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PURPOSE: Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Five-year survival is approaching 90%. In efforts to further improve outcomes, it is critical to consider the cost of ALL care. MATERIALS AND METHODS: Commercial insurance data from OptumLabs Data Warehouse were used to identify patients with ALL, age 1-30 years, diagnosed in 1993-2017 in the United States, with 36 months of continuous insurance coverage. Patients treated with hematopoietic cell transplantation were excluded. Inpatient and outpatient utilization and cumulative reimbursements (inflation-adjusted to December 2020) were computed 8 and 36 months from diagnosis and stratified by age (1-9, 10-12, and ≥ 13 years) as proxies for National Cancer Institute risk groups. Regression models were constructed to assess associations with demographic and clinical characteristics. RESULTS: Among 927 patients (median age, 6 years; interquartile range, 3-12 years; 43% female), individuals age ≥ 10 years had 23-25 more inpatient days and 22 more outpatient encounters compared with younger patients. The 36-month median cost was $394,000 (USD) (interquartile range, $256,000-$695,000 [USD]), and 64% of the total cost was incurred during the initial 8 months. The 36-month cost was 1.5-fold higher for those age 10-12 years and 1.7-fold higher for those age ≥ 13 years compared with 1-9 years. The cost for those diagnosed in 2013-2017 was 70% higher compared with 1993-2002, and was not different on the basis of sex, race, or ethnicity. CONCLUSION: Older age was associated with higher utilization and cost, and the cost of treatment increased significantly over time. These data provide valuable benchmarks for future studies examining the cost-benefit of ALL therapy modifications.

Aim: Sertraline is a CYP2C19 substrate commonly prescribed to children with anxiety. Materials & methods: This medical record review examined dosing trends and treatment discontinuation in children prescribed sertraline with documented CYP2C19 genotypes. Variables collected included age, weight, diagnosis, concomitant medications, initial sertraline dose, dose changes and CYP2C19 genotypes. Results: A total of 90 individuals (average age: 10.5 years; 40% female) were included. Nearly 80% were prescribed sertraline for anxiety. Initial weight-adjusted doses were similar, but mean weight-adjusted doses of sertraline were 65% higher in increased metabolizers (1.5 mg/kg/day) compared with normal metabolizers (0.91 mg/kg/day; p = 0.067) at the second dose change. Conclusion: While all children started at a similar sertraline dose, different trends in prescribed doses were observed across CYP2C19 genotypes at subsequent dose changes.

ObjectiveThrombosis is a major complication after cardiac surgery in children with congenital heart disease (CHD). The mechanisms underlying thrombosis development remain poorly understood. We aimed to identify novel circulating metabolites before cardiac surgery that are associated with the development of thrombosis after surgery in children with CHD.Approach and resultsAll blood samples were drawn right before surgical incision and after the induction of anesthesia, and plasma was separated immediately under 4 °C. Untargeted metabolomic data were measured by Metabolon in plasma from children (age range: 0 days-18 years) with CHD undergoing cardiac surgery. The primary outcome was thrombosis within 30 days of surgery or before discharge. Associations of individual metabolites with thrombosis were assessed with logistic regression with false discovery rate (FDR) correction for multiple comparison and adjustment for clinical characteristics; elastic net regression was used to select a prediction model. Out of 1,115 metabolites measured in samples from 203 children, 776 met the quality control criteria. In total, 26 children (12.8%) developed thrombosis. Among the 776 metabolites, 195 were significantly associated with thrombosis (FDR q-value < 0.05). The top three metabolites showing the strongest associations with thrombosis were eicosapentaenoate, steroid monosulfate C19H28O6S, and formiminoglutamate (FDR = 0.01 for all). Pathway analysis showed that the pathways of nicotinate and nicotinamide metabolism (P = 0.0007) and glycerophospholipid metabolism (P = 0.002) were enriched and had significant impacts on the development of thrombosis. In elastic net regression analysis, the area under the receiver operating-characteristic curve of a prediction model for thrombosis was 0.94 in the training sample (70% of the total sample) and 0.84 in the testing sample (the remaining 30%).ConclusionWe have identified promising novel metabolites and metabolic pathways associated with thrombosis. Future studies are warranted to confirm the findings and examine the mechanistic pathways to thrombosis.

