Brick kiln pollution and its impact on health: A systematic review and meta-analysis.

Brick kiln emissions adversely affect air pollution and the health of workers and individuals living near the kilns; however, evidence of their impacts remains limited. We conducted a systematic review of brick kiln pollution (emissions, source contributions and personal exposures) and its effects on health. We extracted articles from electronic databases and through manual citation searching. We estimated pooled, sample-size-weighted means and standard deviations for personal exposures by job type; computed mean emission factors and pollutant concentrations by brick kiln design; and meta-analyzed differences in means or proportions for health outcomes between brick kiln workers and controls or for participants living near or far away from kilns. We identified 104 studies; 74 were conducted in South Asia. The most evaluated pollutants were particulate matter (PM; n=48), sulfur dioxide (SO2; n=24) and carbon monoxide (CO; n=22), and the most evaluated health outcomes were respiratory health (n=34) and musculoskeletal disorders (n=9). PM and CO emissions were higher among traditional than improved brick kilns. Mean respirable silica exposures were only measured in 4 (4%) studies and were as high as 620 µg/m3, exceeding the NIOSH recommended exposure limit by a factor of over 12. Brick kiln workers had consistently worse lung function, more respiratory symptoms, more musculoskeletal complaints, and more inflammation when compared to unexposed participants across studies; however, most studies had a small sample size and did not fully describe methods used for sampling or data collection. On average, brick kiln workers had worse health outcomes when compared to unexposed controls but study quality supporting the evidence was low. Few studies reported silica concentrations or personal exposures, but the few that did suggest that exposures are high. Further research is needed to better understand the relationship between brick kiln pollution and health among workers, and to evaluate exposure mitigation strategies.

Nasal and pharyngeal mucosal immunity to poliovirus in children following routine immunization with inactivated polio vaccine (IPV) in the United States of America.

BACKGROUND: Although polioviruses (PVs) replicate in lymphoid tissue of both the pharynx and ileum, research on polio vaccine-induced mucosal immunity has predominantly focused on intestinal neutralizing and binding antibody levels measured in stool. METHODS: To investigate the extent to which routine immunization with intramuscularly injected inactivated polio vaccine (IPV) may induce nasal and pharyngeal mucosal immunity, we measured PV type-specific neutralization and immunoglobulin (Ig) G, IgA, and IgM levels in nasal secretions, adenoid cell supernatants, and sera collected from 12 children, aged 2 to 5 years, undergoing planned adenoidectomies. All participants were routinely immunized with IPV and had no known contact with live PVs. RESULTS: PV-specific mucosal neutralization was detected in nasal and adenoid samples, mostly from children who had previously received four IPV doses. Across the three PV serotypes, both nasal (Spearman's rho ≥ 0.87, p≤0.0003 for all) and adenoid (Spearman's rho ≥0.57, p≤0.05 for all) neutralization titers correlated with serum neutralization titers. In this small study sample, there was insufficient evidence to determine which Ig isotype(s) was correlated with neutralization. CONCLUSIONS: Our findings provide policy-relevant evidence that routine immunization with IPV may induce nasal and pharyngeal mucosal immunity. The observed correlations of nasal and pharyngeal mucosal neutralization with serum neutralization contrast with previous observations of distinct intestinal and serum responses to PV vaccines. Further research is warranted to determine which antibody isotype(s) correlate with polio vaccine-induced nasal and pharyngeal mucosal neutralizing activity and to understand the differences from intestinal mucosal immunity.

Current surgical approaches to pediatric renal tumors.

Pediatric renal tumors are among the most common pediatric solid malignancies. Surgical resection is a key component in the multidisciplinary therapy for children with kidney tumors. Therefore, it is imperative that surgeons caring for children with renal tumors fully understand the current standards of care in order to provide appropriate surgical expertise within this multimodal framework. Fortunately, the last 60 years of international, multidisciplinary pediatric cancer cooperative group studies have enabled high rates of cure for these patients. This review will highlight the international surgical approaches to pediatric patients with kidney cancer to help surgeons understand the key differences and similarities between the European (International Society of Pediatric Oncology) and North American (Children's Oncology Group) recommendations.

Assessing the Quality of Cotranscriptional Folding Simulations.

