Modeling of a spatially resolved ion temperature diagnostic for inertial confinement fusion.

The performance of modern laser-driven inertial confinement fusion (ICF) experiments is degraded by contamination of the deuterium-tritium (DT) fuel with high-Z material during compression. Simulations suggest that this mix can be described by the ion temperature distribution of the implosion, given that such contaminants deviate in temperature from the surrounding DT plasma. However, existing neutron time-of-flight (nTOF) diagnostics only measure the spatially integrated ion temperature. This paper describes the techniques and forward modeling used to develop a novel diagnostic imaging system to measure the spatially resolved ion temperature of an ICF implosion for the first time. The technique combines methods in neutron imaging and nTOF diagnostics to measure the ion temperature along one spatial dimension at yields currently achievable on the OMEGA laser. A detailed forward model of the source and imaging system was developed to guide instrument design. The model leverages neutron imaging reconstruction algorithms, radiation hydrodynamics and Monte Carlo simulations, optical ray tracing, and more. The results of the forward model agree with the data collected on OMEGA using the completed diagnostic. The analysis of the experimental data is still ongoing and will be discussed in a separate publication.

Comparing Effectiveness of a Generic Oral Nutritional Supplement With Specialized Formula in the Treatment of Active Pediatric Crohn's Disease.

BACKGROUND: Exclusive enteral nutrition (EEN) is the recommended induction treatment of mild to moderate active pediatric Crohn's disease (CD). This study compared outcomes of 2 proprietary polymeric formulas. Treatment effectiveness was examined along with practical aspects of formula delivery and differences in estimated treatment costs. METHODS: Data were retrospectively collected from patients with CD who received a generic oral nutritional supplement (Fortisip) across 2 centers (RCH, Melbourne and RHSC, Edinburgh). This was compared with a prospective cohort (RHC, Glasgow) that used a specialized formula (Modulen IBD). The data collected included patient demographics, remission rates, biochemical markers, administration method, and anthropometrics. The estimated treatment cost was performed by comparing price per kcal between each formula. RESULTS: One hundred seventy-one patients were included (106 Fortisip, 65 Modulen IBD, 70 female; median age 13.3 yrs). No difference was demonstrated in remission rate (Fortisip n = 67 of 106 [63%] vs Modulen IBD n = 41 of 64 [64%], P = .89), nonadherence rate (Fortisip n = 7 of 106 [7%] vs Modulen IBD 3 of 64 [5%], P = .57) or method of administration (NGT Fortisip use n = 16 of 106 [12%] vs Modulen IBD 14 of 65 [22%]; P = .31). There was no difference in reduction of biochemical disease markers between the groups (C-reactive protein , P = .13; erythrocyte sedimentation rate, P = .49; fecal calprotectin, P = .94). However, there was a cost-saving of around £500/patient/course if the generic oral nutritional supplement was used. CONCLUSIONS: The generic oral nutritional supplement and specialized formulas both had similar clinical effectiveness in induction of remission in pediatric CD. However, there is considerable cost-saving when using a generic oral nutritional supplement.

Malignancy and mortality in paediatric-onset inflammatory bowel disease: a 3-year prospective, multinational study from the paediatric IBD Porto group of ESPGHAN.

BACKGROUND: Risk benefit strategies in managing inflammatory bowel diseases (IBD) are dependent upon understanding the risks of uncontrolled inflammation vs those of treatments. Malignancy and mortality in IBD have been associated with disease-related inflammation and immune suppression, but data are limited due to their rare occurrence. AIM: To identify and describe the most common causes of mortality, types of cancer and previous or current therapy among children and young adults with paediatric-onset IBD. METHODS: Information on paediatric-onset IBD patients diagnosed with malignancy or mortality was prospectively collected via a survey in 25 countries over a 42-month period. Patients were included if death or malignancy occurred after IBD diagnosis but before the age of 26 years. RESULTS: In total, 60 patients were identified including 43 malignancies and 26 fatal cases (9 due to cancer). Main causes of fatality were malignancies (n = 9), IBD or IBD-therapy related nonmalignant causes (n = 10; including 5 infections), and suicides (n = 3). Three cases, all fatal, of hepatosplenic T-cell lymphoma were identified, all were biologic-naïve but thiopurine-exposed. No other haematological malignancies were fatal. The 6 other fatal cancer cases included 3 colorectal adenocarcinomas and 3 cholangiocarcinomas (CCAs). Primary sclerosing cholangitis (PSC) was present in 5 (56%) fatal cancers (1 colorectal carcinoma, 3 CCAs and 1 hepatosplenic T-cell lymphoma). CONCLUSIONS: We report the largest number of paediatric-onset IBD patients with cancer and/or fatal outcomes to date. Malignancies followed by infections were the major causes of mortality. We identified PSC as a significant risk factor for cancer-associated mortality. Disease-related adenocarcinomas were a commoner cause of death than lymphomas.