PURPOSE: Pleuropulmonary blastoma (PPB) is the most common lung cancer of infancy and early childhood and is associated with germline DICER1 variants. Type I and Ir PPB are cystic lesions treated surgically, with a subset of children with type I receiving chemotherapy. Type II and III are more aggressive lesions treated surgically and with intensive chemotherapy and potentially radiation. We sought to assess health-related quality of life (HRQoL) in children with PPB and known germline DICER1 variants. METHODS: Children with a diagnosis of PPB or germline DICER1 pathogenic variant without history of PPB or other DICER1-related neoplasm (DICER1+ only) were enrolled in the International PPB/DICER1 Registry. Parent reports for participants aged 2–17 years for the PedsQL v.4 and PedsQL Multidimensional Fatigue Scale v.3 were collected. Fatigue, physical, and psychosocial function scores were compared. RESULTS: Analysis included 84 participants (PPB type Ir=20, type I=15, type II/III=27, DICER1+ only=22). Total fatigue scores of participants with type I and II/III PPB were lower compared to DICER1+ only, with effect size larger in type II/III (−0.82 vs −0.40). Total psychosocial and physical functioning scores were lower in participants with type I and type II/III PPB compared to DICER1+ only with larger effects noted in type II/III. Female sex was suggestive of worse HRQoL for both type I/Ir and type II/III cohorts. CONCLUSIONS: These data demonstrate the importance of regular HRQoL assessment in patients with a history of PPB as well as the importance and feasibility of studying HRQoL in children with rare tumors.

The aim of this study was to determine the accuracy and interrater reliability of (1) point-of-care ultrasound (POCUS) image interpretation for identification of intussusception and (2) reliability of secondary signs associated with intussusception among experts compared with novice POCUS reviewers.We conducted a planned secondary analysis of a prospective, convenience sample of children aged 3 months to 6 years who were evaluated with POCUS for intussusception across 17 international pediatric emergency departments between October 2018 and December 2020. A random sample of 100 POCUS examinations was reviewed by novice and expert POCUS reviewers. The primary outcome was identification of the presence or absence of intussusception. Secondary outcomes included intussusception size and the presence of trapped free fluid or echogenic foci. Accuracy was summarized using sensitivity and specificity, which were estimated via generalized mixed effects logistic regression. Interrater reliability was summarized via Light's κ statistics with bootstrapped standard errors (SEs). Accuracy and reliability of expert and novice POCUS reviewers were compared.Eighteen expert and 16 novice POCUS reviewers completed the reviews. The average expert sensitivity was 94.5% (95% confidence interval [CI], 88.6-97.5), and the specificity was 94.3% (95% CI, 90.3-96.7), significantly higher than the average novice sensitivity of 84.7% (95% CI, 74.3-91.4) and specificity of 80.4% (95% CI, 72.4, 86.7). κ was significantly greater for expert (0.679, SE 0.039) compared with novice POCUS reviewers (0.424, SE 0.044; difference 0.256, SE 0.033). For our secondary outcome measure of intussusception size, κ was significantly greater for experts (0.661, SE 0.038) compared with novices (0.397, SE 0.041; difference 0.264, SE 0.029). Interrater reliability was weak for expert and minimal for novice reviewers regarding the detection of trapped free fluid and echogenic foci.Expert POCUS reviewers demonstrate high accuracy and moderate interrater reliability when identifying intussusception via image interpretation and perform better than novice reviewers.

OBJECTIVESEnoxaparin has been studied for prophylaxis and treatment of thromboembolism in the pediatric population. Dose-finding studies have suggested higher mean maintenance dose requirements in younger children; however, the current recommended dosing schema endorsed by the American College of Chest Physicians remains conservative, likely secondary to limited data on the safety and efficacy of escalated starting doses. Primary objectives of this study included the identification of patient characteristics and risk factors with associations to anti–factor Xa (anti-Xa) values. The secondary objective was to determine an association between the initial anti-Xa value and thrombus resolution. Safety outcomes related to bleeding were also assessed.METHODSThis retrospective cohort study reviewed records of all pediatric patients ≤18 years of age who were initiated on therapeutic subcutaneous enoxaparin between October 1, 2008, and October 1, 2018, at Children's Hospitals and Clinics of Minnesota for an indication of incident thrombus (N = 283).RESULTSSuccessful resolution of thrombus was directly associated with attaining a therapeutic anti-Xa concentration upon first laboratory evaluation. Other characteristics with associations to initial anti-Xa values included age, body mass index, and certain diagnoses. The rate of composite bleeding was consistent across concentrations of anti-Xa (p = 0.4944).CONCLUSIONSDespite adherence to protocol, the current enoxaparin dosing nomogram is only successful at achieving a therapeutic anti-Xa concentration (0.5–1.0 unit/mL) 55.8% of the time. A more aggressive enoxaparin dosing nomogram is warranted, as delaying time to therapeutic anti-Xa values impacts clinical outcomes, specifically thrombus resolution. Further investigation into characteristics with association to anti-Xa concentrations is needed.

