IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling.

Mechanisms that degrade inflammatory mRNAs are well known; however, stabilizing mechanisms are poorly understood. Here, we show that Act1, an interleukin-17 (IL-17)-receptor-complex adaptor, binds and stabilizes mRNAs encoding key inflammatory proteins. The Act1 SEFIR domain binds a stem-loop structure, the SEFIR-binding element (SBE), in the 3' untranslated region (UTR) of Cxcl1 mRNA, encoding an inflammatory chemokine. mRNA-bound Act1 directs formation of three compartmentally distinct RNA-protein complexes (RNPs) that regulate three disparate events in inflammatory-mRNA metabolism: preventing mRNA decay in the nucleus, inhibiting mRNA decapping in P bodies and promoting translation. SBE RNA aptamers decreased IL-17-mediated mRNA stabilization in vitro, IL-17-induced skin inflammation and airway inflammation in a mouse asthma model, thus providing a therapeutic strategy for autoimmune diseases. These results reveal a network in which Act1 assembles RNPs on the 3' UTRs of select mRNAs and consequently controls receptor-mediated mRNA stabilization and translation during inflammation.

Genomic Contributors to Esophageal Atresia and Tracheoesophageal Fistula: A 12 Year Retrospective Review.

OBJECTIVE: To evaluate genetic testing utilization and diagnostic yield in infants with esophageal atresia (EA)/tracheoesophageal fistula (TEF) over the past 12 years to inform future practices and individualize prognostication and management. STUDY DESIGN: A retrospective cohort study was performed for all infants with EA or EA/TEF hospitalized between January 2011 and January 2023 at a quaternary children's hospital. For each infant, demographic information, prenatal and postnatal history, and genetic testing were reviewed. RESULTS: There were 212 infants who were classified as follows: 1) complex/syndromic with EA/TEF plus an additional major anatomic anomaly (n = 114, of which 74 met VACTERL criteria); 2) isolated/nonsyndromic EA/TEF (n = 88) and 3) isolated/nonsyndromic EA (n = 10). A range of genetic tests were sent with varying diagnostic rates including karyotype analysis in 12 (all with complex/syndromic phenotypes and all positive), chromosomal microarray analysis in 189 (114 of whom were complex/syndromic with an overall diagnostic rate of 3/189), single gene testing for CHD7 in 18 (4 positive), and exome analysis in 37 complex/syndromic patients (8 positive). CONCLUSIONS: EA/TEF with and without additional anomalies is genetically heterogeneous with a broad range of associated phenotypes. While the genetic etiology of EA/TEF with or without VACTERL remains largely unknown, genome wide testing (exome or genome) including copy number analysis is recommended over chromosomal microarray testing. We anticipate that expanded genetic/genomic testing modalities such as RNA sequencing and tissue specific molecular testing are needed in this cohort to improve our understanding of the genomic contributors to EA/TEF.

Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF).

Interleukin 17 (IL-17) promotes the expression of chemokines and cytokines via the induction of gene transcription and post-transcriptional stabilization of mRNA. We show here that IL-17 enhanced the stability of chemokine CXCL1 mRNA and other mRNAs through a pathway that involved the adaptor Act1, the adaptors TRAF2 or TRAF5 and the splicing factor SF2 (also known as alternative splicing factor (ASF)). TRAF2 and TRAF5 were necessary for IL-17 to signal the stabilization of CXCL1 mRNA. Furthermore, IL-17 promoted the formation of complexes of TRAF5-TRAF2, Act1 and SF2 (ASF). Overexpression of SF2 (ASF) shortened the half-life of CXCL1 mRNA, whereas depletion of SF2 (ASF) prolonged it. SF2 (ASF) bound chemokine mRNA in unstimulated cells, whereas the SF2 (ASF)-mRNA interaction was much lower after stimulation with IL-17. Our findings define an IL-17-induced signaling pathway that links to the stabilization of selected mRNA species through Act1, TRAF2-TRAF5 and the RNA-binding protein SF2 (ASF).

The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammation.