NOX1 loss-of-function genetic variants in patients with inflammatory bowel disease.

Genetic defects that affect intestinal epithelial barrier function can present with very early-onset inflammatory bowel disease (VEOIBD). Using whole-genome sequencing, a novel hemizygous defect in NOX1 encoding NAPDH oxidase 1 was identified in a patient with ulcerative colitis-like VEOIBD. Exome screening of 1,878 pediatric patients identified further seven male inflammatory bowel disease (IBD) patients with rare NOX1 mutations. Loss-of-function was validated in p.N122H and p.T497A, and to a lesser degree in p.Y470H, p.R287Q, p.I67M, p.Q293R as well as the previously described p.P330S, and the common NOX1 SNP p.D360N (rs34688635) variant. The missense mutation p.N122H abrogated reactive oxygen species (ROS) production in cell lines, ex vivo colonic explants, and patient-derived colonic organoid cultures. Within colonic crypts, NOX1 constitutively generates a high level of ROS in the crypt lumen. Analysis of 9,513 controls and 11,140 IBD patients of non-Jewish European ancestry did not reveal an association between p.D360N and IBD. Our data suggest that loss-of-function variants in NOX1 do not cause a Mendelian disorder of high penetrance but are a context-specific modifier. Our results implicate that variants in NOX1 change brush border ROS within colonic crypts at the interface between the epithelium and luminal microbes.

18F FDG positron-emission tomography findings of gliomatosis peritonei: A case report and review of the literature.

•Gliomatosis peritonei (GP) is a rare benign complication of ovarian teratomas that does not impact overall survival.•GP exhibits high 18-F FDG uptake unlike other non-malignant forms of mature teratoma.•The specific characteristics of GP on functional imaging may be used to follow it with active surveillance in select cases.

First Liquid Layer Inertial Confinement Fusion Implosions at the National Ignition Facility.

The first cryogenic deuterium and deuterium-tritium liquid layer implosions at the National Ignition Facility (NIF) demonstrate D_{2} and DT layer inertial confinement fusion (ICF) implosions that can access a low-to-moderate hot-spot convergence ratio (1230) DT ice layer implosions. Although high CR is desirable in an idealized 1D sense, it amplifies the deleterious effects of asymmetries. To date, these asymmetries prevented the achievement of ignition at the NIF and are the major cause of simulation-experiment disagreement. In the initial liquid layer experiments, high neutron yields were achieved with CRs of 12-17, and the hot-spot formation is well understood, demonstrated by a good agreement between the experimental data and the radiation hydrodynamic simulations. These initial experiments open a new NIF experimental capability that provides an opportunity to explore the relationship between hot-spot convergence ratio and the robustness of hot-spot formation during ICF implosions.

Integrative epigenome-wide analysis demonstrates that DNA methylation may mediate genetic risk in inflammatory bowel disease.

Epigenetic alterations may provide important insights into gene-environment interaction in inflammatory bowel disease (IBD). Here we observe epigenome-wide DNA methylation differences in 240 newly-diagnosed IBD cases and 190 controls. These include 439 differentially methylated positions (DMPs) and 5 differentially methylated regions (DMRs), which we study in detail using whole genome bisulphite sequencing. We replicate the top DMP (RPS6KA2) and DMRs (VMP1, ITGB2 and TXK) in an independent cohort. Using paired genetic and epigenetic data, we delineate methylation quantitative trait loci; VMP1/microRNA-21 methylation associates with two polymorphisms in linkage disequilibrium with a known IBD susceptibility variant. Separated cell data shows that IBD-associated hypermethylation within the TXK promoter region negatively correlates with gene expression in whole-blood and CD8+ T cells, but not other cell types. Thus, site-specific DNA methylation changes in IBD relate to underlying genotype and associate with cell-specific alteration in gene expression.

Triggering apoptosis in cancer cells with an analogue of cribrostatin 6 that elevates intracellular ROS.