Temperate propolis is collected by bees from the sticky secretions produced by the buds of poplar species. It is used to coat and seal the hive thus protecting against infections. Extensive research indicates that propolis has strong anti-protozoal activity. There have been some large clinical trials testing propolis against a variety of conditions but despite there is no information on whether or not the active components in propolis are absorbed by humans. In order to answer this question, a small study was carried out in order to determine whether or not propolis components could be detected in the urine of 5 human subjects taking a small dose of propolis tincture. In two of the subjects, levels of several of the flavonoids present in the propolis tincture many times above the baseline levels were detected following hydrolysis of the urine samples with a glucuronidase/sulfatase. Analysis of urine samples prior to hydrolysis indicated the presence of glucuronides and sulfates of the main flavonoids in propolis. Flavonoid absorption occurred to some degree in all subjects, apparent lower levels of flavonoid absorption in 3 out of five subjects might indicate genuine differences in level of absorption between subjects.

PURPOSE Pleuropulmonary blastoma (PPB) is the most common primary lung neoplasm of infancy and early childhood. Type II and type III PPB have historically been associated with a poor prognosis. METHODS Patients with known or suspected PPB were enrolled in the International PPB/ DICER1 Registry. Medical records were abstracted with follow-up ascertained annually. All PPB diagnoses were confirmed by central pathology review. Beginning in 2007, the IVADo regimen (ifosfamide, vincristine, actinomycin-D, and doxorubicin) was recommended as a potential treatment regimen for children with type II and type III PPB. This regimen was compared with a historical control cohort. RESULTS From 1987 to 2021, 314 children with centrally confirmed type II and type III PPB who received upfront chemotherapy were enrolled; 132 children (75 with type II and 57 with type III) received IVADo chemotherapy. Adjusted analyses suggest improved overall survival for children treated with IVADo in comparison with historical controls with an estimated hazard ratio of 0.65 (95% CI, 0.39 to 1.08). Compared with localized disease, distant metastasis at diagnosis was associated with worse PPB event-free survival and overall survival with hazard ratio of 4.23 (95% CI, 2.42 to 7.38) and 4.69 (95% CI, 2.50 to 8.80), respectively. CONCLUSION The use of IVADo in children with type II and type III PPB resulted in similar-to-improved outcomes compared with historical controls. Inferior outcomes with metastatic disease suggest the need for novel therapies. This large cohort of uniformly treated children with advanced PPB serves as a benchmark for future multicenter therapeutic studies for this rare pediatric tumor.

Background: Childhood acute lymphoblastic leukemia (ALL) treatment requires numerous lumbar punctures (LPs) with intrathecal (IT) chemotherapy to prevent and treat central nervous system disease. Historically, LPs in this setting are performed using propofol sedation. At our institution, LPs are often alternatively performed under nitrous oxide (N2O). To date, there have been no large scale assessments comparing these sedation methods for this purpose. Procedures: Retrospective cohort study of patients aged 0-31 years with ALL treated between 1/1/2013-12/31/2018 at the Children’s Minnesota Cancer and Blood Disorders Center, including all therapeutic LPs performed in the clinic setting under either propofol or N2O. Results: Among 215 patients and 2677 therapeutic LPs, 56.6% (n = 1515) occurred under N2O with 43.3% (n = 93) of patients using exclusively N2O with all LPs. The incidence of traumatic LPs (RBC ≥ 10 cells/µL) were similar between both treatments (27.3% vs 30.2). Successful IT chemotherapy delivery (99.7% N2O vs 99.8% propofol) did not differ between sedation types. Experiencing a traumatic LP under N2O was associated with a sedation switch for the subsequent LP (aOR 2.40, p=0.002) while older age (aOR 1.08, p

