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Tributary phosphorus (P) loads are one of the main drivers of eutrophication problems in freshwater lakes. Being able to predict P loads can aid in understanding subsequent load patterns and elucidate potential degraded water quality conditions in downstream surface waters. We demonstrate the development and performance of an integrated multimedia modeling system that uses machine learning (ML) to assess and predict monthly total P (TP) and dissolved reactive P (DRP) loads. Meteorological variables from the Weather Research and Forecasting model, hydrological variables from the Variable Infiltration Capacity model, and agricultural management practice variables from the Environmental Policy Integrated Climate agroecosystem model are utilized to train the ML models to predict P loads. Our study presents a new modeling methodology using as testbeds the Maumee, Sandusky, Portage, and Raisin watersheds, which discharge into Lake Erie and contribute to significant P loads to the lake. Two models were built, one for TP loads using ten environmental variables, and one for DRP loads using nine environmental variables. Both models ranked streamflow as the most important predictive variable. Compared to observations, TP and DRP loads were predicted very well temporally and spatially. Modeling results of TP loads are within the ranges of those obtained from other studies and on some occasions more accurate. Modeling results of DRP loads exceed performance measures from other studies. We explore both of the ML-based models’ ability to further improve as more data becomes available over time. This integrated multimedia approach is recommended for studying other freshwater systems and water quality variables using available decadal data from physics-based model simulations.

Introduction Cloacal malformations comprise a heterogeneous group of anomalies that are considered the most complex anorectal malformations (ARMs) in females. Precise evaluation to identify the unique anatomy prior to reconstruction with collaboration between colorectal surgeons, urologists, and gynecologists is vital. Here, we present a rare anatomical variation in a patient with a cloacal malformation which affected operative and postoperative management. Case description A 6-year-old female with cloaca who underwent colostomy, vaginostomy, and vesicostomy as a newborn presented for reconstruction. Her VACTERL workup was negative except for an atretic right kidney. Her ARM index included the cloaca, a normal spine, and sacrum with a lateral sacral ratio of 0.7, predicting good potential for bowel continence. Cystoscopy through the vesicostomy showed a small bladder with normal ureteral orifices, and a closed bladder neck, with no identifiable urethra. A cloacagram showed an atretic common channel, a single small vagina, and a rectum below the pubococcygeal line. The patient underwent a posterior sagittal anorectovaginourethroplasty, vaginal patch using rectum, rectoplasty, and perineal body reconstruction. The urethra was not amenable to reconstruction, so the vesicostomy was preserved and a future Mitrofanoff was planned. Conclusion Urethral atresia is a rare and challenging finding in cloaca patients, and a vesicostomy is needed to drain urine in the newborn period. Preoperative examination under anesthesia, cystoscopy, vaginoscopy, and cloacagram are crucial to identify the precise anatomy and to plan accordingly.

The objective of this study was to evaluate the clinical utility of a routine pre-discharge white blood cell count (RPD-WBC) for predicting post-discharge organ space infection (OSI) in children with complicated appendicitis.This was a multicenter study using NSQIP-Pediatric data from 14 hospitals augmented with RPD-WBC data obtained through supplemental chart review. Children with fever or surgical site infection diagnosed during the index admission were excluded. Positive predictive value (PPV) for post-discharge OSI was calculated for RPD-WBC values of persistent leukocytosis (≥9.0x103 cells per microliter), increasing leukocytosis (RPD-WBCpreoperative WBC), quartiles of absolute RPD-WBC, and quartiles of relative proportional change from preoperative WBC. Logistic regression was used to calculate predictive values adjusted for patient age, appendicitis severity, and use of post-discharge antibiotics.1264 children were included, of which 348 (27.5%) had a RPD-WBC obtained (hospital range: 0.8-100%, P0.01). Median RPD-WBC was similar between children who did and did not develop a post-discharge OSI (9.0 vs. 8.9; p=0.57), and leukocytosis was absent in 50% of children who developed a post-discharge OSI. The PPV of RPD-WBC was poor for both persistent and increasing leukocytosis (3.9% and 9.8%, respectively), and for thresholds based on the quartiles of highest RPD-WBC values (11.1, PPV: 6.4%) and greatest proportional change (32% decrease from preoperative WBC; PPV: 7.8%).Routine pre-discharge WBC data have poor predictive value for identifying children at risk for post-discharge OSI following appendectomy for complicated appendicitis.