Interleukin 17 (IL-17) is critical in the pathogenesis of inflammatory and autoimmune diseases. Here we report that Act1, the key adaptor for the IL-17 receptor (IL-7R), formed a complex with the inducible kinase IKKi after stimulation with IL-17. Through the use of IKKi-deficient mice, we found that IKKi was required for IL-17-induced expression of genes encoding inflammatory molecules in primary airway epithelial cells, neutrophilia and pulmonary inflammation. IKKi deficiency abolished IL-17-induced formation of the complex of Act1 and the adaptors TRAF2 and TRAF5, activation of mitogen-activated protein kinases (MAPKs) and mRNA stability, whereas the Act1-TRAF6-transcription factor NF-κB axis was retained. IKKi was required for IL-17-induced phosphorylation of Act1 on Ser311, adjacent to a putative TRAF-binding motif. Substitution of the serine at position 311 with alanine impaired the IL-17-mediated Act1-TRAF2-TRAF5 interaction and gene expression. Thus, IKKi is a kinase newly identified as modulating IL-17 signaling through its effect on Act1 phosphorylation and consequent function.

Prevalence and incidence of chronic conditions among adults with cerebral palsy: A systematic review and meta-analysis.

AIM: To assess the prevalence and incidence of chronic conditions among adults with cerebral palsy (CP) and compare them to the prevalence and incidence among adults without CP. METHOD: We searched MEDLINE and Embase for studies reporting the prevalence or incidence of one or more chronic conditions among adults with CP. Two independent reviewers screened titles, abstracts, and full-text articles. Two independent reviewers extracted data relating to prevalence and incidence and appraised study quality. We performed random-effects meta-analyses to pool prevalence and incidence. RESULTS: We identified 69 studies; 65 reported the prevalence of 53 conditions and 13 reported the incidence of 21 conditions. At least 20% of adults had the following conditions: depression (21%); anxiety (21%); mood affective disorders (23%); asthma (24%); hypertension (26%); epilepsy (28%); urinary incontinence (32%); malnutrition (38%); and scoliosis (46%). Adults with CP were more likely to have type 2 diabetes, anxiety, bipolar disorder, depression, schizophrenia, hypertension, ischaemic heart disease, stroke, cerebrovascular disease, asthma, liver disease, osteoarthritis, osteoporosis, underweight, and chronic kidney disease than adults without CP. INTERPRETATION: These data from 18 countries, which provide an international perspective, may be used to promote awareness, identify targets for intervention, and inform the development of appropriate supports for adults with CP.

Predictors of enteral tube dependence in pediatric esophageal atresia.

Children with esophageal atresia (EA) may require enteral tube feedings in infancy and a subset experience ongoing feeding difficulties and enteral tube dependence. Predictors of enteral tube dependence have never been systematically explored in this population. We hypothesized that enteral tube dependence is multifactorial in nature, with likely important contributions from anastomotic stricture. Cross-sectional clinical, feeding, and endoscopic data were extracted from a prospectively collected database of endoscopies performed in EA patients between August 2019 and August 2021 at an international referral center for EA management. Clinical factors known or hypothesized to contribute to esophageal dysphagia, oropharyngeal dysphagia, or other difficulties in meeting caloric needs were incorporated into regression models for statistical analysis. Significant predictors of enteral tube dependence were statistically identified. Three-hundred thirty children with EA were eligible for analysis. Ninety-seven were dependent on enteral tube feeds. Younger age, lower weight Z scores, long gap atresia, neurodevelopmental risk factor(s), significant cardiac disease, vocal fold movement impairment, and smaller esophageal anastomotic diameter were significantly associated with enteral tube dependence in univariate analyses; only weight Z scores, vocal fold movement impairment, and anastomotic diameter retained significance in a multivariable logistic regression model. In the current study, anastomotic stricture is the only potentially modifiable significant predictor of enteral tube dependence that is identified.

Indications and techniques for non-articulating spacers in massive bone loss following prosthetic knee joint infection: a scoping review.