Structural changes in RNAs are an important contributor to controlling gene expression not only at the posttranscriptional stage but also during transcription. A subclass of riboswitches and RNA thermometers located in the 5' region of the primary transcript regulates the downstream functional unit - usually an ORF - through premature termination of transcription. Not only such elements occur naturally, but they are also attractive devices in synthetic biology. The possibility to design such riboswitches or RNA thermometers is thus of considerable practical interest. Since these functional RNA elements act already during transcription, it is important to model and understand the dynamics of folding and, in particular, the formation of intermediate structures concurrently with transcription. Cotranscriptional folding simulations are therefore an important step to verify the functionality of design constructs before conducting expensive and labor-intensive wet lab experiments. For RNAs, full-fledged molecular dynamics simulations are far beyond practical reach because of both the size of the molecules and the timescales of interest. Even at the simplified level of secondary structures, further approximations are necessary. The BarMap approach is based on representing the secondary structure landscape for each individual transcription step by a coarse-grained representation that only retains a small set of low-energy local minima and the energy barriers between them. The folding dynamics between two transcriptional elongation steps is modeled as a Markov process on this representation. Maps between pairs of consecutive coarse-grained landscapes make it possible to follow the folding process as it changes in response to transcription elongation. In its original implementation, the BarMap software provides a general framework to investigate RNA folding dynamics on temporally changing landscapes. It is, however, difficult to use in particular for specific scenarios such as cotranscriptional folding. To overcome this limitation, we developed the user-friendly BarMap-QA pipeline described in detail in this contribution. It is illustrated here by an elaborate example that emphasizes the careful monitoring of several quality measures. Using an iterative workflow, a reliable and complete kinetics simulation of a synthetic, transcription-regulating riboswitch is obtained using minimal computational resources. All programs and scripts used in this contribution are free software and available for download as a source distribution for Linux® or as a platform-independent Docker® image including support for Apple macOS® and Microsoft Windows®.

Elective Pelvic Lymph Node Radiation Therapy and the Risk of Death in Patients With Unfavorable-Risk Prostate Cancer: A Postrandomization Analysis.

PURPOSE: Although a contemporary randomized clinical trial has led to the use of whole-pelvic radiation therapy (WPRT), long-term data evaluating a potential reduction in mortality are lacking and are addressed in the current study. MATERIALS AND METHODS: From 2005 to 2015, 350 men with localized, unfavorable-risk prostate cancer (PC) were randomly assigned to receive androgen deprivation therapy (ADT) and RT plus docetaxel versus ADT and RT. Treatment of the pelvic lymph nodes was at the discretion of the treating physician. Multivariable Cox and Fine and Grays regression analyses were performed to assess whether a significant association existed between radiation treatment volume and all-cause mortality (ACM) and PC-specific mortality (PCSM), respectively, adjusting for known PC prognostic factors and comorbidity. An interaction term between age (categorized by dichotomization at 65 years to enable clinical interpretation and applicability of the results and which approximates the median (66 years [IQR, 61-70]) and radiation treatment volume was included in the analysis. RESULTS: After a median follow-up of 10.20 years (IQR, 7.96-11.41), 89 men died (25.43%); of these, 42 died of PC (47.19%). Of the 350 randomly assigned patients, 88 (25.14%) received WPRT. In men younger than 65 years, WPRT was associated with a significantly lower ACM risk (adjusted hazard ratio [AHR], 0.33 [95% CI, 0.11 to 0.97]; P = .04) and lower PCSM risk (AHR, 0.17 [95% CI, 0.02 to 1.35]; P = .09) after adjusting for covariates, whereas this was not the case for men 65 years or older. CONCLUSION: WPRT has the potential to reduce mortality in younger men with unfavorable-risk PC.

The AMPK activator ATX-304 alters cellular metabolism to protect against cisplatin-induced acute kidney injury.