Study objective: To determine the diagnostic accuracy of point-of-care ultrasound (POCUS) performed by experienced clinician sonologists compared to radiology-performed ultrasound (RADUS) for detection of clinically important intussusception, defined as intussusception requiring radiographic or surgical reduction. Methods: We conducted a multicenter, noninferiority, observational study among a convenience sample of children aged 3 months to 6 years treated in tertiary care emergency departments across North and Central America, Europe, and Australia. The primary outcome was diagnostic accuracy of POCUS and RADUS with respect to clinically important intussusception. Sample size was determined using a 4-percentage-point noninferiority margin for the absolute difference in accuracy. Secondary outcomes included agreement between POCUS and RADUS for identification of secondary sonographic findings. Results: The analysis included 256 children across 17 sites (35 sonologists). Of the 256 children, 58 (22.7%) had clinically important intussusception. POCUS identified 60 (23.4%) children with clinically important intussusception. The diagnostic accuracy of POCUS was 97.7% (95% confidence interval [CI] 94.9% to 99.0%), compared to 99.3% (95% CI 96.8% to 99.9%) for RADUS. The absolute difference between the accuracy of RADUS and that of POCUS was 1.5 percentage points (95% CI −0.6 to 3.6). Sensitivity for POCUS was 96.6% (95% CI 87.2% to 99.1%), and specificity was 98.0% (95% CI 94.7% to 99.2%). Agreement was high between POCUS and RADUS for identification of trapped free fluid (83.3%, n=40/48) and decreased color Doppler signal (95.7%, n=22/23). Conclusion: Our findings suggest that the diagnostic accuracy of POCUS performed by experienced clinician sonologists may be noninferior to that of RADUS for detection of clinically important intussusception. Given the limitations of convenience sampling and spectrum bias, a larger randomized controlled trial is warranted.

Pleuropulmonary blastoma (PPB) is a primary embryonal malignancy of childhood that is characterized by distinct morphologic types: type Ir (regressed), type I (cystic), type II (cystic and solid), and type III (solid). Prognosis varies by PPB type. Most cases are associated with a germline pathogenic mutation in DICER1; however, there is limited data on the factor(s) at a cellular level that drive progression from type I to type III. In this study, we evaluated the expression of p53 and its prognostic implications. A total of 143 PPB cases were included in the study with the following distribution in PPB types: Ir (14%), I (23%), II (32%), and III (31%). P53 expression by immunohistochemistry (IHC) was recorded as four groups: 0%, 1-25%, 26-75%, and 76-100%. All type I PPBs showed 0-25% p53 expression compared to the higher p53 expression (25%) in type III PPB (p 0.0001), to support the argument that p53 has a role in tumor progression. In addition, type Ir with the architectural hallmarks of type I PPB, but lacking the primitive cell population, has negligible p53 expression. High p53 expression (staining observed in25% of the tumor cells) was significantly associated with age over 1 year (p = 0.0033), neoadjuvant therapy (p = 0.0009), positive resection margin (p = 0.0008) and anaplasia (p 0.0001). P53 expression was significantly associated with recurrence-free survival (p 0.0001) and overall survival (p = 0.0350), with higher p53 expression associated with worse prognosis. Comparisons of concordance statistics showed no significant difference in prognostication when using morphologic types compared to p53 expression groups (p = 0.647). TP53 sequence was performed in 16 cases; the most common variant identified was a missense variant (12 cases), and in one case a frameshift truncating variant was noted. Based on these findings, we recommend performing p53 IHC in all newly diagnosed cases of types II and III PPB to further aid in risk stratification.

Serratia can cause serious bloodstream infections (BSIs). This retrospective cohort study identified 5,312 pediatric inpatient encounters with BSIs from 2009 to 2016, of which 82 (0.01%) had Serratia BSIs. The rate among hospitalized patients increased significantly from 0.4 in 2009 to 1.0 in 2016 per 10,000 admissions. Risk factors differed and outcomes were worse for Serratia BSIs compared with non-Serratia BSIs.

OBJECTIVES The goal of this study was to evaluate trends in medical claim submissions for limited ultrasound studies performed (1) during emergency department (ED) encounters and (2) by ED providers compared to radiologists. METHODS We conducted a retrospective, descriptive study using medical claims data from Medica Health Plans from January 1, 2011 to December 31, 2015. Current procedural terminology codes were abstracted for limited ultrasound applications performed during an ED visit and further stratified by studies performed by ED providers compared with radiologists. We excluded claims for which we could not determine provider specialty. RESULTS We identified 42,576 encounters with limited US claims, of which, 32,666 were submitted by ED providers (N = 9649) or radiologists (N = 23,017). Among ED providers, there was a significant linear increase in the annual number of claims for retroperitoneal (P

