University of Minnesota Children's Hospital

OBJECTIVE: The aim was to develop a consensus-based method of risk adjustment for in-hospital mortality among children younger than 18 years after surgery for congenital heart disease (designated RACHS-1). METHODS: An 11-member national panel of pediatric cardiologists and cardiac surgeons used clinical judgment to place surgical procedures into six risk categories. Categories were refined after review of information from the Pediatric Cardiac Care Consortium and three statewide hospital discharge data sets. The effects of including additional clinical variables were explored by comparing areas under receiver-operator characteristic curves. RESULTS: Among 4602 surgical patients in the Pediatric Cardiac Care Consortium data set and 4493 in the hospital discharge data, 3767 (81.9%) and 3832 (85.3%), respectively, had a single cardiac procedure, and 98.5% and 89.2%, respectively, were able to be assigned to one of six risk categories defined by the panel. Mortality rates showed expected trends (P <.001). For the Pediatric Cardiac Care Consortium data, mortality rates were 0.4% in category 1, 3.8% in 2, 8.5% in 3, 19.4% in 4, and 47.7% in 6; rates were similar in the hospital discharge data. There were too few cases in category 5 to estimate mortality rates. In multivariable models, younger age, prematurity, and the presence of a major noncardiac structural anomaly added to the risk of in-hospital death predicted by risk category alone. Best performance was obtained when cases with multiple procedures were placed in the risk category of the most complex procedure. CONCLUSION: The RACHS-1 method should adjust for baseline risk differences and allow meaningful comparisons of in-hospital mortality for groups of children undergoing surgery for congenital heart disease.

The intent of this review is to provide the clinician with a summary of what is currently known about the contribution of genetics to the origin of congenital heart disease. Techniques are discussed to evaluate children with heart disease for genetic alterations. Many of these techniques are now available on a clinical basis. Information on the genetic and clinical evaluation of children with cardiac disease is presented, and several tables have been constructed to aid the clinician in the assessment of children with different types of heart disease. Genetic algorithms for cardiac defects have been constructed and are available in an appendix. It is anticipated that this summary will update a wide range of medical personnel, including pediatric cardiologists and pediatricians, adult cardiologists, internists, obstetricians, nurses, and thoracic surgeons, about the genetic aspects of congenital heart disease and will encourage an interdisciplinary approach to the child and adult with congenital heart disease.

Importance: Refinement of criteria for multisystem inflammatory syndrome in children (MIS-C) may inform efforts to improve health outcomes. Objective: To compare clinical characteristics and outcomes of children and adolescents with MIS-C vs those with severe coronavirus disease 2019 (COVID-19). Setting, Design, and Participants: Case series of 1116 patients aged younger than 21 years hospitalized between March 15 and October 31, 2020, at 66 US hospitals in 31 states. Final date of follow-up was January 5, 2021. Patients with MIS-C had fever, inflammation, multisystem involvement, and positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reverse transcriptase-polymerase chain reaction (RT-PCR) or antibody test results or recent exposure with no alternate diagnosis. Patients with COVID-19 had positive RT-PCR test results and severe organ system involvement. Exposure: SARS-CoV-2. Main Outcomes and Measures: Presenting symptoms, organ system complications, laboratory biomarkers, interventions, and clinical outcomes. Multivariable regression was used to compute adjusted risk ratios (aRRs) of factors associated with MIS-C vs COVID-19. Results: Of 1116 patients (median age, 9.7 years; 45% female), 539 (48%) were diagnosed with MIS-C and 577 (52%) with COVID-19. Compared with patients with COVID-19, patients with MIS-C were more likely to be 6 to 12 years old (40.8% vs 19.4%; absolute risk difference [RD], 21.4% [95% CI, 16.1%-26.7%]; aRR, 1.51 [95% CI, 1.33-1.72] vs 0-5 years) and non-Hispanic Black (32.3% vs 21.5%; RD, 10.8% [95% CI, 5.6%-16.0%]; aRR, 1.43 [95% CI, 1.17-1.76] vs White). Compared with patients with COVID-19, patients with MIS-C were more likely to have cardiorespiratory involvement (56.0% vs 8.8%; RD, 47.2% [95% CI, 42.4%-52.0%]; aRR, 2.99 [95% CI, 2.55-3.50] vs respiratory involvement), cardiovascular without respiratory involvement (10.6% vs 2.9%; RD, 7.7% [95% CI, 4.7%-10.6%]; aRR, 2.49 [95% CI, 2.05-3.02] vs respiratory involvement), and mucocutaneous without cardiorespiratory involvement (7.1% vs 2.3%; RD, 4.8% [95% CI, 2.3%-7.3%]; aRR, 2.29 [95% CI, 1.84-2.85] vs respiratory involvement). Patients with MIS-C had higher neutrophil to lymphocyte ratio (median, 6.4 vs 2.7, P < .001), higher C-reactive protein level (median, 152 mg/L vs 33 mg/L; P < .001), and lower platelet count (<150 ×103 cells/μL [212/523 {41%} vs 84/486 {17%}, P < .001]). A total of 398 patients (73.8%) with MIS-C and 253 (43.8%) with COVID-19 were admitted to the intensive care unit, and 10 (1.9%) with MIS-C and 8 (1.4%) with COVID-19 died during hospitalization. Among patients with MIS-C with reduced left ventricular systolic function (172/503, 34.2%) and coronary artery aneurysm (57/424, 13.4%), an estimated 91.0% (95% CI, 86.0%-94.7%) and 79.1% (95% CI, 67.1%-89.1%), respectively, normalized within 30 days. Conclusions and Relevance: This case series of patients with MIS-C and with COVID-19 identified patterns of clinical presentation and organ system involvement. These patterns may help differentiate between MIS-C and COVID-19.