INTRODUCTION: Prosthetic joint infection (PJI) is a destructive complication of knee replacement surgery (KR). In two-stage revision a spacer is required to maintain limb length and alignment and provide a stable limb on which to mobilise. Spacers may be articulating or static with the gold standard spacer yet to be defined. The aims of this scoping review were to summarise the types of static spacer used to treat PJI after KR, their indications for use and early complication rates. METHODS: We conducted a scoping review based on the Joanna Briggs Institute's "JBI Manual for Evidence Synthesis" Scoping review reported following Preferred Reporting Items for Systematic Review and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. MEDLINE, EMBASE and CINAHL were searched from 2005 to 2022 for studies on the use of static spacers for PJI after KR. RESULTS: 41 studies (1230 patients/knees) were identified describing 42 static spacer constructs. Twenty-three (23/42 [54.2%]) incorporated cement augmented with metalwork, while nineteen (19/42, [45.9%]) were made of cement alone. Spacers were most frequently anchored in the diaphysis (22/42, [53.3%]), particularly in the setting of extensive bone loss (mean AORI Type = F3/T3; 11/15 studies 78.3% diaphyseal anchoring). 7.1% (79 of 1117 knees) of static spacers had a complication requiring further surgery prior to planned second stage with the most common complication being infection (86.1%). CONCLUSIONS: This study has summarised the large variety in static spacer constructs used for staged revision KR for PJI. Static spacers were associated with a high risk of complications and further work in this area is required to improve the quality of care in this vulnerable group.

Outcomes based on histopathologic response to preoperative chemotherapy in children with bilateral Wilms tumor: A prospective study (COG AREN0534).

BACKGROUND: An objective of the Children's Oncology Group AREN0534 Study was to improve the survival of patients with bilateral Wilms tumors (BWT) by using preoperative chemotherapy of limited duration and tailoring postoperative therapy based on histopathologic response. The authors report outcomes based on postoperative histopathologic responses. METHODS: Patients with BWT received treatment with vincristine, dactinomycin, and doxorubicin for 6 or 12 weeks followed by surgery. Postoperative therapy was prescribed based on the highest risk tumor according to the International Society of Pediatric Oncology classification and the Children's Oncology Group staging system. RESULTS: Analyses were performed on data from 180 evaluable children. The 4-year event-free survival (EFS) and overall survival (OS) rates were 81% (95% CI, 74%-87%) and 95% (95% CI, 91%-99%), respectively. Seven patients who had completely necrotic tumors had a 4-year EFS rate of 100%. Of 118 patients who had tumors with intermediate-risk histopathology, the 4-year EFS and OS rates were 82% (95% CI, 74%-90%) and 97% (95% CI, 94%-100%), respectively. Fourteen patients who had blastemal-type tumors had 4-year EFS and OS rates of 79% (95% CI, 56%-100%) and 93% (95% CI, 79%-100%), respectively. Eighteen patients who had diffuse anaplasia had 4-year EFS and OS rates of 61% (95% CI, 35%-88%) and 72% (95% CI, 47%-97%), respectively; and the 4-year EFS and OS rates of 7 patients who had focal anaplasia were 71% (95% CI, 38%-100%) and 100%, respectively. There was no difference in the outcomes of patients who had different histopathologic subtypes within the intermediate-risk group (P = .54). CONCLUSIONS: A risk-adapted treatment approach for BWT results in excellent outcomes. This approach was not successful in improving the outcome of patients who had diffuse anaplasia.

Blockade or deficiency of PD-L1 expression in intestinal allograft accelerates graft tissue injury in mice.

The importance of PD-1/PD-L1 interaction to alloimmune response is unknown in intestinal transplantation. We tested whether PD-L1 regulates allograft tissue injury in murine intestinal transplantation. PD-L1 expression was observed on the endothelium and immune cells in the intestinal allograft. Monoclonal antibody treatment against PD-L1 led to accelerated allograft tissue damage, characterized by severe cellular infiltrations, massive destruction of villi, and increased crypt apoptosis in the graft. Interestingly, PD-L1-/- allografts were more severely rejected than wild-type allografts, but the presence or absence of PD-L1 in recipients did not affect the degree of allograft injury. PD-L1-/- allografts showed increased infiltrating Ly6G+ and CD11b+ cells in lamina propria on day 4, whereas the degree of CD4+ or CD8+ T cell infiltration was comparable to wild-type allografts. Gene expression analysis revealed that PD-L1-/- allografts had increased mRNA expressions of Cxcr2, S100a8/9, Nox1, IL1rL1, IL1r2, and Nos2 in the lamina propria cells on day 4. Taken together, study results suggest that PD-L1 expression in the intestinal allograft, but not in the recipient, plays a critical role in mitigating allograft tissue damage in the early phase after transplantation. The PD-1/PD-L1 interaction may contribute to immune regulation of the intestinal allograft via the innate immune system.