Acute kidney injury (AKI) disrupts energy metabolism. Targeting metabolism through AMP-activated protein kinase (AMPK) may alleviate AKI. ATX-304, a pan-AMPK activator, was evaluated in C57Bl/6 mice and tubular epithelial cell (TEC) cultures. Mice received ATX-304 (1 mg/g) or control chow for 7 days before cisplatin-induced AKI (CI-AKI). Primary cultures of tubular epithelial cells (TECs) were pre-treated with ATX-304 (20 µM, 4 h) prior to exposure to cisplatin (20 µM, 23 h). ATX-304 increased acetyl-CoA carboxylase phosphorylation, indicating AMPK activation. It protected against CI-AKI measured by serum creatinine (control 0.05 + 0.03 mM vs ATX-304 0.02 + 0.01 mM, P = 0.03), western blot for neutrophil gelatinase-associated lipocalin (NGAL) (control 3.3 + 1.8-fold vs ATX-304 1.2 + 0.55-fold, P = 0.002), and histological injury (control 3.5 + 0.59 vs ATX-304 2.7 + 0.74, P = 0.03). In TECs, pre-treatment with ATX-304 protected against cisplatin-mediated injury, as measured by lactate dehydrogenase release, MTS cell viability, and cleaved caspase 3 expression. ATX-304 protection against cisplatin was lost in AMPK-null murine embryonic fibroblasts. Metabolomic analysis in TECs revealed that ATX-304 (20 µM, 4 h) altered 66/126 metabolites, including fatty acids, tricarboxylic acid cycle metabolites, and amino acids. Metabolic studies of live cells using the XFe96 Seahorse analyzer revealed that ATX-304 increased the basal TEC oxygen consumption rate by 38%, whereas maximal respiration was unchanged. Thus, ATX-304 protects against cisplatin-mediated kidney injury via AMPK-dependent metabolic reprogramming, revealing a promising therapeutic strategy for AKI.

Embracing the hidden potential: The contribution of majority world research to developmental science.

Research on adolescence from the Majority World possesses major hidden potential in contributing to global adolescent research and developmental science more broadly. In this commentary, the authors (1) describe the background and the process through which this special issue came into fruition, (2) introduce the emic approaches to study the influences of macro-contextual variations on developmental science and provide several pertinent examples on the contributions of Majority World research, (3) elaborate on challenges and barriers that Majority World scholars often face in conducting and disseminating their research, and (4) a few actionable steps and recommendations in promoting the representation and inclusion of Majority World research into global developmental science. Only when our field fully integrates findings from all regions of the world will we be able to develop a fundamental scientific representation and understanding of what it means to be an adolescent, how adolescents develop over time, and what tasks or phenomena in adolescent development are truly universal or specific to particular groups, regions, or areas.

Family Medicine Clinician Screening and Barriers to Communication on Food Insecurity: A CERA General Membership Survey.

PURPOSE: Food insecurity (FI) is a hidden epidemic associated with worsening health outcomes affecting 33.8 million people in the US in 2021. Although studies demonstrate the importance of health care clinician assessment of a patient's food insecurity, little is known about whether Family Medicine clinicians (FMC) discuss FI with patients and what barriers influence their ability to communicate about FI. This study evaluated FM clinicians' food insecurity screening practices to evaluate screening disparities and identify barriers that influence the decision to communicate about FI. METHODS: Data were gathered and analyzed as part of the 2022 Council of Academic Family Medicine's Educational Research Alliance survey of Family Medicine general membership. RESULTS: The majority of respondents reported (66.9%) that their practice has a screening system for food insecurity, and most practices used a verbal screen with staff other than the clinician (41%) at specific visits (63.8%). Clinicians reported "rarely or never asking about FI" 40% of the time and only asking "always or frequently" 6.7% of the time. Inadequate time during appointments (44.5%) and other medical issues taking priority (29.4%) were identified as the most common barriers. The lack of resources available in the community was a significant barrier for clinicians who worked in rural areas. CONCLUSIONS: This survey provides insight into food insecurity screening disparities and identifies obstacles to FMC screening, such as time constraints, lack of resources, and knowledge of available resources. Understanding current communication practices could create opportunities for interventions to identify food insecurity and impact "Food as Medicine."

The case of young people who use e-cigarettes infrequently: Who is this population? What becomes of them?

BACKGROUND: Emerging data indicate that many adolescents and young adults ("youth") engage in infrequent, or occasional, e-cigarette use. However, little is known about this population as they are often subsumed into the broader "any past-30-day use" category used to define youth "current use." This study aimed to focus on infrequent e-cigarette use by youth, examining its correlates and transitional outcomes. METHODS: Participants were from a prospective cohort study of youth (aged 15-24 at baseline). Among youth who had used e-cigarettes, we classified "infrequent use" as using e-cigarettes ≤5 days in the last 30 days (n=273) and "frequent use" as using e-cigarettes ≥6 days in the last 30 days (n=278). Descriptive statistics, Markov modeling, and logistic regression were utilized. RESULTS: By the 12-month follow-up, 76.8% of those using infrequently at baseline remained in the "infrequent use" category, 6.3% reported no recent use, and 16.8% had escalated to the "frequent use" category. Among the youth using infrequently at baseline, those who did (vs. did not) escalate to frequent use by follow-up had higher baseline nicotine dependence and were more likely to have family members who used tobacco. CONCLUSIONS: Infrequent e-cigarette use is extremely common, and often fairly stable, among young people. Prevention efforts must certainly attempt to reduce escalation and attend to both individual and interpersonal factors (e.g., nicotine dependence, family use). Yet prevention efforts must additionally attend to the case of continued infrequent use, given the high prevalence of people in this category and their regular exposure to e-cigarette harms.