This Policy Statement was reaffirmed October 2023. Maternal prenatal nutrition and the child's nutrition in the first 2 years of life (1000 days) are crucial factors in a child’s neurodevelopment and lifelong mental health. Child and adult health risks, including obesity, hypertension, and diabetes, may be programmed by nutritional status during this period. Calories are essential for growth of both fetus and child but are not sufficient for normal brain development. Although all nutrients are necessary for brain growth, key nutrients that support neurodevelopment include protein; zinc; iron; choline; folate; iodine; vitamins A, D, B6, and B12; and long-chain polyunsaturated fatty acids. Failure to provide key nutrients during this critical period of brain development may result in lifelong deficits in brain function despite subsequent nutrient repletion. Understanding the complex interplay of micro- and macronutrients and neurodevelopment is key to moving beyond simply recommending a “good diet” to optimizing nutrient delivery for the developing child. Leaders in pediatric health and policy makers must be aware of this research given its implications for public policy at the federal and state level. Pediatricians should refer to existing services for nutrition support for pregnant and breastfeeding women, infants, and toddlers. Finally, all providers caring for children can advocate for healthy diets for mothers, infants, and young children in the first 1000 days. Prioritizing public policies that ensure the provision of adequate nutrients and healthy eating during this crucial time would ensure that all children have an early foundation for optimal neurodevelopment, a key factor in long-term health.