IMPORTANCE: The clinical significance of gangrenous, suppurative, or exudative (GSE) findings is poorly characterized in children with nonperforated appendicitis. OBJECTIVE: To evaluate whether GSE findings in children with nonperforated appendicitis are associated with increased risk of surgical site infections and resource utilization. DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study used data from the Appendectomy Targeted Database of the American College of Surgeons Pediatric National Surgical Quality Improvement Program, which were augmented with operative report data obtained by supplemental medical record review. Data were obtained from 15 hospitals participating in the Eastern Pediatric Surgery Network (EPSN) research consortium. The study cohort comprised children (aged ≤18 years) with nonperforated appendicitis who underwent appendectomy from July 1, 2015, to June 30, 2020. EXPOSURES: The presence of GSE findings was established through standardized, keyword-based audits of operative reports by EPSN surgeons. Interrater agreement for the presence or absence of GSE findings was evaluated in a random sample of 900 operative reports. MAIN OUTCOMES AND MEASURES: The primary outcome was 30-day postoperative surgical site infections (incisional and organ space infections). Secondary outcomes included rates of hospital revisits, postoperative abdominal imaging, and postoperative length of stay. Multivariable mixed-effects regression was used to adjust measures of association for patient characteristics and clustering within hospitals. RESULTS: Among 6133 children with nonperforated appendicitis, 867 (14.1%) had GSE findings identified from operative report review (hospital range, 4.2%-30.2%; P

Eutrophication and excessive algal growth pose a threat on aquatic organisms and the health of the public, environment, and the economy. Understanding what drives excessive algal growth can inform mitigation measures and aid in advance planning to minimize impacts. We demonstrate how simulated data from weather, hydrological, and agroecosystem numerical prediction models can be combined with machine learning (ML) to assess and predict chlorophyll a (chl a) concentrations, a proxy for lake eutrophication and algal biomass. The study area is Lake Erie for a 16-year period, 2002–2017. A total of 20 environmental variables from linked and coupled physical models are used as input features to train the ML model with chl a observations from 16 measuring stations. Included are meteorological variables from the Weather Research and Forecasting (WRF) model, hydrological variables from the Variable Infiltration Capacity (VIC) model, and agricultural management practice variables from the Environmental Policy Integrated Climate (EPIC) agroecosystem model. The consolidation of these variables is conducive to a successful prediction of chl a. Aside from the synergistic effects that weather, hydrology, and fertilizers have on eutrophication and excessive algal growth, we found that the application of different forms of both P and N fertilizers are highly ranked for the prediction of chl a concentration. The developed ML model successfully predicts chl a with a coefficient of determination of 0.81, bias of −0.12 μg/l and RMSE of 4.97 μg/l. The developed ML-based modeling approach can be used for impact assessment of agriculture practices in a changing climate that affect chl a concentrations in Lake Erie.

Parkinson's disease (PD) is the second-most prevalent neurodegenerative disorder in the U.S. α-Synuclein (α-Syn) preformed fibrils (PFFs) have been shown to propagate PD pathology in neuronal populations. However, little work has directly characterized the morphological changes on membranes associated with α-Syn PFFs at a cellular level. Scanning ion conductance microscopy (SICM) is a noninvasive

Background The posterior sagittal anorectoplasty (PSARP) used to repair an anorectal malformation (ARM) with a rectovestibular fistula involves incising the perineal body skin and the sphincter muscles and a posterior sagittal incision to the coccyx. Perineal body dehiscence is the most common and morbid complication post-PSARP which can have a negative impact on future bowel control. With consideration of all the other approaches described to repair this anomaly, we developed a perineal body sparing modification of the standard PSARP technique. Methods Four patients with ARM with a rectovestibular fistula were repaired with a perineal body sparing modified PSARP at a single institution between 2020 and 2021. The incision used was limited, involving only the length of the anal sphincter, with no incision anterior or posterior to the planned anoplasty. Dissection of the distal rectum and fistula was performed without cutting the perineal body. Once the distal rectum was mobilized off the posterior vaginal wall and out of the vestibule, the perineal body muscles, where the fistula had been, were reinforced and an anoplasty was then performed. Results Operative time was the same as for a standard PSARP. There were no intraoperative or postoperative complications. No postoperative dilations were performed. All patients healed well with an excellent cosmetic result. All are too young to assess for bowel control. Conclusion We present a new technique, a modification of the traditional PSARP for rectovestibular fistula, which spares the perineal body. This approach could eliminate the potential complication of perineal body dehiscence.