Feeding and Growth Outcomes in Infants with Type C Esophageal Atresia Who Undergo Early Primary Repair.

OBJECTIVES: To describe growth and feeding outcomes in patients with type C esophageal atresia who underwent early primary repair and to identify predictors for poor growth. STUDY DESIGN: This single-center, retrospective, cohort study included all patients with type C esophageal atresia who underwent early primary repair from 2013 to 2019. Weight-for-age z score (WAZ) was calculated at birth, and every 6 months until 3 years postoperatively. Longitudinal median regression was used to evaluate WAZ over time. A multivariable logistic regression model explored predictors of growth outcomes. RESULTS: Of 46 infants who met the inclusion criteria, 72% were term. The median age at repair was 1.5 days of life (IQR, 1-2 days of life) and the hospital length of stay was 20 days (IQR-14, 30 days). Two patients had esophageal leak (4.3%). The median WAZ at birth was below average (-0.72; IQR, -1.37 to -0.40), but improved to reach average by 3 years (-0.025; IQR, -0.85 to 0.97, P < .001). At discharge, 72% of patients were receiving full oral nutrition, which improved to 95% by 3 years. The only independent predictor of poor growth at 1 year (WAZ < -1 [33%]) was WAZ at discharge (P = .02). CONCLUSIONS: Infants with esophageal atresia who undergo early primary repair are capable of achieving standard growth curves by 3 years of age. However, poor discharge WAZ score was predictive of poor WAZ score at 1 year. Efforts to identify at-risk patients and institute targeted inpatient and outpatient nutrition interventions are needed to improve their growth trajectory.

Kidney Preservation and Wilms Tumor Development in Children with Diffuse Hyperplastic Perilobar Nephroblastomatosis: A Report from the Children's Oncology Group Study AREN0534.

INTRODUCTION: Diffuse hyperplastic perilobar nephroblastomatosis (DHPLN) represents a unique category of nephroblastomatosis. Treatment has ranged from observation to multiple regimens of chemotherapy. Wilms tumors (WTs) develop in 100% of untreated patients and between 32 and 52% of treated patients. Renal preservation rates have not been previously reported. An aim of the Children's Oncology Group (COG) study AREN0534 was to prospectively evaluate the efficacy of chemotherapy in preserving renal units and preventing WT development in children with DHPLN. METHODS: Patients were enrolled through the COG protocol AREN03B2 with central radiological review. DHPLN was defined as the cortical surface of the kidney being composed of hyperplastic rests, with the entire nephrogenic zone involved, and with a thick rind capping all of one or both kidneys. Treatment was with vincristine and dactinomycin (regimen EE4A), with cross-sectional imaging at weeks 6 and 12. If the patient's disease was stable or decreasing, treatment was continued for 19 weeks. Renal preservation, WT development rates at 1 year, and overall survival (OS) are reported. RESULTS: Nine patients were enrolled (five females and four males), with a median age at enrollment of 10.22 months (range 2.92-29.11). One patient who was enrolled was deemed unevaluable because they did not meet the radiological criteria for DHPLN, resulting in eight evaluable patients. These eight patients had DHPLN confirmed via radiological criteria (all bilateral). Initial chemotherapy was EE4A for all eight patients, with seven of eight patients starting chemotherapy without tissue diagnosis.One patient who had an upfront partial nephrectomy was found to have DHPLN in the specimen and was subsequently treated with EE4A. All patients remained alive, with a median follow-up of 6.6 years (range 4.5-9.1). No patients were anephric; 14 of 16 kidneys were functioning (87.5%). Six of eight patients (75%) did not have WT on therapy, but two of these patients relapsed within 6 months of stopping therapy; both had favorable histology WT. One patient who was diagnosed with WT on therapy relapsed at 12 months (one of eight [12.5%]) and developed anaplastic histology. CONCLUSIONS: Chemotherapy for patients with DHPLN was effective in preserving kidney function. Five-year OS is excellent, however the ideal type and duration of chemotherapy to prevent WT development remains elusive.