OBJECTIVES: Pancreatitis is the most common and serious complication of diagnostic and therapeutic ERCP. The aim of this study is to examine the potential patient- and procedure-related risk factors for post-ERCP pancreatitis in a prospective multicenter study. METHODS: A 160-variable database was prospectively collected by a defined protocol on patients undergoing diagnostic or therapeutic ERCP at 15 centers in the Midwest Pancreaticobiliary Group and participating in a randomized controlled study evaluating whether prophylactic corticosteroids will reduce the incidence of post-ERCP pancreatitis. Data were collected prior to the procedure, at the time of procedure, and 24-72 h after discharge. Post-ERCP pancreatitis was diagnosed and its severity graded according to consensus criteria. RESULTS: Of the 1,115 patients enrolled, diagnostic ERCP with or without sphincter of Oddi manometry (SOM) was performed in 536 (48.1%) and therapeutic ERCP in 579 (51.9%). Suspected sphincter of Oddi dysfunction (SOD) was the indication for the ERCP in 378 patients (33.9%). Pancreatitis developed in 168 patients (15.1%) and was graded mild in 112 (10%), moderate in 45 (4%), and severe in 11(1%). There was no difference in the incidence of pancreatitis or the frequency of investigated potential pancreatitis risk factors between the corticosteroid and placebo groups. By univariate analysis, the incidence of post-ERCP pancreatitis was significantly higher in 19 of 30 investigated variables. In the multivariate risk model, significant risk factors with adjusted odds ratios (OR) were: minor papilla sphincterotomy (OR: 3.8), suspected SOD (OR: 2.6), history of post-ERCP pancreatitis (OR: 2.0), age <60 yr (OR: 1.6), > or =2 contrast injections into the pancreatic duct (OR: 1.5), and trainee involvement (OR: 1.5). Female gender, history of recurrent idiopathic pancreatitis, pancreas divisum, SOM, difficult cannulation, and major papilla sphincterotomy (either biliary or pancreatic) were not multivariate risk factors for post-ERCP pancreatitis. CONCLUSION: This study emphasizes the role of patient factors (age, SOD, prior history of post-ERCP pancreatitis) and technical factors (number of PD injections, minor papilla sphincterotomy, and operator experience) as the determining high-risk predictors for post-ERCP pancreatitis.

BACKGROUND: In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allogeneic hematopoietic stem-cell transplantation. METHODS: We enrolled boys with cerebral adrenoleukodystrophy in a single-group, open-label, phase 2-3 safety and efficacy study. Patients were required to have early-stage disease and gadolinium enhancement on magnetic resonance imaging (MRI) at screening. The investigational therapy involved infusion of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector. In this interim analysis, patients were assessed for the occurrence of graft-versus-host disease, death, and major functional disabilities, as well as changes in neurologic function and in the extent of lesions on MRI. The primary end point was being alive and having no major functional disability at 24 months after infusion. RESULTS: A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6 to 42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No treatment-related death or graft-versus-host disease had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, had died from disease progression. Another patient, who had had evidence of disease progression on MRI, had withdrawn from the study to undergo allogeneic stem-cell transplantation and later died from transplantation-related complications. CONCLUSIONS: Early results of this study suggest that Lenti-D gene therapy may be a safe and effective alternative to allogeneic stem-cell transplantation in boys with early-stage cerebral adrenoleukodystrophy. Additional follow-up is needed to fully assess the duration of response and long-term safety. (Funded by Bluebird Bio and others; STARBEAM ClinicalTrials.gov number, NCT01896102 ; ClinicalTrialsRegister.eu number, 2011-001953-10 .).

AIMS: To identify the magnitude of and potential risk factors for violence within a major occupational population. METHODS: Comprehensive surveys were sent to 6300 Minnesota licensed registered (RNs) and practical (LPNs) nurses to collect data on physical and non-physical violence for the prior 12 months. Re-weighting enabled adjustment for potential biases associated with non-response, accounting for unknown eligibility. RESULTS: From the 78% responding, combined with non-response rate information, respective adjusted rates per 100 persons per year (95% CI) for physical and non-physical violence were 13.2 (12.2 to 14.3) and 38.8 (37.4 to 40.4); assault rates were increased, respectively, for LPNs versus RNs (16.4 and 12.0) and males versus females (19.4 and 12.9). Perpetrators of physical and non-physical events were patients/clients (97% and 67%, respectively). Consequences appeared greater for non-physical than physical violence. Multivariate modelling identified increased rates for both physical and non-physical violence for working: in a nursing home/long term care facility; in intensive care, psychiatric/behavioural or emergency departments; and with geriatric patients. CONCLUSIONS: Results show that non-fatal physical assault and non-physical forms of violence, and relevant consequences, are frequent among both RNs and LPNs; such violence is mostly perpetrated by patients or clients; and certain environmental factors appear to affect the risk of violence. This serves as the basis for further analytical studies that can enable the development of appropriate prevention and control efforts.