Introduction: Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood, with a current incidence of 3,000 cases annually. Incremental alterations in treatment over time have resulted in overall survival rates that now exceed 90%. Although minor differences exist between ALL treatment protocols from different cooperative groups, risk-stratified treatment for ALL is generally standard across the country. As more has been understood about ALL biology and outcomes, treatments have been further risk stratified to optimize outcomes for higher risk individuals while minimizing toxicities for those with more favorable disease characteristics. With the improvements in outcome for ALL, cost of care is a critical component and financial toxicity for patients and society requires evaluation. Methods: Using commercial insurance data from the OptumLabs ® Data Warehouse, a cohort of 1941 ALL patients was identified, aged 1-30 years and diagnosed between 2000 and 2017 in the United States. ALL diagnosis was confirmed based on ICD-9 and ICD-10 diagnostic codes, in combination with bone marrow and lumbar puncture procedure codes within 14 days of diagnosis. Individuals were followed up to 36 months from diagnosis. Mean monthly and cumulative costs were computed for the initial 8 months of therapy and for 36 months from diagnosis, as were mean number of inpatient and outpatient days. Costs were further broken down by the types of services provided. All results were stratified by age group (1-9 years, 10-12 years, ≥13 years) as a proxy for risk group, with the younger group most consistent with standard risk disease and the older groups indicating high risk and very high risk disease, respectively. Results: Among the 1941 identified ALL patients (1-9 years, 1233; 10-12 years, 162; ≥13 years, 546), 44% were female, 51% were white, median age at diagnosis was 6 years (interquartile range 3-14 years) and 941 of enrolled patients had continuous data through 36 months. Mean cost of care over the approximate 3 years of therapy was $537,000, with approximately 58% of costs incurred within the initial intensive 8 months of therapy. Mean cost was highest among the ≥13 year age group, both for the initial 8 months of therapy ($487,000, 95% CI $449,300-530,400)), as well as over the 36 months following diagnosis ($850,000, 95% CI $778,400-937,100) (Figure). This was reflective of the highest mean number of inpatient days among the ≥13 year age group (88.1 days over 36 months, 95% CI 82.1-94.9) compared to the 10-12 year group (73.2 days, 95% CI 64.3-85.1) and the 1-9 year group (47.5 days, 95% CI 45.2-50.9). Mean number of outpatient visits over 36 months was not significantly different between 1-9 and 10-12 year age groups but was significantly higher among the ≥13 year age group compared with the 1-9 year group. Thirty-six month survival varied by age group and was highest among the 1-9 year group (95.9%, 95% CI 94.6-97.2) compared with the 10-12 year group (90.5%, 95% CI 85-4-95.8) and the ≥13 year group (79.6%, 95% CI 75.8-83.6). Conclusions: This robust real-world cost analysis shows for the first time that the average cost of ALL care in the current treatment era, including inpatient and outpatient data, is more than $500,000. We showed that the cost of care is highest among the oldest pediatric age group, indicating increasing cost with increased therapeutic intensity. This study provides a valuable benchmark that can be used to analyze the financial toxicity of ALL therapy on patients and families and can be re-assessed over time as novel therapeutics are introduced into ALL therapy. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background The prevalence of primary headache disorders in the general population provides a unique challenge in the evaluation of headache occurring in the context of sport. Despite a wealth of studies exploring the epidemiology of headache in the layperson, little is known about the prevalence and nature of headaches in collegiate student-athletes. These scenarios are challenging in the return to play context, as it is often unclear whether an athlete has an exacerbation of a primary headache disorder, new onset headache unrelated to trauma, or has suffered a concussive injury. Purpose To establish the prevalence and nature of headaches in collegiate student-athletes. Study design Retrospective cross-sectional survey. Methods This cross-sectional survey evaluated the characteristics and prevalence of headache in 834 student-athletes from four NCAA Division-I institutions. Because headache occurrence may vary by sport (collision, contact, non-contact), by sex, and medical history, our sample included male and female athletes in a variety of sports, with differing degrees of contact exposure. The 20 question survey collected data on personal and family history of headache, as well as concussion history. Results A total of 23.7% (n = 198) of participants reported having a personal history of migraine, 25.2% (n = 210) history of sinus headache, and 12.3% (n = 103) history of tension type headache. Among athletes with a prior history of concussion, 46.3% (n = 25) of females reported a history of migraine, while only 32.2% of males reported history of migraine (χ2 = 3.421, P = .064). Conclusions The etiology of increased prevalence of migraine in our study is unclear. Whether this is due to increased awareness of headache disorders, a consequence of contact exposure, or a predisposition for migraine development in this age group remains unclear. Further studies are indicated.