To evaluate whether redosing antibiotics within an hour of incision is associated with a reduction in incisional surgical site infection (iSSI) in children with appendicitis.Existing data remain conflicting as to whether children with appendicitis receiving antibiotics at diagnosis benefit from antibiotic redosing prior to incision.This was a multicenter retrospective cohort study using data from the Pediatric National Surgical Quality Improvement Program augmented with antibiotic utilization and operative report data obtained though supplemental chart review. Children undergoing appendectomy at 14 hospitals participating in the Eastern Pediatric Surgery Network from 7/2016-6/2020 who received antibiotics upon diagnosis of appendicitis between 1-6 hours prior to incision were included. Multivariable logistic regression was used to compare odds of iSSI in those who were and were not redosed with antibiotics within one hour of incision, adjusting for patient demographics, disease severity, antibiotic agents, and hospital-level clustering of events.3,533 children from 14 hospitals were included. Overall, 46.5% were redosed (hospital range: 1.8%-94.4%, P0.001) and iSSI rates were similar between groups (redosed: 1.2% vs. non-redosed: 1.3%; OR 0.84, [95%CI 0.39-1.83]). In subgroup analyses, redosing was associated with lower iSSI rates when cefoxitin was used as the initial antibiotic (redosed: 1.0% vs. non-redosed: 2.5%; OR 0.38, [95%CI 0.17-0.84]), but no benefit was found with other antibiotic regimens, longer periods between initial antibiotic administration and incision, or with increased disease severity.Redosing of antibiotics within one hour of incision in children who received their initial dose within 6 hours of incision was not associated with reduction in risk of incisional site infection unless cefoxitin was used as the initial antibiotic.

Management of refractory constipation in children has not been standardized. We propose a protocolized approach which includes a contrast enema, anorectal manometry and exclusion of Hirschsprung disease (HD). For those without HD or with normal sphincters, an assessment of the colonic motility may be needed. The subgroups of dysmotility include (1) slow motility with contractions throughout, (2) segmental dysmotility (usually the sigmoid), or (3) a diffusely inert colon. We offered a Malone appendicostomy in all groups with the hope that this would avoid colonic resection in most cases.Patients with medically refractory constipation were reviewed at a single institution (2020 to 2021). For patients without HD or an anal sphincter problem, assessment of colonic motility using colonic manometry was performed followed by a Malone appendicostomy for antegrade flushes.Of 196 patients evaluated for constipation refractory to medical management, 22 were felt to have a colonic motility cause. These patients underwent colonic manometry and Malone appendicostomy. 13 patients (59%) had a slow colon but with HAPCs throughout, 5 (23%) had segmental dysmotility, and 4 (18%) had a diffuse colonic dysmotility. 19 (86%) responded well to antegrade flushes with 17 reporting no soiling and 2 having occasional accidents. 3 patients (14%) failed flushes and underwent a colon resection within 6-month following Malone procedure.We propose a protocol for medically refractory constipation which provides a collaborative framework to standardize evaluation and management of these patients with antegrade flushes, which aids in avoidance of colonic resection in most cases.Level IV.

In patients with Hirschsprung disease (HSCR), soiling may be related to anal sphincter damage following the initial pull-through. No optimal treatment has been developed for such patients, although enemas (rectal or antegrade) have been applied with some success. We present the one-year outcomes of a new technique for anal sphincter reconstruction.All patients with HSCR referred from other institutions for post pull-through soiling were studied. Seven patients with patulous sphincters underwent sphincter reconstruction. Six had a full preoperative evaluation and were included in the study. Their 12-month outcomes were assessed.All six patients had soiling without voluntary bowel movements (VBMs). One patient was clean on Malone flushes when referred. Three underwent pre- and post-reconstruction non-sedated three-dimensional anorectal manometry, and objectively were able to close their sphincters following the reconstruction. All patients without Down syndrome (4 of 6) showed improvement in the abbreviated Baylor Continence Scale (4.5 vs. 0.75). One patient has achieved total bowel control without antegrade flushes, three now have VBMs which they did not have before but have occasional accidents and use antegrade flushes intermittently. They reported higher productivity, the ability to participate in sports and be away from home with confidence in their regimen. Two of 6 patients have Down syndrome and required a redo pull-through for other indications and underwent empiric sphincter reconstruction. For these two patients we do not have an outcomes assessment.A new technique for sphincter reconstruction shows promising results in improvement of bowel control at one year.IV.