Importance: Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear. Objective: To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19. Setting, Design, and Participants: Case series of patients (age <21 years) hospitalized between March 15, 2020, and December 15, 2020, with positive severe acute respiratory syndrome coronavirus 2 test result (reverse transcriptase-polymerase chain reaction and/or antibody) at 61 US hospitals in the Overcoming COVID-19 public health registry, including 616 (36%) meeting criteria for multisystem inflammatory syndrome in children. Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening involvement was adjudicated by experts based on clinical and/or neuroradiologic features. Exposures: Severe acute respiratory syndrome coronavirus 2. Main Outcomes and Measures: Type and severity of neurologic involvement, laboratory and imaging data, and outcomes (death or survival with new neurologic deficits) at hospital discharge. Results: Of 1695 patients (909 [54%] male; median [interquartile range] age, 9.1 [2.4-15.3] years), 365 (22%) from 52 sites had documented neurologic involvement. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 of 365 [22%]) compared with those without (113 of 1330 [8%]), but a similar number were previously healthy (195 [53%] vs 723 [54%]) and met criteria for multisystem inflammatory syndrome in children (126 [35%] vs 490 [37%]). Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), central nervous system infection/demyelination (n = 8), Guillain-Barré syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4). Compared with those without life-threatening conditions (n = 322), those with life-threatening neurologic conditions had higher neutrophil-to-lymphocyte ratios (median, 12.2 vs 4.4) and higher reported frequency of D-dimer greater than 3 μg/mL fibrinogen equivalent units (21 [49%] vs 72 [22%]). Of 43 patients who developed COVID-19-related life-threatening neurologic involvement, 17 survivors (40%) had new neurologic deficits at hospital discharge, and 11 patients (26%) died. Conclusions and Relevance: In this study, many children and adolescents hospitalized for COVID-19 or multisystem inflammatory syndrome in children had neurologic involvement, mostly transient symptoms. A range of life-threatening and fatal neurologic conditions associated with COVID-19 infrequently occurred. Effects on long-term neurodevelopmental outcomes are unknown.

MALABSORPTION of the carbohydrate lactose is a common cause of flatulence, abdominal discomfort, and diarrhea in otherwise healthy persons. The possibility that such symptoms could result from malabsorption of the other major dietary carbohydrates (sucrose or starch) has received little consideration since these carbohydrates are assumed to be completely absorbed in health.We measured breath hydrogen to assess the absorption of the carbohydrate in white, all-purpose wheat flour. These studies demonstrate that nearly all normal subjects fail to absorb an appreciable portion of this form of starch, possibly because of an interaction between the starch and protein moieties of wheat . . .

Abstract Rationale The cystic fibrosis (CF) modulator drug, elexacaftor/tezacaftor/ivacaftor (ETI), proved highly effective in controlled clinical trials for individuals with at least one F508del allele, which occurs in at least 85% of people with CF. Objectives PROMISE is a postapproval study to understand the broad effects of ETI through 30 months’ clinical use in a more diverse U.S. patient population with planned analyses after 6 months. Methods Prospective, observational study in 487 people with CF age 12 years or older with at least one F508del allele starting ETI for the first time. Assessments occurred before and 1, 3, and 6 months into ETI therapy. Outcomes included change in percent predicted FEV1 (ppFEV1), sweat chloride concentration, body mass index (BMI), and self-reported respiratory symptoms. Measurements and Main Results Average age was 25.1 years, and 44.1% entered the study using tezacaftor/ivacaftor or lumacaftor/ivacaftor, whereas 6.7% were using ivacaftor, consistent with F508del homozygosity and G551D allele, respectively. At 6 months into ETI therapy, ppFEV1 improved 9.76 percentage points (95% confidence interval [CI], 8.76 to 10.76) from baseline, cystic fibrosis questionnaire–revised respiratory domain score improved 20.4 points (95% CI, 18.3 to 22.5), and sweat chloride decreased −41.7 mmol/L (95% CI, −43.8 to −39.6). BMI also significantly increased. Changes were larger in those naive to modulators but substantial in all groups, including those treated with ivacaftor at baseline. Conclusions ETI by clinical prescription provided large improvements in lung function, respiratory symptoms, and BMI in a diverse population naive to modulator drug therapy, using existing two-drug combinations, or using ivacaftor alone. Each group also experienced significant reductions in sweat chloride concentration, which correlated with improved ppFEV1 in the overall study population. Clinical trial registered with www.clinicaltrials.gov (NCT NCT04038047).