Mapping the interaction sites of human and avian influenza A viruses and complement factor H.

The complement system is an innate immune mechanism against microbial infections. It involves a cascade of effector molecules that is activated via classical, lectin and alternative pathways. Consequently, many pathogens bind to or incorporate in their structures host negative regulators of the complement pathways as an evasion mechanism. Factor H (FH) is a negative regulator of the complement alternative pathway that protects "self" cells of the host from non-specific complement attack. FH has been shown to bind viruses including human influenza A viruses (IAVs). In addition to its involvement in the regulation of complement activation, FH has also been shown to perform a range of functions on its own including its direct interaction with pathogens. Here, we show that human FH can bind directly to IAVs of both human and avian origin, and the interaction is mediated via the IAV surface glycoprotein haemagglutinin (HA). HA bound to common pathogen binding footprints on the FH structure, complement control protein modules, CCP 5-7 and CCP 15-20. The FH binding to H1 and H3 showed that the interaction overlapped with the receptor binding site of both HAs, but the footprint was more extensive for the H3 HA than the H1 HA. The HA - FH interaction impeded the initial entry of H1N1 and H3N2 IAV strains but its impact on viral multicycle replication in human lung cells was strain-specific. The H3N2 virus binding to cells was significantly inhibited by preincubation with FH, whereas there was no alteration in replicative rate and progeny virus release for human H1N1, or avian H9N2 and H5N3 IAV strains. We have mapped the interaction between FH and IAV, the in vivo significance of which for the virus or host is yet to be elucidated.

Differential Item Functioning via Robust Scaling.

This paper proposes a method for assessing differential item functioning (DIF) in item response theory (IRT) models. The method does not require pre-specification of anchor items, which is its main virtue. It is developed in two main steps: first by showing how DIF can be re-formulated as a problem of outlier detection in IRT-based scaling and then tackling the latter using methods from robust statistics. The proposal is a redescending M-estimator of IRT scaling parameters that is tuned to flag items with DIF at the desired asymptotic type I error rate. Theoretical results describe the efficiency of the estimator in the absence of DIF and its robustness in the presence of DIF. Simulation studies show that the proposed method compares favorably to currently available approaches for DIF detection, and a real data example illustrates its application in a research context where pre-specification of anchor items is infeasible. The focus of the paper is the two-parameter logistic model in two independent groups, with extensions to other settings considered in the conclusion.

Histologically Overt Stromal Response and the Risk of Progression after Radical Prostatectomy for Prostate Cancer.

PURPOSE: Given the variable clinical course of prostate cancer and the limitations of current prognostic factors, this study was conducted to investigate the impact of a histologically overt stromal response (HOST-response) to prostate cancer on clinical outcomes after radical prostatectomy. METHODS: This retrospective analysis utilized The Cancer Genome Atlas (TCGA) to evaluate data from individuals with a confirmed diagnosis of prostate cancer who underwent radical prostatectomy and had available pathology slides. These slides were assessed for the presence of a HOST-response, similar to desmoplasia. The primary endpoint was progression-free survival (PFS). A multivariable competing risk regression analysis was used to assess whether a significant association existed between HOST-response and PFS, adjusting for known prostate cancer prognostic factors. RESULTS: Among the 348 patients analyzed, 166 (47.70%) demonstrated a HOST-response. After a median follow-up of 37.87 months (IQR: 21.20, 65.50), the presence of a HOST-response was significantly associated with a shorter PFS (SDHR, 2.10; 95% CI, 1.26 to 3.50; p = 0.004), after adjusting for covariates. CONCLUSIONS: HOST-response in prostate cancer patients treated with radical prostatectomy is significantly associated with reduced PFS, suggesting a potential benefit from adjuvant therapy and highlighting the need for further investigation in a prospective randomized clinical trial.

Finite element analysis of patient-specific additive-manufactured implants.