We used linked and coupled physical models to identify relationships among environmental variables across multiple sources and pathways to examine the impact of nitrogen loadings on chlorophyll α concentrations.

Purpose The goal of this study was to characterize contemporary practice among pediatric surgeons in the use of mechanical bowel preparation (MBP) and oral antibiotics (OA) for elective colorectal surgery. Methods A survey of the American Pediatric Surgical Association membership was conducted to characterize variation in the use of MBP and OA for commonly performed elective colorectal procedures in children. Results Three-hundred thirteen members completed the survey. The most common approach used was MBP alone (31.1%), followed by diet modification only (26.8%), MBP combined with OA (19.6%), no preparation or dietary modification (12.2%), and OA alone (5.4%). The most common MBP used was a polyethylene glycol–based solution (92.6%), and the most common OA approach was neomycin combined with erythromycin (55.9%). Although MBP alone was the preferred approach among pediatric surgeons, the greatest relative change reported over time was in the adoption of dietary modifications only or no preparation at all. Conclusions Significant variation exists in the use of bowel preparation among pediatric surgeons. Although use of MBP alone remains the preferred approach for most procedures, an increasing number of surgeons report abandoning this approach in favor of dietary modification alone or no preparation at all.

Purpose Despite rigorous data from adult literature demonstrating that oral antibiotics (OA) reduce infectious complications and mechanical bowel preparation (MBP) alone does not, MBP alone remains the preferred approach among pediatric surgeons. We aimed to explore the nature of this discrepancy through a survey of the American Pediatric Surgical Association membership. Methods Surgeons were queried for their choice of bowel preparation, factors influencing their practice, and their impression of the strength and relevance of the adult literature to pediatric practice. Results Surgeons who used MBP alone (31%) cited a reduction in stool burden and infectious complications as important factors, whereas surgeons choosing not to use OA (70%) reported a lack of benefit in reducing infectious complications as the primary reason. Although 53% of surgeons reported that evidence from adult literature was the most important influence, 73% of surgeons reported there was poor evidence supporting the use of OA (±MBP), and only 25% used a preparation supported by adult randomized data. Conclusions Wide variation exists among pediatric surgeons in the perceived utility of MBP and OA. Although the majority of pediatric surgeons cited the adult literature as the strongest influence on their practice, this is not consistent with stated perceptions or practice.

The objective of this study was to examine the use of WBC count and polymorphonuclear leukocyte differential (PMN%) for improving the predictive value of ultrasound (US) in children with suspected appendicitis.We conducted a retrospective cohort study of children undergoing US for suspected appendicitis between January 1, 2010 and December 31, 2012 at a single children's hospital (n=845). Negative (NPV) and positive predictive values (PPV) for appendicitis were calculated for common constellations of US findings and compared with and without the use of laboratory thresholds (WBC9×10(3)/μL and PMN%65% for PPV; WBC≤9×10(3)/μL and PMN%≤65% for NPV).Fifty-one percent of US were considered "equivocal" (ie, appendix incompletely visualized, no primary or secondary signs, or presence of fluid only) and NPV increased significantly for this cohort using laboratory thresholds (41.9% vs 95.8%; p0.001). Primary signs of appendicitis, without secondary signs, were documented in 18% of examinations, and the PPV associated with this cohort increased from 79.1% to 91.3% (p0.001) using laboratory thresholds. Secondary signs with or without primary signs were documented in 24% of examinations, and laboratory thresholds improved the PPV in this cohort from 89.1% to 96.8% (p0.001). Guidelines recommending against the use of CT for very high-risk and low-risk categories (NPV95% and PPV95%) on the basis of combined US and laboratory data could have reduced the number of CTs by 27.1% (101 of 373) during the study period.The incorporation of WBC count and PMN% can substantially improve the predictive value of US in the diagnosis of suspected appendicitis in children.