Holoprosencephaly (HPE) is a common developmental anomaly of the human forebrain and midface where the cerebral hemispheres fail to separate into distinct left and right halves. We have previously reported haploinsufficiency for Sonic Hedgehog ( SHH ) as a cause for HPE. We have now performed mutational analysis of the complete coding region and intron-exon junctions of the SHH gene in 344 unrelated affected individuals. Herein, we describe 13 additional unrelated affected individuals with SHH mutations, including nonsense and missense mutations, deletions and an insertion. These mutations occur throughout the extent of the gene. No specific genotype-phenotype association is evident based on the correlation of the type or position of the mutations. In conjunction with our previous studies, we have identified a total of 23 mutations in 344 unrelated cases of HPE. They account for 14 cases of familial HPE and nine cases of sporadic HPE. Mutations in SHH were detected in 10 of 27 (37%) families showing autosomal dominant transmission of the HPE spectrum, based on structural anomalies. Interestingly, three of the patients with an SHH mutation also had abnormalities in another gene that is expressed during forebrain development. We suggest that the interactions of multiple gene products and/or environmental elements may determine the final phenotypic outcome for a given individual and that variations among these factors may cause the wide variability in the clinical features seen in HPE.

The Growth Hormone Research Society (GRS) convened a Workshop in March 2019 to evaluate the diagnosis and therapy of short stature in children. Forty-six international experts participated at the invitation of GRS including clinicians, basic scientists, and representatives from regulatory agencies and the pharmaceutical industry. Following plenary presentations addressing the current diagnosis and therapy of short stature in children, breakout groups discussed questions produced in advance by the planning committee and reconvened to share the group reports. A writing team assembled one document that was subsequently discussed and revised by participants. Participants from regulatory agencies and pharmaceutical companies were not part of the writing process. Short stature is the most common reason for referral to the pediatric endocrinologist. History, physical examination, and auxology remain the most important methods for understanding the reasons for the short stature. While some long-standing topics of controversy continue to generate debate, including in whom, and how, to perform and interpret growth hormone stimulation tests, new research areas are changing the clinical landscape, such as the genetics of short stature, selection of patients for genetic testing, and interpretation of genetic tests in the clinical setting. What dose of growth hormone to start, how to adjust the dose, and how to identify and manage a suboptimal response are still topics to debate. Additional areas that are expected to transform the growth field include the development of long-acting growth hormone preparations and other new therapeutics and diagnostics that may increase adult height or aid in the diagnosis of growth hormone deficiency.

BACKGROUND: The safety and efficacy of early, low-dose, prolonged therapy with inhaled nitric oxide in premature newborns with respiratory failure are uncertain. METHODS: We performed a multicenter, randomized trial involving 793 newborns who were 34 weeks of gestational age or less and had respiratory failure requiring mechanical ventilation. Newborns were randomly assigned to receive either inhaled nitric oxide (5 ppm) or placebo gas for 21 days or until extubation, with stratification according to birth weight (500 to 749 g, 750 to 999 g, or 1000 to 1250 g). The primary efficacy outcome was a composite of death or bronchopulmonary dysplasia at 36 weeks of postmenstrual age. Secondary safety outcomes included severe intracranial hemorrhage, periventricular leukomalacia, and ventriculomegaly. RESULTS: Overall, there was no significant difference in the incidence of death or bronchopulmonary dysplasia between patients receiving inhaled nitric oxide and those receiving placebo (71.6 percent vs. 75.3 percent, P=0.24). However, for infants with a birth weight between 1000 and 1250 g, as compared with placebo, inhaled nitric oxide therapy reduced the incidence of bronchopulmonary dysplasia (29.8 percent vs. 59.6 percent); for the cohort overall, such treatment reduced the combined end point of intracranial hemorrhage, periventricular leukomalacia, or ventriculomegaly (17.5 percent vs. 23.9 percent, P=0.03) and of periventricular leukomalacia alone (5.2 percent vs. 9.0 percent, P=0.048). Inhaled nitric oxide therapy did not increase the incidence of pulmonary hemorrhage or other adverse events. CONCLUSIONS: Among premature newborns with respiratory failure, low-dose inhaled nitric oxide did not reduce the overall incidence of bronchopulmonary dysplasia, except among infants with a birth weight of at least 1000 g, but it did reduce the overall risk of brain injury. (ClinicalTrials.gov number, NCT00006401 [ClinicalTrials.gov].).