Predictors and Outcomes of Fully Covered Stent Treatment for Anastomotic Esophageal Strictures in Esophageal Atresia.

BACKGROUND AND AIMS: Anastomotic strictures following surgical repair is one of the most common complications in esophageal atresia (EA). The utility of esophageal stenting to treat anastomotic esophageal strictures in pediatrics is unclear. Our primary aim was to evaluate whether esophageal stenting, in conjunction with dilation and other endoscopic therapies, prevented surgical stricture resection (SR). Our secondary aims were to evaluate predictors of successful esophageal stenting and evaluate adverse events from stent placement. METHODS: A retrospective review of pediatric patients with EA complicated by esophageal strictures was performed. The change in stricture diameter in millimeters from the time of stent removal to subsequent endoscopy was defined as delta diameter (ΔD). A receiver operating characteristic (ROC) curve analysis was performed to determine the discriminatory ability of ΔD. Youden J index was used to identify optimal cutoff-point in predicting stent success. A univariate and multivariate analysis were done to assess predictors of success. RESULT: Forty-nine esophageal anastomoses were stented to treat esophageal strictures. Stents prevented SR in 41% of patients. ROC curve analysis utilizing Youden J index identified ΔD of ≤4 mm (area under the curve = 0.790; 95% confidence interval: 0.655-0.924; P < 0.001) as the optimal cutoff point in differentiating stent success. The most common adverse events were erosions/ulcerations, granulation tissue formation, and vomiting/retching. CONCLUSION: Stent therapy in preventing SR at the site of EA repair was successful in 41% in our population with good long term follow-up. The most significant predictor of success in this study was the change in luminal diameter (≤4 mm) at initial poststent follow-up.

Radiographic assessment of traction-induced esophageal growth and traction-related complications of the Foker process for treatment of long-gap esophageal atresia.

BACKGROUND: Radiographic assessment of esophageal growth in long-gap esophageal atresia while on traction and associated traction-related complications have not been described. OBJECTIVE: To demonstrate how chest radiography can estimate esophageal position while on traction and to evaluate radiography's utility in diagnosing certain traction system complications. MATERIALS AND METHODS: In this retrospective evaluation of portable chest radiographs obtained in infants with long-gap esophageal atresia who underwent the Foker process between 2014 and 2020, we assessed distances between the opposing trailing clips (esophageal gap) and the leading and trailing clips for each esophageal segment on serial radiographs. Growth during traction was estimated using longitudinal random-effects regression analysis to account for multiple chest radiograph measurements from the same child. RESULTS: Forty-three infants (25 male) had a median esophageal gap of 4.5 cm. Median traction time was 14 days. Median daily radiographic esophageal growth rate for both segments was 2.2 mm and median cumulative growth was 23.6 mm. Traction-related complications occurred in 13 (30%) children with median time of 8 days from traction initiation. Daily change >12% in leading-to trailing clip distance demonstrated 86% sensitivity and 92% specificity for indicating traction-related complications (area under the curve [AUC] 0.853). Cumulative change >30% in leading- to trailing-clip distance during traction was 85% sensitive and 85% specific for indicating traction complications (AUC 0.874). CONCLUSION: Portable chest radiograph measurements can serve as a quantitative surrogate for esophageal segment position in long-gap esophageal atresia. An increase of >12% between two sequential chest radiographs or >30% increase over the traction period in leading- to trailing-clip distance is highly associated with traction system complications.

Preoperative Severe Acute Respiratory Syndrome Coronavirus 2 Polymerase Chain Reaction Test at Between 48 and 72 Hours Preoperatively is Safe for Patients Undergoing Primary and Revision Hip and Knee Arthroplasty: A Multicentre International Study.

