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Accurate presumptive and confirmatory test use for forensic body fluid identification is essential for gaining contextual information for crime scene investigators. Loop-mediated isothermal amplification (LAMP) is an ideal method for forensic body fluid identification because it is highly specific and generates multi-sized amplicon DNA, and successful amplification results can be read out colorimetrically. Here, we show preliminary data on a LAMP method that rapidly identifies body fluids including venous blood, semen, and saliva, based on colorimetric response and image analysis. The method is designed for easy implementation into forensic casework protocols with minimal disruption to DNA analysis. LAMP naturally increases target specificity due to the use of multiple primers for one target and mRNA targets were used for tissue and human specificity. With colorimetric detection as an inherent part of LAMP, samples that are positive or negative for any of the body fluids are readily identified by image capture and analysis, thus eliminating subjectivity. Results show by using the 3D-printed imaging system specific color ranges can be set for easy determination of body fluids. The resulting color change can be seen in

Subtherapeutic drug concentrations contribute to both primary and secondary nonresponse to infliximab in children with Crohn disease (CD). The aim of this study was to evaluate treatment outcomes and infliximab concentrations at infusions 2 and 3 with an objective to establish infliximab targets during induction for primary responders.Single-center, prospective cohort of anti- tumor necrosis factor-alpha naïve CD patients younger than 22 years starting infliximab. Clinical response was defined with the weighted pediatric CD activity index at the fourth infusion. Rates of biological response (50% improvement in fecal calprotectin) and maintenance concentrations ≥5 μg/mL were secondary outcomes.We enrolled 72 patients with CD with 70 of 72 receiving infliximab monotherapy. Clinical response, biological response, and start of maintenance concentrations ≥5 μg/mL were achieved in 64%, 54%, and 22%, respectively. The median (interquartile range) infliximab concentrations at infusion 2 and 3 in clinical responders were 27.8 μg/mL (19.5-40) and 14 μg/mL (8.3-24) compared to 18.8 μg/mL (9.1-23, P 0.001) and 7.8 μg/mL (4-13.2, P 0.01) in nonresponders. Receiver operating characteristic analysis determined that an infliximab concentration ≥15.9 μg/mL at infusion 3 was associated with clinical response (area under the curve [AUC] 0.73), whereas an infusion 3 level ≥18 μg/mL was associated with a start of maintenance concentration5 μg/mL (AUC 0.85). Independent predictors for infusion 3 levels18 μg/mL included pretreatment prednisone, low body mass index, elevated erythrocyte sedimentation rate and C-reactive protein, hypoalbuminemia, and an infusion 2 infliximab level29 μg/mL.We found that infusion 2 (≥29 μg/mL) and infusion 3 (≥18 μg/mL) infliximab concentrations were strongly associated with improved early outcomes and higher first maintenance dose levels.

Standard-of-care infliximab dosing regimens were developed prior to the routine use of therapeutic drug monitoring and identification of target concentrations. Not surprisingly, subtherapeutic infliximab concentrations in pediatric Crohn’s disease (CD) are common. The primary aim was to conduct a real-world pharmacokinetic (PK) evaluation to discover blood biomarkers of rapid clearance, identify exposure targets, and a secondary aim to translate PK modeling to the clinic. In a multicenter observational study, 671 peak and trough infliximab concentrations from 78 patients with CD were analyzed with a drug-tolerant assay (Esoterix; LabCorp, Calabasas, CA). Individual area under the curve (AUC) estimates were generated as a measure of drug exposure over time. Population PK modeling (nonlinear mixed-effect modeling) identified serum albumin, antibody to infliximab, erythrocyte sedimentation rate (ESR), and neutrophil CD64 as biomarkers for drug clearance. Week 14 and week 52 biochemical remitters (fecal calprotectin < 250 μg/g) had higher infliximab exposure (AUC) throughout induction. The optimal infliximab AUC target during induction for week 14 biochemical remission was 79,348 μg*h/mL (area under the receiver operating characteristic curve (AUROC) 0.77, [0.63–0.90], 85.7% sensitive, and 64.3% specific) with those exceeding the AUC target more likely to achieve a surgery-free week 52 biochemical remission (OR 4.3, [1.2–14.6]). Pretreatment predictors for subtherapeutic week 14 AUC included neutrophil CD64 > 6 (OR 4.5, [1.4–17.8]), ESR > 30 mm/h (OR 3.8, [1.4–11]), age < 10 years old (OR 4.2, [1.2–20]), and weight < 30 kg (OR 6.6, [2.1–25]). We created a decision-support PK dashboard with an iterative process and embedded the modeling program within the electronic health record. Model-informed precision dosing guided by real-world PKs is now available at the bedside in real-time.