Elevation of reactive oxygen species (ROS) is both a consequence and driver of the upregulated metabolism and proliferation of transformed cells. The resulting increase in oxidative stress is postulated to saturate the cellular antioxidant machinery, leaving cancer cells susceptible to agents that further elevate their intracellular oxidative stress. Several small molecules, including the marine natural product cribrostatin 6, have been demonstrated to trigger apoptosis in cancer cells by increasing intracellular ROS. Here, we report the modular synthesis of a series of cribrostatin 6 derivatives, and assessment of their activity in a number of cell lines. We establish that placing a phenyl ring on carbon 8 of cribrostatin 6 leads to increased potency, and observe a window of selectivity towards cancer cells. The mechanism of activity of this more potent analogue is assessed and demonstrated to induce apoptosis in cancer cells by increasing ROS. Our results demonstrate the potential for targeting tumors with molecules that enhance intracellular oxidative stress.

Systematic review and meta-analysis: Prevalence and possible causes of vitamin D deficiency and insufficiency in pediatric cancer patients.

BACKGROUND AND AIMS: Vitamin D inadequacy is now an internationally recognized health problem and pediatric cancer patients may be at even higher risk than healthy children. We aimed to evaluate primary research to establish the prevalence of vitamin D inadequacy and to explore its possible causes in pediatric cancer patients. METHODS: Electronic databases were searched (no restriction-Aug 2013) with no language restrictions and keywords related to cancer and vitamin D. We included studies of patients aged <18 years, diagnosed with and treated for cancer and reporting plasma vitamin D status. Evidence was critically appraised employing the CASP tool. Meta-analysis was performed when appropriate. RESULTS: We included 19 studies, which were mainly of moderate-quality and heterogeneous in the definitions of vitamin D deficiency and insufficiency. The median (range) prevalence of vitamin D deficiency was 14% (0-61.5%) and insufficiency 23% (0-83%). Finally, a significant effect of younger age with vitamin D inadequacy was shown (effect size: -0.132; 95%CI -0.203, -0.060). CONCLUSION: There is a possibility of a high prevalence of vitamin D inadequacy in pediatric cancer patients, especially older children, urging the need for high-quality population-based longitudinal studies using standard definitions.

Anti-TNF therapy for paediatric IBD: the Scottish national experience.

BACKGROUND AND AIMS: Biological agents are being increasingly used in the UK for paediatric-onset inflammatory bowel disease (PIBD) despite limited evidence and safety concerns. We evaluated effectiveness and safety in the clinical setting, highlighting drug cost pressures, using our national Scottish PIBD biological registry. METHODS: Complete usage of the biological agents, infliximab (IFX) and adalimumab (ADA) for treatment of PIBD (in those aged <18 years) from 1 January 2000 to 30 September 2010 was collated from all treatments administered within the Scottish Paediatric Gastroenterology, Hepatology and Nutrition (PGHAN) national managed service network (all regional PGHAN centres and paediatric units within their associated district general hospitals). RESULTS: 132 children had biological therapy; 24 required both agents; 114 had Crohn's disease (CD), 16 had ulcerative colitis (UC) and 2 had IBD Unclassified (IBDU). 127 children received IFX to induce remission; 61 entered remission, 49 had partial response and 17 had no response. 72 were given maintenance IFX and 23 required dose escalation. 18 had infusion reactions and 27 had adverse events (infections/other adverse events). 29 had ADA to induce remission (28 CD and 1 UC), 24 after IFX; 10 entered remission, 12 had partial response and 7 had no response. All had maintenance; 19 required dose escalation. 12 children overall required hospitalisation due to drug toxicity. No deaths occurred with either IFX or ADA. CONCLUSIONS: Complete accrual of the Scottish nationwide 'real-life' experience demonstrates moderate effectiveness of anti tumour necrosis factor agents in severe PIBD but duration of effect is limited; significant financial issues (drug cost-need for dose escalation and/or multiple biological usage) and safety issues exist.

Complementary and alternative medicine usage in Scottish children and adolescents during cancer treatment.

AIM: To determine the prevalence of the use of CAM and spiritual practices in the paediatric oncology population of SE Scotland and to establish both the reasons for their use and the perceived benefits. METHODS: A retrospective survey was performed using previously piloted questionnaires. These were distributed to families whose children were <18 years and diagnosed with cancer. Demographic and clinical data were collected, descriptive statistics were used to establish frequencies and univariate associations were established by χ(2) test. RESULTS: Of 169 families approached, 74 (44%) returned completed questionnaires. 41 (55%) families used CAM and 42 (57%) sought spiritual remedies whilst receiving conventional treatment. Higher socioeconomic status was the only factor associated with CAM usage and the most popular therapies were vitamins and minerals (n = 22; 53%), followed by massage (n = 12; 29%) and fish oils (n = 12; 29%). Most families used CAM to reduce stress and, overall, CAM was perceived to be beneficial. CONCLUSION: The high prevalence of CAM usage in this population highlights the need for physicians to enquire routinely about CAM use and warrants high-quality interventional studies to assess safety and efficacy. SUMMARY: The use of Complementary and Alternative Medicine (CAM) among paediatric patients during cancer treatment is popular worldwide, yet data from the UK are scarce. This study showed that more than half of this Scottish cohort used CAM and that there was an overall positive perception of the effect that these therapies had on the patients. Also, socio-economically advantaged families might be more likely to use CAM in Scotland.