BACKGROUND: Patients undergoing lower limb arthroplasty who are severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive at the time of surgery have a high risk of mortality. The National Institute for Health and Clinical Care Excellence and the British Orthopaedic Association advise self-isolation for 14 days preoperatively in patients at a high risk of adverse outcomes due to COVID-19. The aim of the study is to assess whether preoperative polymerase chain reaction (PCR) for SARS-CoV-2 could be performed at between 48 and 72 hours preoperatively with specific advice about minimizing the risk of SARS-CoV-2 restricted to between PCR and admission. METHODS: A multicentre, international, observational cohort study of 1,000 lower limb arthroplasty cases was performed. The dual primary outcomes were 30-day conversion to SARS-CoV-2 positive and 30-day SARS-CoV-2 mortality. Secondary outcomes included 30-day SARS-CoV-2 morbidity. RESULTS: Of the 1,000 cases, 935 (94%) had a PCR between 48 and 72 hours preoperatively. All cases were admitted to and had surgery through a COVID-free pathway. Primary knee arthroplasty was performed in 41% of cases, primary hip arthroplasty in 40%, revision knee arthroplasty in 11%, and revision hip arthroplasty in 9%. Six percent of operations were emergency operations. No cases of SARS-CoV-2 were identified within the first 30 days. CONCLUSION: Preoperative SARS-CoV-2 PCR test between 48 and 72 hours preoperatively with advice about minimizing the risk of SARS-CoV-2 restricted to between PCR and admission in conjunction with a COVID-free pathway is safe for patients undergoing primary and revision hip and knee arthroplasty. Preoperative SARS-CoV-2 PCR test alone may be safe but further adequately powered studies are required. This information is important for shared decision making with patients during the current pandemic.

The effect of obesity on revision rate in unicompartmental knee arthroplasty: a systematic review and meta-analysis.

The number of patients with knee osteoarthritis, the proportion that is obese and the number undergoing unicompartmental knee arthroplasty (UKA) are all increasing. The primary aim of this systematic review was to determine the effects of obesity on outcomes in UKA. A systematic review was performed using PRISMA guidelines and the primary outcome was revision rate per 100 observed component years, with a BMI of ≥ 30 used to define obesity. The MINORS criteria and OCEBM criteria were used to assess risk of bias and level of evidence, respectively. 9 studies were included in the analysis. In total there were 4621 knees that underwent UKA. The mean age in included studies was reported to be 63 years (mean range 59.5-72 years old)) and range of follow up was 2-18 years. Four studies were OCEBM level 2b and the average MINORS score was 13. The mean revision rate in obese patients (BMI > 30) was 0.33% pa (95% CI - 3.16 to 2.5) higher than in non-obese patients, however this was not statistically significant (p = 0.82). This meta-analysis concludes that there is no significant difference in outcomes between obese and non-obese patients undergoing UKA. There is currently no evidence that obesity should be considered a definite contraindication to UKA. Further studies are needed to increase the numbers in meta-analysis to explore activity levels, surgeon's operative data, implant design and perioperative complications and revision in more depth.Level of evidence Level III.

Results of Treatment for Patients With Multicentric or Bilaterally Predisposed Unilateral Wilms Tumor (AREN0534): A report from the Children's Oncology Group.