It is well established through randomized trials that oral antibiotics given with or without a mechanical bowel preparation (MBP) prior to colorectal procedures reduce complications, while MBP given alone provides no benefit. We aimed to characterize trends surrounding bowel preparation in children and determine whether contemporary practice is evidence-based.Retrospective analysis of patients undergoing colorectal procedures at 42 children's hospitals (1/2/2007-12/31/2011) was performed. Patients were analyzed for diagnosis, pre-admission status, and inpatient bowel preparation. Bowel preparation was considered evidence-based if oral antibiotics were utilized with or without a MBP.49% of all patients were pre-admitted (n=5,473), and the most common diagnoses were anorectal malformations (55%), inflammatory bowel disease (26%), and Hirschsprung's Disease (19%). The most common preparation approaches were MBP alone (54.3%), MBP+oral antibiotics (18.8%), and oral antibiotics alone (4.2%), although significant variation was found in hospital-specific rates for each approach (MBP alone: 0-96.1%, MBP+oral antibiotics: 0-83.6%, orals alone: 0-91.6%, p0.0001). Only 22.9% of all patients received an evidence-based preparation (range by hospital: 0-92.3%, p0.0001), and this rate decreased significantly during the five-year study period (27.6% in 2007 vs. 17.3% in 2011, p0.0001).According to the best available clinical evidence, less than a quarter of all children pre-admitted for elective colorectal procedures receive a bowel preparation proven to reduce infectious complications.

Transamniotic stem cell therapy (TRASCET) with amniotic fluid mesenchymal stem cells (afMSCs) has been shown to mitigate bowel damage in a rodent model of gastroschisis. As a prerequisite to clinical translation, we sought to study TRASCET in a larger animal model.New Zealand rabbit fetuses (n=64) with surgically created gastroschisis were divided into three groups. One group (untreated) had no further manipulations. Two groups received volume-matched intraamniotic injections of either saline or a suspension of afMSCs. Nonmanipulated fetuses served as controls. Histomorphologic measurements of intestinal damage, along with biochemical profiling of inflammation markers, were performed at term. Statistical comparisons were by Fisher's exact test, ANOVA and the Wald test (P0.05).Overall survival was 62.5%. Segmental and total intestinal wall thicknesses were significantly decreased in the afMSC group compared with the untreated and saline groups (all P0.001), with no significant differences between untreated and saline groups (P=0.24 to 1.00, depending on layer). Muscularis and serosal layers were significantly thicker in the afMSC group than in normal controls (P=0.045 and P0.001, respectively).Concentrated intraamniotic injection of afMSC lessens, yet does not prevent, intestinal damage in a leporine model of gastroschisis. TRASCET may become a valuable strategy in the management of gastroschisis.N/A - animal/experimental studies.

We compared placental-derived and amniotic fluid-derived mesenchymal stem cells (pMSCs and afMSCs, respectively) in transamniotic stem cell therapy (TRASCET) for experimental spina bifida.Pregnant dams (n=29) exposed to retinoic acid for the induction of fetal spina bifida were divided into four groups. Three groups received volume-matched intraamniotic injections of either saline (n=38 fetuses) or a suspension of 2×10(6) cells/mL of syngeneic, labeled afMSCs (n=73) or pMSCs (n=115) on gestational day 17 (term=21-22days). Untreated fetuses served as controls. Animals were killed before term. Statistical comparisons were by Fisher's exact test (p0.05).Survival was similar across treatment groups (p=0.08). In fetuses with isolated spina bifida (n=100), there were higher percentages of defect coverage (either partial or complete) in both afMSC and pMSC groups compared with saline and untreated groups (p0.001-0.03 in pairwise comparisons). There were no differences in coverage rates between afMSC and pMSC groups (p=0.94) or between saline and untreated groups (p=0.98).Both pMSC and afMSC can induce comparable rates of coverage of experimental spina bifida after concentrated intraamniotic injection in the rodent model. This broadens the options for timing and cell source for TRASCET as a potential alternative in the prenatal management of spina bifida.