Summary Clinical and laboratory observations of 133 children and adolescents with Crohn's disease were used to validate an index of severity of illness previously developed by a group of senior pediatric gastroenterologists at a research forum in April 1990. This pediatric Crohn's disease activity index (PCDAI) included (a) subjective reporting of the degree of abdominal pain, stool pattern, and general well‐being; (b) presence of extraintestinal manifestations, such as fever, arthritis, rash, and uveitis; (c) physical examination findings; (d) weight and height; and (e) hematocrit, erythrocyte sedimentation rate, and serum albumin. Independent evaluation of each patient by two physician‐observers was performed at the time of a visit, and each physician completed a PCDAI index and a modified Harvey‐Bradshaw index and made a “global assessment” of disease activity as none, mild, moderate, or severe. Excellent interobserver agreement was noted for the PCDAI, modified Harvey‐Bradshaw index, and global assessment. There was a strong correlation between global assessment and both the PCDAI or modified Harvey‐Bradshaw. Increasing PCDAI scores were noted with increasing disease severity, and significant differences in scores were noted between the severity groups. We propose that the PCDAI could be used in multicenter projects to facilitate patient stratification by disease severity and that longitudinal PCDAI scores might provide a numerical measure of response to therapeutic regimens.

BACKGROUND: High-dose erythropoietin has been shown to have a neuroprotective effect in preclinical models of neonatal brain injury, and phase 2 trials have suggested possible efficacy; however, the benefits and safety of this therapy in extremely preterm infants have not been established. METHODS: In this multicenter, randomized, double-blind trial of high-dose erythropoietin, we assigned 941 infants who were born at 24 weeks 0 days to 27 weeks 6 days of gestation to receive erythropoietin or placebo within 24 hours after birth. Erythropoietin was administered intravenously at a dose of 1000 U per kilogram of body weight every 48 hours for a total of six doses, followed by a maintenance dose of 400 U per kilogram three times per week by subcutaneous injection through 32 completed weeks of postmenstrual age. Placebo was administered as intravenous saline followed by sham injections. The primary outcome was death or severe neurodevelopmental impairment at 22 to 26 months of postmenstrual age. Severe neurodevelopmental impairment was defined as severe cerebral palsy or a composite motor or composite cognitive score of less than 70 (which corresponds to 2 SD below the mean, with higher scores indicating better performance) on the Bayley Scales of Infant and Toddler Development, third edition. RESULTS: A total of 741 infants were included in the per-protocol efficacy analysis: 376 received erythropoietin and 365 received placebo. There was no significant difference between the erythropoietin group and the placebo group in the incidence of death or severe neurodevelopmental impairment at 2 years of age (97 children [26%] vs. 94 children [26%]; relative risk, 1.03; 95% confidence interval, 0.81 to 1.32; P = 0.80). There were no significant differences between the groups in the rates of retinopathy of prematurity, intracranial hemorrhage, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, or death or in the frequency of serious adverse events. CONCLUSIONS: High-dose erythropoietin treatment administered to extremely preterm infants from 24 hours after birth through 32 weeks of postmenstrual age did not result in a lower risk of severe neurodevelopmental impairment or death at 2 years of age. (Funded by the National Institute of Neurological Disorders and Stroke; PENUT ClinicalTrials.gov number, NCT01378273.).

