat illness susceptibility. However, little is known about the responses of other HSPs important to immune responses and pathophysiology. HSP27, -60, and -90 are fundamental HSPs important in cellular proteostasis and pathophysiology associated with immune dysregulation. Therefore, we aimed to characterize responses of HSP27, -60, and –90 during a race known to introduce extreme levels of exercise-heat stress that annually result in high incidences of exertional heat stroke. Methods: Thirty participants (45.3±11.7 yr, 175.6±8.9 cm, 74.9±13.5 kg, 19.7±3.6 % body fat) registered to run in the Falmouth Road Race (Falmouth, MA) were recruited. Gastrointestinal temperature (TGI) and blood plasma HSP27, -60, and -90 (by commercially available ELISA) were measured at pre- (PRE) and post-race (POST). Results: TGI, [HSP27], and [HSP90] increased at POST (pGI at POST (p>0.05). In conclusion, HSPs are important for constitutive cellular function and measurably increase circulation post-exercise-heat stress. Correlation between HSPs and pre- or post-event core temperature to determine utility as predictive biomarkers require further study.

A standardized imaging protocol for pediatric oncology patients is essential for accurate and efficient imaging, while simultaneously promoting collaborative understanding of pathologies and radiologic assessment of treatment response. The objective of this article is to provide standardized pediatric imaging guidelines and parameters for evaluation of tumors of the pediatric orbit, calvarium, skull base, and temporal bone. This article was drafted based on current scientific literature as well as consensus opinions of imaging experts in collaboration with the Children's Oncology Group Diagnostic Imaging Committee, Society of Pediatric Radiology Oncology Committee, and American Society of Pediatric Neuroradiology.