Purpose The purpose of this study was to characterize the rates of surgical site infections (SSI) associated with colorectal procedures in children and the relative burden of these events within the scope of pediatric surgical practice. Methods The NSQIP-Pediatric Public Use File was queried for all pediatric surgery procedures captured from 50 hospitals during 2012—2013. Rates of incisional and deep organ/space SSIs (ISSI and OSI, respectively) were calculated for all procedures, and the relative burden of SSIs from the entire dataset attributable to colorectal procedures was determined. Results Colorectal procedures accounted for 2.5% (2872/114,395) of the NSQIP-P caseload and contributed 7.1% of the SSI burden. The SSI rate for all colorectal procedures was 5.9% (ISSI:3.2%; OSI:2.7%), and the highest rates were associated with total abdominal colectomy (11.4%) partial colectomy (8.3%), and colostomy closure (5.0%). Inflammatory bowel disease contributed the greatest relative burden of SSIs among colorectal diagnoses (24.9%; ISSI:22%; OSI:28.6%), followed by Hirschsprung's Disease (14.2%; ISSI:15.4%; OSI:12.8%) and anorectal malformations (12.4%; ISSI:17.6%; OSI:6.4%). Conclusion Colorectal procedures are responsible for a disproportionate burden of SSIs within pediatric surgery. The rate and relative burden of SSIs are particularly high for colostomy closure, partial colectomy, and procedures for inflammatory bowel disease. Efforts to reduce SSI burden may be best focused on this cohort of children.

The purpose of the study was to explore the relationship between the degree of peritoneal contamination and postoperative resource utilization in children with complicated appendicitis.Intraoperative findings were collected prospectively at a single children's hospital from 2012 to 2014. The degree of peritoneal contamination was categorized as either "localized" (confined to the right lower quadrant and pelvis) or "extensive" (extending to the liver). Imaging utilization, postoperative length of stay (pLOS), hospital cost, and readmission rates were compared between groups.Of 88 patients with complicated appendicitis, 38% had extensive contamination. Preoperative characteristics were similar between groups. Patients with extensive contamination had higher rates of postoperative imaging (58.8% vs 27.7%, P0.01), a 50% longer median pLOS (6days [IQR 4-9] vs 4days [IQR 2-5], P=0.003), a 30% higher median hospital cost ($17,663 [IQR $12,564-$23,697] vs $13,516 [IQR $10,546-$16,686], P=0.004), and a nearly four-fold higher readmission rate (20.6% vs 5.6%, P=0.04) compared to children with localized contamination.Extensive peritoneal contamination is associated with significantly higher resource utilization compared to localized contamination in children with complicated appendicitis. These findings may have important severity-adjustment implications for reimbursement and readmission rate reporting for hospitals that serve populations where late presentation is common.

We sought to determine whether intraamniotic delivery of concentrated amniotic-derived mesenchymal stem cells (afMSCs) could reduce damage to exposed bowel in experimental gastroschisis.Rat fetuses (n=117) with surgically created gastroschisis were divided into three groups: untreated animals (n=62) and two groups receiving volume-matched intraamniotic injections of either saline (n=25) or 2 × 10(6) cells/mL of syngeneic, labeled afMSCs (n=30). Animals were killed before term, along with normal controls (NL). Blinded observers performed computerized measurements of total and segmental (serosa, muscularis, and mucosa) intestinal wall thicknesses. Statistical comparisons were by ANOVA (P0.05).Among survivors with gastroschisis, there were statistically significant decreases in total bowel wall, serosal, muscular, and mucosal thicknesses in the afMSC group vs. the untreated group (P=0.001/0.035/0.001/0.005, respectively) and vs. the saline group (P=0.003/0.05/0.001/0.026, respectively). There were no such significant differences between the untreated and saline groups. There were no differences between the afMSC group and NL, except for a significantly thicker muscular layer in the afMSC group (P=0.014). Labeled afMSCs were scarcely identified, suggesting a paracrine effect.Amniotic mesenchymal stem cells mitigate bowel damage in experimental gastroschisis after concentrated intraamniotic injection. Transamniotic stem cell therapy (TRASCET) may become a practical component of the treatment of gastroschisis.

We sought to study the impact of trans-amniotic stem cell therapy (TRASCET) in the Chiari-II malformation in experimental spina bifida.Sprague-Dawley fetuses (n=62) exposed to retinoic acid were divided into three groups at term (21-22 days gestation): untreated isolated spina bifida (n=21), isolated spina bifida treated with intra-amniotic injection of concentrated, syngeneic, labeled amniotic fluid mesenchymal stem cells (afMSCs) on gestational day 17 (n=28), and normal controls (n=13). Analyses included measurements of brainstem and cerebellar placement on high resolution MRI and histology. Statistical comparisons included ANOVA.In parallel to the expected induced coverage of the spina bifida in the afMSC-treated group (P0.001), there were statistically significant differences in brainstem displacement across the groups (P0.001), with the highest caudal displacement in the untreated group. Significant differences in cerebellar displacement were also noted, albeit less pronounced. Pairwise comparisons were statistically significant, with P=0.014 between treated and normal controls in caudal brainstem displacement and P0.001 for all other comparisons. Labeled afMSCs were identified in 71% of treated fetuses.Induced coverage of spina bifida by TRASCET minimizes the Chiari-II malformation in the retinoic acid rodent model, further suggesting it as a practical alternative for the prenatal management of spina bifida.