BACKGROUND AND STUDY AIMS: Postpolypectomy bleeding is a rare but serious adverse event. The aim of this study was to identify factors associated with the risk of severe delayed postpolypectomy bleeding. PATIENTS AND METHODS: This was a case-control study, comparing cases who developed hematochezia and required medical evaluation 6 hours to 14 days after colonoscopic polypectomy, and control patients who underwent polypectomy without delayed bleeding, and who were selected in approximately a 3 : 1 ratio. The following risk factors were specified a priori: resuming anticoagulation (within 1 week following polypectomy), aspirin use, hypertension, and polyp diameter. RESULTS: Of the 4592 patients who underwent colonoscopy with polypectomy, 41 patients (0.9 %) developed delayed postpolypectomy bleeding (cases), and 132 patients were selected as controls. The mean age was 64.3 years for cases and 65.4 years for controls. Cases presented on average 6 days after polypectomy (range 1 - 14 days), and 48 % required blood transfusion (average 4.2 units, range 0 - 17). Two patients required surgery. Anticoagulation was resumed following polypectomy in 34 % of cases compared with 9 % of controls (OR 5.2; 95 % CI 2.2 - 12.5; P < 0.001). For every 1 mm increase in polyp diameter, the risk of hemorrhage increased by 9 % (OR 1.09; 95 % CI 1.0 - 1.2; P = 0.008). Hypertension (OR 1.1) and aspirin use (OR 1.1) did not increase the risk of postpolypectomy bleeding. In exploratory analysis, diabetes (OR 2.5) and coronary artery disease (OR 3.0) were associated with postpolypectomy hemorrhage, but the association was no longer statistically significant once adjusted for the use of anticoagulation. CONCLUSIONS: Resuming anticoagulation following polypectomy and polyp diameter were strongly associated with increased risk of severe delayed postpolypectomy bleeding.

BACKGROUND: Serum ferritin measurements are used in clinical populations to estimate total body iron stores and the risk of subsequent iron deficiency or overload. The lack of normative newborn serum ferritin concentration data between 23 and 41 weeks has led to difficulty in establishing the incidence and degree of abnormal iron status in the neonatal period. OBJECTIVES: The primary objective of this review was to summarize the maternal and gestational factors that determine ferritin concentrations in full-term and pre-term newborn infants and to generate comprehensive reference values. The secondary objective was to assess serum ferritin concentrations in newborn infants at risk for abnormal fetal iron metabolism, including maternal diabetes mellitus, intrauterine growth restriction and maternal smoking during pregnancy. METHODS: Serum ferritin and gestational age data at birth from 457 low-risk pre-term and term infants of 23-41 weeks gestation obtained from 35 published studies reviewed from a period of 25 years and from recently collected data from our centers were assessed by regression analysis. Slopes and intercepts of the high-risk groups were compared with the standard curve. RESULTS: Umbilical cord serum ferritin concentrations increased with advancing gestational age, from a mean of 63 mug/l at 23 weeks to 171 mug/l at 41 weeks gestation (p < 0.001). The infants of diabetic mothers had a lower intercept than the control infants (p < 0.001). CONCLUSIONS: Iron deficiency and overload have been implicated in neurodevelopmental impairments. Normative cord serum ferritin data may permit a more precise assessment of infants who are at risk for abnormal iron status at birth.