Introduction: Bone tumors, characterized by diverse locations and shapes, often necessitate surgical excision followed by custom implant placement to facilitate targeted bone reconstruction. Leveraging additive manufacturing, patient-specific implants can be precisely tailored with complex geometries and desired stiffness, enhancing their suitability for bone ingrowth. Methods: In this work, a finite element model is employed to assess patient-specific lattice implants in femur bones. Our model is validated using experimental data obtained from an animal study (n = 9). Results: The results demonstrate the accuracy of the proposed finite element model in predicting the implant mechanical behavior. The model was used to investigate the influence of reducing the elastic modulus of a solid Ti6Al4V implant by tenfold, revealing that such a reduction had no significant impact on bone behavior under maximum compression and torsion loading. This finding suggests a potential avenue for reducing the endoprosthesis modulus without compromising bone integrity. Discussion: Our research suggests that employing fully lattice implants not only facilitates bone ingrowth but also has the potential to reduce overall implant stiffness. This reduction is crucial in preventing significant bone remodeling associated with stress shielding, a challenge often associated with the high stiffness of fully solid implants. The study highlights the mechanical benefits of utilizing lattice structures in implant design for enhanced patient outcomes.

Mapping Novel Frataxin Mitochondrial Networks Through Protein- Protein Interactions.

Friedreich's Ataxia (FRDA) is a neuromuscular degenerative disorder caused by trinucleotide expansions in the first intron of the frataxin (FXN) gene, resulting in insufficient levels of functional FNX protein. Deficits in FXN involve mitochondrial disruptions including iron-sulfur cluster synthesis and impaired energetics. These studies were to identify unique protein-protein interactions with FXN to better understand its function and design therapeutics. Two complementary approaches were employed, BioID and Co-IP, to identify protein interactions with FXN at the direct binding, indirect binding, and non-proximal levels. Forty-one novel protein interactions were identified by BioID and IP techniques. The FXN protein landscape was further analyzed incorporating both interaction type and functional pathways using a maximum path of 6 proteins with a potential direct interaction between FXN and NFS1. Probing the intersection between FXN-protein landscape and biological pathways associated with FRDA, we identified 41 proteins of interest. Peroxiredoxin 3 (Prdx3) was chosen for further analysis because of its role in mitochondrial oxidative injury. Our data has demonstrated the strengths of employing complementary methods to identify a unique interactome for FXN. Our data provides new insights into FXN function and regulation, a potential direct interaction between FXN and NFS1, and pathway interactions between FXN and Prdx3.

Moss-produced human complement factor H with modified glycans has an extended half-life and improved biological activity.

Most drugs that target the complement system are designed to inhibit the complement pathway at either the proximal or terminal levels. The use of a natural complement regulator such as factor H (FH) could provide a superior treatment option by restoring the balance of an overactive complement system while preserving its normal physiological functions. Until now, the systemic treatment of complement-associated disorders with FH has been deemed unfeasible, primarily due to high production costs, risks related to FH purified from donors' blood, and the challenging expression of recombinant FH in different host systems. We recently demonstrated that a moss-based expression system can produce high yields of properly folded, fully functional, recombinant FH. However, the half-life of the initial variant (CPV-101) was relatively short. Here we show that the same polypeptide with modified glycosylation (CPV-104) achieves a pharmacokinetic profile comparable to that of native FH derived from human serum. The treatment of FH-deficient mice with CPV-104 significantly improved important efficacy parameters such as the normalization of serum C3 levels and the rapid degradation of C3 deposits in the kidney compared to treatment with CPV-101. Furthermore, CPV-104 showed comparable functionality to serum-derived FH in vitro, as well as similar performance in ex vivo assays involving samples from patients with atypical hemolytic uremic syndrome, C3 glomerulopathy and paroxysomal nocturnal hematuria. CPV-104 - the human FH analog expressed in moss - will therefore allow the treatment of complement-associated human diseases by rebalancing instead of inhibiting the complement cascade.

Pushing the envelope: the feasibility of using a mailed contrast sensitivity test to prioritise cataract waiting lists.