BACKGROUND AND OBJECTIVES: Children with established type 1 diabetes (T1D) who present to the emergency department (ED) with mild diabetic ketoacidosis (DKA) are often hospitalized, although outpatient management may be appropriate. Our aim was to reduce hospitalization rates for children with established T1D presenting to our ED with mild DKA who were considered low risk for progression of illness. METHODS: We conducted a quality improvement initiative between January 1, 2012, and December 31, 2018 among children and young adults ≤21 years of age with established T1D presenting to our tertiary care ED with low-risk DKA. Children transferred to our institution were excluded. DKA severity was classified as low, medium, or high risk on the basis of laboratory and clinical criteria. Our quality improvement initiative consisted of development and implementation of an evidence-based treatment guideline after review by a multidisciplinary team. Our primary outcome was hospitalization rate, and our balancing measure was 3-day ED revisits. Statistical process control methods were used to evaluate outcome changes. RESULTS: We identified 165 patients presenting with low-risk DKA. The baseline preimplementation hospitalization rate was 74% (95% confidence interval 64%–82%), and after implementation, this decreased to 55% (95% confidence interval 42%–67%) (−19%; P = .011). The postimplementation hospitalization rate revealed special cause variation. One patient in the postimplementation period returned to the ED within 3 days but did not have DKA and was not hospitalized. CONCLUSIONS: Hospitalization rates for children and young adults presenting to the ED with low-risk DKA can be safely reduced without an increase in ED revisits.

Background Studies suggest that local food may contribute to well-being, but do not use standardized measures, or control groups. Methods An online survey compared participants of local food initiatives (n = 302) with members of the general population (n = 157) in terms of scores on standardized measures of well-being and distress. Using hierarchical ordinary least squares regression models, we explored the relationship between participation and well-being via four mediators—nature connectedness, psychological need satisfaction, diet and physical activity. Results Participants scored higher than non-participants on life satisfaction (t(346) = 2.30, P = 0.02, ρr = 0.12) and the WEMWBS scale (t(335) = 2.12, P = 0.04, ρr = 0.10), but differences in psychological distress were insignificant. More actively engaged participants scored higher on positive well-being and longer duration participation was associated with higher life satisfaction and less psychological distress. Finally, we found that participation contributes to psychological need satisfaction, better diet and connection to nature, three known drivers of well-being. Conclusions Well-being may be a co-benefit of local food initiatives beyond the physical and psychological benefits of growing food. Further research is needed to explore the mediators driving these effects, quantify benefits, and track impacts over time and across different social groups.

In order to meet the growing needs of the global food system, whilst at the same time mitigating the effects of climate change and other production limiting factors and reducing negative environmental externalities, maize, wheat and rice agri-food systems will be required to sustainably intensify production. In the irrigated systems of developing countries, significant scope exists for increasing water use efficiency through new soil, water and fertiliser management approaches (such as Conservation Agriculture, Direct Seeding, Alternate Wetting and Drying, Site Specific Nutrient Management and Nutrient Expert) and crop diversification. In addition to the development of weather agro-advisory services and weather index insurance, the options available in rain-fed systems differ markedly from those available in irrigated systems, namely, to optimise every drop of available rainfall or to avoid drought stress situations. Whilst breeding for heat tolerance and diversified cropping systems are likely to be the principal short-term responses to increased mean global temperatures and extreme heat events, changes over the longer term are predicted to be quite dramatic, especially with regard to a productive expansion of temperate crops towards the poles. Whilst significant opportunities exist to ameliorate the effects of climate change, these opportunities generally involve risk. In developed countries, the private sector (seed, fertiliser, pesticide, irrigation, credit and insurance suppliers) is generally at hand to advise farmers how to address the challenges posed by climate change. Conversely, in most developing countries, there are few sources of advice and support for smallholder farmers. This situation leaves many smallholder farmers in developing countries without the advice and support that they desperately need. Ultimately, the most vulnerable farmers and communities, namely, smallholder subsistence and market oriented farmers in marginal environments, are those who face the most extreme climate change-related challenges at the same time as being the least able to adapt. Whilst international agricultural research centres (CGIAR), advanced research and development-focused centres of developed countries, and both local and international NGOs strive to both develop and translate evolving crop management approaches; the dissemination of climate smart agricultural practices is extremely slow.