Neutron source reconstruction from pinhole imaging at National Ignition Facility.

The neutron imaging system at the National Ignition Facility (NIF) is an important diagnostic tool for measuring the two-dimensional size and shape of the neutrons produced in the burning deuterium-tritium plasma during the ignition stage of inertial confinement fusion (ICF) implosions at NIF. Since the neutron source is small (∼100 µm) and neutrons are deeply penetrating (>3 cm) in all materials, the apertures used to achieve the desired 10-µm resolution are 20-cm long, single-sided tapers in gold. These apertures, which have triangular cross sections, produce distortions in the image, and the extended nature of the pinhole results in a non-stationary or spatially varying point spread function across the pinhole field of view. In this work, we have used iterative Maximum Likelihood techniques to remove the non-stationary distortions introduced by the aperture to reconstruct the underlying neutron source distributions. We present the detailed algorithms used for these reconstructions, the stopping criteria used and reconstructed sources from data collected at NIF with a discussion of the neutron imaging performance in light of other diagnostics.

Measurements of an ablator-gas atomic mix in indirectly driven implosions at the National Ignition Facility.

We present the first results from an experimental campaign to measure the atomic ablator-gas mix in the deceleration phase of gas-filled capsule implosions on the National Ignition Facility. Plastic capsules containing CD layers were filled with tritium gas; as the reactants are initially separated, DT fusion yield provides a direct measure of the atomic mix of ablator into the hot spot gas. Capsules were imploded with x rays generated in hohlraums with peak radiation temperatures of ∼294 eV. While the TT fusion reaction probes conditions in the central part (core) of the implosion hot spot, the DT reaction probes a mixed region on the outer part of the hot spot near the ablator-hot-spot interface. Experimental data were used to develop and validate the atomic-mix model used in two-dimensional simulations.

Systematic review: MRI enterography for assessment of small bowel involvement in paediatric Crohn's disease.

BACKGROUND: Barium meal enteroclysis (BM) is the recommended imaging technique for small bowel inaccessible by ileo-colonoscopy when diagnosing paediatric-onset inflammatory bowel disease, but it has poor sensitivity and involves ionising radiation. MRI enterography (MRE) is an alternative methodology. AIMS: To critically appraise the published evidence on MRE in the assessment of Paediatric inflammatory bowel disease by systematic review. METHODS: Review of all English language data reporting MRE for the investigation of patients <18 years with known or suspected IBD. Primary searches of Medline (Jan 1950-April 2012), Cinahl (1966-April 2012) and Pubmed (Jan 1950-April 2012) were performed using keyword and MeSH terms; IBD; Magnetic resonance imaging; small bowel imaging; EMBASE was then searched. Two authors independently assessed the quality of studies using the quality assessment of diagnostic accuracy studies tool. RESULTS: Searches yielded 930 035 hits, combination word searches limited to 1983 titles. Fifty-two studies were fully reviewed, 41 were excluded due to lack of paediatric data. Eleven studies of 496 children were included. All studies used endoscopy as the reference test. 10/496 patients required jejunal intubation for bowel preparation. Meta-analysis of six comparable studies gave a pooled sensitivity and specificity for MRE detection of active terminal ileal Crohn's disease of 84% and 97% respectively. Studies displayed heterogeneity in bowel preparation, scanning technique, reporting methodology and timing of ileo-colonoscopy in relation to MRE. In three studies comparing BM, MRE had greater sensitivity and specificity. CONCLUSIONS: MRE is a sensitive and specific tool for diagnosis in paediatric inflammatory bowel disease. Technical considerations require refinement and standardisation; however, MRE has no radiation. Current data suggest that MRE should supersede BM as the SB imaging technique in centres with appropriate expertise.

The neutron imaging diagnostic at NIF (invited).