IMPORTANCE: Pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) are poorly understood. OBJECTIVE: To characterize and identify risk factors associated with ARP and CP in childhood. DESIGN, SETTING, AND PARTICIPANTS: A multinational cross-sectional study of children with ARP or CP at the time of enrollment to the INSPPIRE (International Study Group of Pediatric Pancreatitis: In Search for a Cure) study at participant institutions of the INSPPIRE Consortium. From August 22, 2012, to February 8, 2015, 155 children with ARP and 146 with CP (aged ≤19 years) were enrolled. Their demographic and clinical information was entered into the REDCap (Research Electronic Data Capture) database at the 15 centers. Differences were analyzed using 2-sample t test or Wilcoxon rank sum test for continuous variables and Pearson χ2 test or Fisher exact test for categorical variables. Disease burden variables (pain variables, hospital/emergency department visits, missed school days) were compared using Wilcoxon rank sum test. MAIN OUTCOMES AND MEASURES: Demographic characteristics, risk factors, abdominal pain, and disease burden. RESULTS: A total of 301 children were enrolled (mean [SD] age, 11.9 [4.5] years; 172 [57%] female); 155 had ARP and 146 had CP. The majority of children with CP (123 of 146 [84%]) reported prior recurrent episodes of acute pancreatitis. Sex distribution was similar between the groups (57% female in both). Hispanic children were less likely to have CP than ARP (17% vs 28%, respectively; odds ratio [OR] = 0.51; 95% CI, 0.29-0.92; P = .02). At least 1 gene mutation in pancreatitis-related genes was found in 48% of patients with ARP vs 73% of patients with CP (P < .001). Children with PRSS1 or SPINK1 mutations were more likely to present with CP compared with ARP (PRSS1: OR = 4.20; 95% CI, 2.14-8.22; P < .001; and SPINK1: OR = 2.30; 95% CI, 1.03-5.13; P = .04). Obstructive risk factors did not differ between children with ARP or CP (33% in both the ARP and CP groups), but toxic/metabolic risk factors were more common in children with ARP (21% overall; 26% in the ARP group and 15% in the CP group; OR = 0.55; 95% CI, 0.31-0.99; P = .046). Pancreatitis-related abdominal pain was a major symptom in 81% of children with ARP or CP within the last year. The disease burden was greater in the CP group compared with the ARP group (more emergency department visits, hospitalizations, and medical, endoscopic, and surgical interventions). CONCLUSIONS AND RELEVANCE: Genetic mutations are common in both ARP and CP. Ethnicity and mutations in PRSS1 or SPINK1 may influence the development of CP. The high disease burden in pediatric CP underscores the importance of identifying predisposing factors for progression of ARP to CP in children.

Naturally occurring compounds belonging to two chemical groups were studied for their capacities to inhibit N-nitrosodiethylamine (NDEA)-induced carcinogenesis in female A/J mice. One group consists of organosulfur compounds found in Allium species, including garlic, onions, leeks, and shallots, and the other, two monoterpenes, i.e., D-limonene and D-carvone. In an initial experiment, in which organosulfur compounds were investigated, diallyl disulfide, allyl mercaptan, and allyl methyl disulfide were found to produce a marked inhibition of NDEA-induced neoplasia of the forestomach when the test compounds were administered p.o. 96 and 48 h prior to NDEA. The most potent was diallyl disulfide which reduced forestomach tumor formation by more than 90%. Pulmonary adenoma formation also was inhibited but to a considerably lesser extent, i.e., about 30%. In three additional experiments, test compounds were given p.o. either 15 min or 1 h prior to NDEA. Under these conditions diallyl disulfide and allyl mercaptan again inhibited forestomach tumor formation substantially, i.e., greater than 75%, and pulmonary adenoma formation marginally, i.e., less than 20%. In these experiments D-limonene and D-carvone were tested and reduced forestomach tumor formation by slightly over 60% and pulmonary adenoma formation by about 35%. The results of these studies provide evidence of an increasing diversity of naturally occurring compounds having the capacity to inhibit nitrosamine carcinogenesis.

Peatlands occupy approximately 15% of boreal and sub‐arctic regions, contain approximately one third of the world's soil carbon pool, and supply most of the dissolved organic carbon (DOC) entering boreal lakes and rivers and the Arctic Ocean. The high latitudes occupied by these peatlands are expected to see the greatest amount of climatic warming in the next several decades. In addition to increasing temperatures, climatic change could also affect the position of the water‐table level and discharge from these peatlands. Changes in temperature, water tables, and discharge could affect delivery of DOC to downstream ecosystems where it exerts significant control over productivity, biogeochemical cycles, and attenuation of visible and UV radiation. We experimentally warmed and controlled water tables while measuring discharge in a factorial experiment in large mesocosms containing peat monoliths and intact plant communities from a bog and fen to determine the effects of climate change on DOC budgets. We show that the DOC budget is controlled largely by changes in discharge rather than by any effect of warming or position of the water‐table level on DOC concentrations. Furthermore, we identify a critical discharge rate in bogs and fens for which the DOC budget switches from net export to net retention. We also demonstrate an exponential increase in trace gas CO 2 –C and CH 4 –C emissions coincident with increased retention of dissolved organic carbon from boreal peatlands.