5547 Background: Sertoli-Leydig cell tumors (SLCT) are rare ovarian sex cord-stromal tumors which occur primarily in adolescents and young adults and are associated with DICER1 pathogenic variants. Methods: Informed consent for participation in the International PPB/ DICER1 or OTST Registry was obtained. When available, pathology was centrally reviewed. Staging was evaluated by Registry review using the International Federation of Gynecology and Obstetrics (FIGO) classification system. Results: Eighty-three patients with stage I SLCT were enrolled. Median age at diagnosis was 15 (range 1-60) years. Most (57/83) patients had germline DICER1 testing; 35/57 (61%) had germline pathogenic variants. Fifty-six patients had Ia and 27 had Ic SLCT. The distribution of patients receiving chemo based on histology and stage is displayed in Table. One patient with poorly differentiated stage Ia SLCT with sarcomatous elements and no chemo at diagnosis recurred 6 months after surgery and died of disease. Three patients with local diagnosis of stage Ia SLCT, with data unavailable for Registry confirmation of stage, developed a subsequent SLCT 33 to 74 months after diagnosis; of these, 2 died, and 1 remains in treatment for recurrence. Available records and molecular testing in these 3 cases have not provided a distinction between recurrent and metachronous disease. Excluding the latter 3 patients, 3-year overall survival was 97.3% for stage Ia SLCT. Six patients with stage Ic SLCT recurred (Stage Ic1=5 and Stage Ic2=1) with a median time to recurrence of 25 (range 3-53) months. In stage Ic1, 18% (2/11) recurred after upfront chemo compared to 33% (3/9) after surgery alone. Of the 5 patients with stage Ic1 disease that recurred, 4 had intermediate and 1 had poorly differentiated SLCT. One patient had sarcomatous elements and 2 received upfront chemo. Two of the 5 patients are alive, neither received upfront chemo. One patient with poorly differentiated stage Ic2 SLCT with sarcomatous elements and no upfront chemo recurred and died of disease. Three-year event free and overall survival were 86.9 and 88.6% for stage Ic SLCT. Four patients had metachronous SLCT in the contralateral ovary confirmed by clinical review or somatic testing at a median time from diagnosis of 33 (range 28-104) months. All 4 have germline pathogenic variants and no evidence of disease at last follow-up. Conclusions: Individuals with early stage SLCT generally fare well, however, ongoing surveillance for recurrence and metachronous disease is indicated. Novel therapies are needed to address recurrent SLCT.[Table: see text]

Background Bloodstream infections (BSI) cause significant morbidity and mortality in children, leading to longer hospital stays and increased healthcare costs. Recent epidemiology on national trends and pathogens in children is lacking, which could improve prevention strategies and empiric therapy selection. Methods We conducted a retrospective cohort study utilizing demographic and microbiology data from the Premier Healthcare Database, including all inpatient encounters from 2009–2016 among patients

The need to discover and develop alternative therapies to treat methicillin-resistant Staphylococcus aureus (MRSA) infections is timely. This study was undertaken to purify and identify some anti-MRSA constituents from propolis, a natural product from the beehive traditionally used in folk medicine for its antimicrobial properties. A crude extract of propolis originating from the Solomon Islands ('Pacific propolis') was screened, using an agar dilution assay, in vitro against 15 MRSA clinical isolates. Results revealed activity worthy of further investigation, and subsequent purification work on this crude extract afforded 23 fractions. Further purification of active fractions led to the isolation of compounds 1-4, characterized upon analysis of their spectroscopic data (1D- and 2D-NMR, MS) and by comparison with the literature, as the prenylflavanones propolin H (1), propolin G (2), propolin D (3), and propolin C (4). This study is the first to report the anti-MRSA activity of 'Pacific propolis' and the presence of prenylflavanones in the propolis sample selected. The anti-MRSA activity of propolin D (3) (MIC 8-16 mg/L) and propolin C (4) (MIC 8-32 mg/L) is reported for the first time.

This software series is concerned with reconstruction of spatial functions by interpolating a set of discrete observations having two or three independent variables. There are three components in this series: (1) nngridr: an implementation of natural neighbor interpolation, 1994, (2) modemap: an implementation of natural neighbor interpolation on the sphere, 1998 and (3) orebody: an implementation of natural neighbor isosurface generation (publication incomplete). Interpolation is important to geologists because it can offer graphical insights into significant geological structure and behavior, which, although inherent in the data, may not be otherwise apparent. It also is the first step in numerical integration, which provides a primary avenue to detailed quantification of the observed spatial function. Interpolation is implemented by selecting a surface-generating rule that controls the form of a `bridge' built across the interstices between adjacent observations. The cataloging and classification of the many such rules that have been reported is a subject in itself ( Watson, 1992 ), and the merits of various approaches have been debated at length. However, for practical purposes, interpolation methods are usually judged on how satisfactorily they handle problematic data sets. Sparse scattered data or traverse data, especially if the functional values are highly variable, generally tests interpolation methods most severely; but one method, natural neighbor interpolation, usually does produce preferable results for such data.