BACKGROUND: Cataract waiting lists are growing globally. Pragmatic, cost-effective methods are required to prioritise the most urgent cases. Here we investigate the feasibility of using a third-party pen-and-paper contrast sensitivity, CS, test (SpotChecksTM), delivered by mail, and performed by patients at home unsupervised, to flag eyes requiring surgery. METHODS: Pen-and-paper CS tests were mailed to 233 people waiting for a cataract assessment, along with a prepaid return envelope (cross-sectional study). Response rates were tabulated (stratified by age, sex and socioeconomic status), and test scores analysed to see how well the home tests predicted which eyes were listed subsequently for surgery. A subset of patients (N = 39) also underwent in-person follow-up testing, to confirm the accuracy of the home data. RESULTS: Forty-six percent of patients responded (216 eyes). No gross differences were observed between respondents and non-respondents, either in terms of age, sex, socioeconomic status, or geographic location (all P > 0.05). The home-test CS scores predicted which eyes were subsequently listed for surgery, with an AUROC {±CI95%} of 0.69 {0.61-0.76}. Predictive performance was further-improved when machine learning was used to combine CS scores with letter acuity, extracted from patients' medical records (AUROC {±CI95%} = 0.77 {0.70-0.83}). Among 39 patients who underwent follow-up testing, home CS scores were correlated with various measures made in clinic: biometry signal-to-noise (P = 0.032), LogMAR acuity, Pelli-Robson CS and SpotChecks CS (all P < 0.001). CONCLUSIONS: Mailing patients pen-and-paper CS tests may be a feasible, 'low-tech' way of prioritising patients on cataract waiting lists.

Nitrous oxide respiration in acidophilic methanotrophs.

Aerobic methanotrophic bacteria are considered strict aerobes but are often highly abundant in hypoxic and even anoxic environments. Despite possessing denitrification genes, it remains to be verified whether denitrification contributes to their growth. Here, we show that acidophilic methanotrophs can respire nitrous oxide (N2O) and grow anaerobically on diverse non-methane substrates, including methanol, C-C substrates, and hydrogen. We study two strains that possess N2O reductase genes: Methylocella tundrae T4 and Methylacidiphilum caldifontis IT6. We show that N2O respiration supports growth of Methylacidiphilum caldifontis at an extremely acidic pH of 2.0, exceeding the known physiological pH limits for microbial N2O consumption. Methylocella tundrae simultaneously consumes N2O and CH4 in suboxic conditions, indicating robustness of its N2O reductase activity in the presence of O2. Furthermore, in O2-limiting conditions, the amount of CH4 oxidized per O2 reduced increases when N2O is added, indicating that Methylocella tundrae can direct more O2 towards methane monooxygenase. Thus, our results demonstrate that some methanotrophs can respire N2O independently or simultaneously with O2, which may facilitate their growth and survival in dynamic environments. Such metabolic capability enables these bacteria to simultaneously reduce the release of the key greenhouse gases CO2, CH4, and N2O.

Metatranscriptomes of California grassland soil microbial communities in response to rewetting.

When very dry soil is rewet, rapid stimulation of microbial activity has important implications for ecosystem biogeochemistry, yet associated changes in microbial transcription are poorly known. Here, we present metatranscriptomes of California annual grassland soil microbial communities, collected over 1 week from soils rewet after a summer drought-providing a time series of short-term transcriptional response during rewetting.

Bilateral Wilms tumor with anaplasia: A report from the Children's Oncology Group Study AREN0534.

INTRODUCTION: The purpose of this study is to examine the outcomes in children with anaplastic bilateral Wilms tumor (BWT) from study AREN0534 in order to define potential prognostic factors and areas to target in future clinical trials. METHODS: Demographic and clinical data from AREN0534 study patients with anaplasia (focal anaplasia [FA], or diffuse anaplasia [DA]) were compared. Event-free survival (EFS) and overall survival (OS) were reported using Kaplan-Meier estimation with 95% confidence bands, and differences in outcomes between FA and DA compared using log-rank tests. The impact of margin status was analyzed. RESULTS: Twenty-seven children who enrolled on AREN0534 had evidence of anaplasia (17 DA, 10 FA) in at least one kidney and were included in this analysis. Twenty-six (96%) had BWT. Nineteen percent had anaplastic histology in both kidneys (four of 17 DA, and one of 10 FA). Forty-six percent with BWT had bilateral nephron-sparing surgery (NSS); one child who went off protocol therapy, eventually required bilateral completion nephrectomies. Median follow-up for EFS and OS was 8.6 and 8.7 years from enrollment. Four- and 8-year EFS was 53% [95% confidence interval (CI): 34%-83%] for DA; 4-year EFS was 80% [95% CI: 59%-100%], and 8-year EFS 70% [95% CI: 47%-100%] for FA. Three out of 10 children with FA and eight out of 17 children with DA had events. EFS did not differ statistically by margin status (p = .79; HR = 0.88). Among the six children who died (five DA, one FA), all experienced prior relapse or progression within 18 months. CONCLUSION: Events in children with DA/FA in the setting of BWT occurred early. Caution should be taken about interpreting the impact of margin status outcomes in the context of contemporary multimodal therapy. Future targeted investigations in children with BWT and DA/FA are needed.