BACKGROUND: A primary objective of Children's Oncology Group study AREN0534 (Treatment for Patients With Multicentric or Bilaterally Predisposed, Unilateral Wilms Tumor) was to facilitate partial nephrectomy in 25% of children with bilaterally predisposed unilateral tumors (Wilms tumor/aniridia/genitourinary anomalies/range of developmental delays [WAGR] syndrome; and multifocal and overgrowth syndromes). The purpose of this prospective study was to achieve excellent event-free survival (EFS) and overall survival (OS) while preserving renal tissue through preoperative chemotherapy, completing definitive surgery by 12 weeks from diagnosis, and modifying postoperative chemotherapy based on histologic response. METHODS: The treating institution identified whether a predisposition syndrome existed. Patients underwent a central review of imaging studies through the biology and classification study AREN03B2 and then were eligible to enroll on AREN0534. Patients were treated with induction chemotherapy determined by localized or metastatic disease on imaging (and histology if a biopsy had been undertaken). Surgery was based on radiographic response at 6 or 12 weeks. Further chemotherapy was determined by histology. Patients who had stage III or IV disease with favorable histology received radiotherapy as well as those who had stage I through IV anaplasia. RESULTS: In total, 34 patients were evaluable, including 13 males and 21 females with a mean age at diagnosis of 2.79 years (range, 0.49-8.78 years). The median follow-up was 4.49 years (range, 1.67-8.01 years). The underlying diagnosis included Beckwith-Wiedemann syndrome in 9 patients, hemihypertrophy in 9 patients, multicentric tumors in 10 patients, WAGR syndrome in 2 patients, a solitary kidney in 2 patients, Denys-Drash syndrome in 1 patient, and Simpson-Golabi-Behmel syndrome in 1 patient. The 4-year EFS and OS rates were 94% (95% CI, 85.2%-100%) and 100%, respectively. Two patients relapsed (1 tumor bed, 1 abdomen), and none had disease progression during induction. According to Response Evaluation Criteria in Solid Tumor 1.1 criteria, radiographic responses included a complete response in 2 patients, a partial response in 21 patients, stable disease in 11 patients, and progressive disease in 0 patients. Posttherapy histologic classification was low-risk in 13 patients (including the 2 complete responders), intermediate-risk in 15 patients, and high-risk in 6 patients (1 focal anaplasia and 5 blastemal subtype). Prenephrectomy chemotherapy facilitated renal preservation in 22 of 34 patients (65%). CONCLUSIONS: A standardized approach of preoperative chemotherapy, surgical resection within 12 weeks, and histology-based postoperative chemotherapy results in excellent EFS, OS, and preservation of renal parenchyma.

Threshold for Computer- and Robot-Assisted Knee and Hip Replacements in the English National Health Service.

OBJECTIVES: To estimate threshold prices for computer- and robot-assisted knee and hip replacement. METHODS: A lifetime cohort Markov model provided the framework for analysis. Linked primary care and inpatient hospital records informed estimates of outcomes under current practice. Outcomes were estimated under a range of hypothetical relative improvements in quality of life if unrevised and in revision risk after computer or robot-assisted surgery. Threshold prices, a price at which the net health benefit from funding the intervention would be zero, for these improvements were estimated for a cost-effectiveness threshold of £20 000 per additional quality-adjusted life-year (QALY) gained. RESULTS: For average patient profiles under current knee and hip replacement practice, lifetime QALYs were 10.3 (9.9 to 10.7) and 11.0 (10.6 to 11.4), with costs of £6060 (£5947 to £6203) and £6506 (£6335 to £6710) for knee and hip replacement, respectively. A combined 50% relative reduction in risk of revision and 5% improvement in postoperative quality of life if unrevised would, for example, result in QALYs increasing to 10.9 (10.4 to 11.3) and 11.6 (11.2 to 12.0), and costs falling to £5880 (£5816 to £5956) and £6258 (£6149 to £6376) after knee and hip replacement, respectively. These particular improvements would have an associated threshold price of £11 182 (£10 691 to £11 721) for knee replacement and £12 134 (£11 616 to £12 701) for hip replacement. The 50% reduction in revision rate alone would have associated threshold prices of £1094 (£788 to £1488) and £1347 (£961 to £1842), and the 5% improvement in quality of life alone would have associated threshold prices of £9911 (£9476 to £10 296) and £10 578 (£10 171 to £10 982). CONCLUSIONS: At current prices, computer- and robot-assisted knee and hip replacement will likely need to lead to improvements in patient-reported outcomes in addition to any reduction in the risk revision.

Neuron-Specific HuR-Deficient Mice Spontaneously Develop Motor Neuron Disease.

Human Ag R (HuR) is an RNA binding protein in the ELAVL protein family. To study the neuron-specific function of HuR, we generated inducible, neuron-specific HuR-deficient mice of both sexes. After tamoxifen-induced deletion of HuR, these mice developed a phenotype consisting of poor balance, decreased movement, and decreased strength. They performed significantly worse on the rotarod test compared with littermate control mice, indicating coordination deficiency. Using the grip-strength test, it was also determined that the forelimbs of neuron-specific HuR-deficient mice were much weaker than littermate control mice. Immunostaining of the brain and cervical spinal cord showed that HuR-deficient neurons had increased levels of cleaved caspase-3, a hallmark of cell apoptosis. Caspase-3 cleavage was especially strong in pyramidal neurons and α motor neurons of HuR-deficient mice. Genome-wide microarray and real-time PCR analysis further indicated that HuR deficiency in neurons resulted in altered expression of genes in the brain involved in cell growth, including trichoplein keratin filament-binding protein, Cdkn2c, G-protein signaling modulator 2, immediate early response 2, superoxide dismutase 1, and Bcl2. The additional enriched Gene Ontology terms in the brain tissues of neuron-specific HuR-deficient mice were largely related to inflammation, including IFN-induced genes and complement components. Importantly, some of these HuR-regulated genes were also significantly altered in the brain and spinal cord of patients with amyotrophic lateral sclerosis. Additionally, neuronal HuR deficiency resulted in the redistribution of TDP43 to cytosolic granules, which has been linked to motor neuron disease. Taken together, we propose that this neuron-specific HuR-deficient mouse strain can potentially be used as a motor neuron disease model.