In those aged over 65 years depression is the most common psychiatric disorder. Although the prevalence varies according to the criteria used and the methodology involved in making the diagnosis, a figure of around 10–15% is reported (Livingston et al, 1990; Copeland et al, 1987). Depression in older people is too often undetected and untreated, Dave Watson and colleagues explain.

Dementia describes a condition characterized by loss of memory and skills, and a change in personality and behaviour caused by a variety of illnesses, the commonest and most well known being Alzheimer's disease. Practice nurses can be in the forefront of identifying dementia and arranging appropriate intervention.

Demonstration and Results of Grid Integrated Technologies at the Demand to Grid Laboratory (D2G Lab): Phase I Operations Report Girish Ghatikar, Venkata Ganti, Mary Ann Piette, Janie Page, Sila Kiliccote, Chuck McParland Lawrence Berkeley National Laboratory Dave Watson Slice Energy, Inc. July 2013

The authors report on a study that asked students to identify specific dating behaviors that indicate an interest in sex. The study also examined perceptions of what women do that lead men to justify raping them, as well as what men say to justify having raped.

Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC)1. It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions2-4. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients. © 2011 Macmillan Publishers Limited. All rights reserved.

Introduction: This prospective randomized double-blinded in-vitro study was conducted to determine the relative Packing Density (PD) of the new Deltapaq coil (Micrus Endovascular) as compared to Micrus’s conventional filling CHE (Helipaq) and finishing CFS (Ultipaq) coils. Methods: Two physicians independently deployed the coils under fluoroscopy into a 4mm berry shaped glass aneurysm. Each coil tested was a 4mm × 35cm coil specially made for this study. Physicians and observer were blinded as to the type of coil. Five samples per group, per operator, were deployed. Results: mean PD were 36.6% (Helipaq), 37.9% (Ultipaq) and 40.4% (Deltapaq). Two-sample T-test showed a significantly higher PD of Deltapaq versus Helipaq (p < 0.022). Discussion: Higher coil PD and better neck coverage may provide an increased biomechanical stability and may potentially reduce the recanalization rate of aneurysms. Conclusion: The new Deltapaq coil may have the potential to achieve higher packing densities in the treatment of aneurysms.

The need to discover and develop alternative therapies to treat methicillin-resistant Staphylococcus aureus (MRSA) infections is timely. This study was undertaken to purify and identify some anti-MRSA constituents from propolis, a natural product from the beehive traditionally used in folk medicine for its antimicrobial properties. A crude extract of propolis originating from the Solomon Islands ('Pacific propolis') was screened, using an agar dilution assay, in vitro against 15 MRSA clinical isolates. Results revealed activity worthy of further investigation, and subsequent purification work on this crude extract afforded 23 fractions. Further purification of active fractions led to the isolation of compounds 1-4, characterized upon analysis of their spectroscopic data (1D- and 2D-NMR, MS) and by comparison with the literature, as the prenylflavanones propolin H (1), propolin G (2), propolin D (3), and propolin C (4). This study is the first to report the anti-MRSA activity of 'Pacific propolis' and the presence of prenylflavanones in the propolis sample selected. The anti-MRSA activity of propolin D (3) (MIC 8-16 mg/L) and propolin C (4) (MIC 8-32 mg/L) is reported for the first time.

The introduction of drug therapy for the treatment of Alzheimer's disease has implications for primary care in terms of the recognition and referral of patients with memory problems. With a rapidly ageing population demand for services will increase. A specialist memory clinic in the Wirral is proving promising in treatment of mild to moderate dementia.

Triangulation and tesselation methods have proven successful for reconstructing dynamical systems which have approximately the same dynamics as given trajectories or time series. Such reconstructions can produce other trajectories with similar dynamics, so giving a system on which one can conduct experiments, but can also be used to locate equilibria and determine their types, carry out bifurcation studies, estimate state manifolds and so on. In the past, reconstruction by triangulation and tesselation methods has been restricted to low-noise or no-noise cases. This paper shows how to construct triangulation models for noisy systems; the models can then be used in the same ways as models of noise-free systems.

The goal of this contract was to apply chip on glass wire bonding and connection techniques to flat panel displays. This would considerably lower the cost of completed panels by eliminating individual driver chip packaging and as many as 3000 connections for a 640 x 480 pixel display. In addition, there would be benefits in size and reliability. The effort was able to successfully demonstrate that the process could be compatible with the structure and materials present in a flat panel display. A number of displays were fabricated and tested. The reliability of the drive chips proved to be a limiting factor, due to insufficient testing before installation. At present it is cost effective for displays smaller than 640 x 480; however, as the quality of the chips increases, it is expected to become cost effective to use the techniques developed in this program for larger displays.