Importance Practice variation is believed to be a driver of excess health care spending, although few objective data exist to guide the prioritization of comparative effectiveness research (CER) in pediatric surgery. Objective To identify high-priority general pediatric surgical procedures for CER on the basis of the following 2 complementary measures: the magnitude of interhospital cost variation as a surrogate for the need for and potential effect of CER at the patient level and the cumulative fiscal burden of this cost variation when considering the case volume from all hospitals as a surrogate for public health relevance. Design, Setting, and Participants This was a cohort study of patients undergoing 1 of the 30 most costly pediatric surgical operations at 45 children’s hospitals between January 1, 2014, and September 30, 2015. Cost data were extracted from the Pediatric Health Information System database and adjusted for differences in unit-based costing at the hospital level and for differences in case mix and disease severity at the patient level. Main Outcomes and Measures First, the width of the interquartile range (WIQR) of the adjusted procedure-specific median cost across hospitals. Second, the procedure-specific cost variation burden, which was calculated as the aggregate sum of absolute cost differences between the overall adjusted median cost derived from all patients treated at all hospitals and the adjusted cost of each individual patient treated at all hospitals. Results A total of 92 535 encounters were analyzed. The median number of encounters per hospital was 2011 (interquartile range [IQR], 1224-2619), and the median number of encounters per procedure was 610 (IQR, 442-2610). In the final cohort, 66.9% (n = 61 933) of the patients were male, and the median age was 7 years (IQR, 1.9-12.3 years). Cost variation at the hospital level was greatest for gastroschisis (WIQR, $48 471; median, $111 566 [IQR, $91 195-$139 936]), congenital diaphragmatic hernia (WIQR, $43 948; median, $154 730 [IQR, $129 764-$173 712]), tracheoesophageal fistula/esophageal atresia (WIQR, $39 206; median, $105 259 [IQR, $87 335-$126 541]), and total colectomy for ulcerative colitis (WIQR, $24 497; median, $34 910 [IQR, $28 815-$53 312]). The following 5 diagnoses accounted for 52.5% of the cumulative cost variation burden from all 30 conditions: uncomplicated appendicitis (18.0% [$66 205 117]), complicated appendicitis (14.1% [$51 702 402]), gastroschisis (9.5% [$34 940 331]), gastrostomy (5.8% [$21 227 436]), and small-intestinal atresia (5.1% [$18 840 546]). Neonatal cases contributed 3.6% of the case volume and accounted for 26.8% of the cumulative cost variation burden from all 30 conditions. Conclusions and Relevance A small number of procedures account for most of the cost variation burden in pediatric surgery, with some demonstrating wide cost variation among hospitals. Gastroschisis and small-intestinal atresia may be particularly high-yield targets for multidisciplinary CER efforts, while the management of appendicitis and gastrostomy should be considered high-priority conditions among pediatric surgeons.

The serine/threonine phosphatase 2A (PP2A) has been implicated in the pathogenesis of Alzheimer's disease (AD) due to its important role in regulating dephosphorylation of the microtubule-associated protein tau and mitogen-activated protein (MAP) kinase. In the present study, we show that PP2A was responsible for dephosphorylation of the extracellular signal-regulated kinase 1/2 (Erk1/2) following its activation by BK stimulation. Abnormal gene and protein expressions of PP2A, as well as its activity, were found to contribute to the abnormally prolonged Erk1/2 phosphorylation in the AD fibroblasts. Inhibition of PP2A with okadiac acid produced enhanced and more lasting Erk1/2 phosphorylation after BK stimulation, whereas FK506, an inhibitor of PP2B and FK-binding protein, inhibited the BK-stimulated Erk1/2 phosphorylation. Furthermore, while the phosphorylated Erk1/2 was concentrated in the nucleus of AC cells, it was mainly distributed in the extranuclear compartments of AD cells. These results suggest that the delayed dephosphorylation of Erk1/2 in AD cells following its BK-stimulated activation may be due to deficits of PP2A activity and impaired nuclear translocation of phosphorylated Erk1/2.