Rules Are Meant to Be Broken: Examining the "Rule of 3" for Esophageal Dilations in Pediatric Stricture Patients.

BACKGROUND AND AIMS: The "rule of 3" is a 40-year-old expert opinion that suggests dilating an esophageal stricture more than 3 mm is unsafe. Few studies have evaluated this tenet, and do not specify how much larger than 3 mm is reasonable. Our aim was to determine the optimal point for maximum dilation diameter with acceptable risk in a pediatric population. METHODS: A retrospective review in pediatric patients with esophageal strictures was performed. The number of millimeters the stricture was dilated, defined as delta dilation diameter (ΔDD), was determined by subtracting the initial stricture diameter from the diameter of the largest balloon used. Receiver operating characteristic curve analysis was used to evaluate the discriminatory ability of ΔDD. Youden J index was used to identify optimal cut-point in predicting perforation. RESULTS: Two hundred eighty-four patients underwent 1384 balloon dilations. Overall perforation rate was 1.66%. There were 8 perforations in 1075 dilations with ΔDD ≤5 mm (0.7%) and 15 perforations in 309 dilations with ΔDD >5 mm (4.9%). Youden J index found an optimal cutoff to be at a ΔDD of ≤5 mm. The cumulative rate of perforation for all dilations ≤5 mm was 0.74% whereas the cumulative risk of perforation for all dilations ≥6 mm was 4.85% (P < 0.001). CONCLUSIONS: Balloon dilations that expand the initial esophageal anastomosis ≤5 mm in a pediatric population appear to not unduly increase the risk of perforation. Further prospective studies are needed to further investigate the potential for a new rule of 5 for balloon dilation.

Intralesional Steroid Injection Therapy for Esophageal Anastomotic Stricture Following Esophageal Atresia Repair.

OBJECTIVES: The role of intralesional steroid injection (ISI) in the treatment of anastomotic stricture in patients with esophageal atresia remains unclear. The aim of this study was to evaluate the efficacy and safety of ISI. METHODS: A total of 158 patients with esophageal atresia with at least 1 ISI for the treatment of esophageal anastomotic stricture between 2010 and 2017 were identified. The change in stricture diameter (ΔD) was compared between procedures with dilation alone (ISI-) and dilation with steroid injection (ISI+). RESULTS: A total of 1055 balloon dilations were performed (452 ISI+). The median ΔD was significantly greater in the ISI+ group: 1 mm (interquartile range [IQR] 0, 3) versus 0 mm (IQR -1, 1.5) (P < 0.0001). The ISI+ group had greater percentage of improved diameter (P < 0.0001) and lesser percentages of unchanged and decreased diameters at subsequent endoscopy (P = 0.0009, P = 0.003). Multivariable logistic regression confirmed the significance of ISI on increasing the likelihood of improved stricture diameter with an adjusted odds ratio of 3.24 (95% confidence interval: 2.15-4.88) (P < 0.001). The ΔD for the first 3 ISI+ procedures was greater than the ΔD for subsequent ISI+ procedures: 1 mm (IQR 0, 3) versus 0.5 mm (IQR-1.25, 2) (P = 0.001). There was no difference in perforation incidence between ISI+ and ISI- groups (P = 0.82). CONCLUSIONS: ISI with dilation was well tolerated and improved anastomotic stricture diameter more than dilation alone. The benefit of ISI over dilation alone was limited to the first 3 ISI procedures.