A neutron imaging diagnostic has recently been commissioned at the National Ignition Facility (NIF). This new system is an important diagnostic tool for inertial fusion studies at the NIF for measuring the size and shape of the burning DT plasma during the ignition stage of Inertial Confinement Fusion (ICF) implosions. The imaging technique utilizes a pinhole neutron aperture, placed between the neutron source and a neutron detector. The detection system measures the two dimensional distribution of neutrons passing through the pinhole. This diagnostic has been designed to collect two images at two times. The long flight path for this diagnostic, 28 m, results in a chromatic separation of the neutrons, allowing the independently timed images to measure the source distribution for two neutron energies. Typically the first image measures the distribution of the 14 MeV neutrons and the second image of the 6-12 MeV neutrons. The combination of these two images has provided data on the size and shape of the burning plasma within the compressed capsule, as well as a measure of the quantity and spatial distribution of the cold fuel surrounding this core.

Effect of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography-guided management of suspected recurrent papillary thyroid carcinoma: long-term follow-up with tumour marker responses.

AIMS: To investigate the use of recombinant human thyroid-stimulating hormone-stimulated co-registered (18)F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for detecting suspected recurrent papillary thyroid carcinoma among patients with rising tumour markers but negative whole-body iodine-131 scans. Tumour marker responses to (18)F-FDG PET/CT-guided therapy were also measured for these patients. MATERIALS AND METHODS: A prospectively gathered (18)F-FDG PET/CT database and patient charts were reviewed. Patients having previously undergone total thyroidectomy and ablative iodine-131 therapy for papillary carcinoma before (18)F-FDG PET/CT were analysed. RESULTS: Nineteen patients formed the study population: 12 women and seven men, median age 49 years, with elevated thyroglobulin (n = 15), elevated anti-thyroglobulin antibody (n = 4); the median follow-up was 46 months, range 27-56 months. Sixteen patients (84%) had a positive PET/CT scan (15 with disease confined to the head and neck and one with distant disease), whereas three patients (16%) had a negative scan. Eleven of the 15 patients with disease confined to the head and neck underwent potentially curative salvage therapy: surgery (n = 7), external beam radiotherapy (n = 2) or both (n = 2). All patients undergoing surgery had histological confirmation of malignancy. At a median follow-up of 50 months for these 11 patients, eight had detectable tumour markers at levels below pre-scan values, two had levels above, and one patient had an undetectable level. All three patients with negative PET/CT scans were placed on surveillance. At a median follow-up of 45 months for these three patients, two had tumour marker levels below pre-scan values and one had an undetectable level. CONCLUSIONS: Recombinant human thyroid-stimulating hormone-stimulated (18)F-FDG PET/CT detected recurrent disease in most patients. Although subsequent treatment of (18)F-FDG PET/CT-detected disease reduced tumour marker levels in most patients, markers remained detectable, suggesting that not all residual or metastatic disease had been identified, which compromised salvage therapy. This is the largest and most mature study to date reporting tumour marker responses to PET- or PET/CT-guided therapy in this setting.

The effects of anti-TNF-α treatment with adalimumab on growth in children with Crohn's disease (CD).

INTRODUCTION: Adalimumab is used to treat children with Crohn's disease (CD), but the effects of adalimumab on growth in CD have not been studied. AIM: To study growth and disease activity over 12 months (6 months prior to (T-6), baseline (T0) and for 6 months following (T+6) adalimumab). SUBJECTS AND METHODS: Growth and treatment details of 36 children (M: 22) who started adalimumab at a median (10th, 90th) age of 14.7 years (11.3, 16.8) were reviewed. RESULTS: Of 36 cases, 28 (78%) went into remission. Overall 42% of children showed catch up growth, which was more likely in: (i) those who achieved remission (median change in height SDS (ΔHtSDS) increased from -0.2 (-0.9, 1.0) at T0 to 0.2 (-0.6, 1.6) at T+6, (p=0.007)), (ii) in those who were on immunosuppression ΔHtSDS increased from -0.2 (-0.9, 1.0) at T0 to 0.1 (-0.8, 1.3) at T+6, (p=0.03) and (iii) in those whose indication for using adalimumab therapy was an allergic reaction to infliximab, median ΔHtSDS increased significantly from -0.3 (-0.9, 1.0) at T0 to 0.3 (-0.5, 1.6) at T+6, (p=0.02). Median ΔHtSDS also increased from -0.4 (-0.8, 0.7) at T0 to 0.0 (-0.6, 1.6) at T+6, (p=0.04) in 15 children who were on prednisolone therapy when starting adalimumab. CONCLUSION: Clinical response to adalimumab therapy is associated with an improvement in linear growth in a proportion of children with CD. Improved growth is more likely in patients entering remission and on immunosuppression but is not solely due to a steroid sparing effect.