Background The neutrophil fecal biomarkers, calprotectin (FCP) and lactoferrin (LCT), and peripheral blood neutrophil CD64 surface receptor (nCD64) are biomarkers for mucosal inflammation in inflammatory bowel disease (IBD). Although FCP has been evaluated as a biomarker for mucosal healing, cut points for LCT and nCD64 are less known. We aimed to identify the cut points for LCT and nCD64 that were associated with FCP remission, with a secondary aim to evaluate the relationship between biochemical outcomes and infliximab (IFX) trough concentrations. Methods We analyzed FCP, LCT, and nCD64 before and after IFX induction in a pediatric Crohn’s disease (CD) cohort study. Week-14 FCP biomarker remission was defined as FCP 17.5 improvement. Predictive outcomes were calculated by receiver operating characteristics (ROCs). Results Among 56 CD patients, ROC analysis identified an infusion 4 LCT 9.4 µg/mL (AUROC, 0.799, P = 0.002) and >11.5 µg/mL (AUROC, 0.835, P = 0.003) were associated with a FCP 5 µg/mL had a median FCP improvement (dose 1 to dose 4) of 90% compared with a median of 35% with levels Conclusions This study establishes cut points in neutrophil stool and blood biomarkers for both biochemical remission and therapeutic trough levels following induction therapy. Further studies that evaluate pharmacodynamic biomarker targets for endoscopic and histologic healing are warranted.

Author(s): Denson, Lee A; Jurickova, Ingrid; Karns, Rebekah; Shaw, Kelly A; Cutler, David J; Okou, David; Valencia, C Alexander; Dodd, Anne; Mondal, Kajari; Aronow, Bruce J; Haberman, Yael; Linn, Aaron; Price, Adam; Bezold, Ramona; Lake, Kathleen; Jackson, Kimberly; Walters, Thomas D; Griffiths, Anne; Baldassano, Robert N; Noe, Joshua D; Hyams, Jeffrey S; Crandall, Wallace V; Kirschner, Barbara S; Heyman, Melvin B; Snapper, Scott; Guthery, Stephen L; Dubinsky, Marla C; Leleiko, Neal S; Otley, Anthony R; Xavier, Ramnik J; Stevens, Christine; Daly, Mark J; Zwick, Michael E; Kugathasan, Subra | Abstract: BACKGROUND:Granulocyte-macrophage colony-stimulating factor auto-antibodies (GMAbs) suppress neutrophil-extrinsic GM-CSF signaling and increase risk for stricturing behavior in Crohn's disease (CD). We aimed to define clinical, genomic, and functional associations with neutrophil-intrinsic GM-CSF signaling. METHODS:Missense mutations in CSF2RA, CSF2RB, JAK2, STAT5A, and STAT5B were identified using whole-exome sequencing in 543 pediatric inflammatory bowel disease (IBD) patients. Neutrophil-intrinsic GM-CSF signaling was defined using the GM-CSF-induced STAT5 stimulation index (GMSI) in 180 pediatric IBD patients and 26 non-IBD controls. Reduced GM-CSF signaling (GMSI-Lo) was defined as the 20th percentile within the control group. Variation in neutrophil phospho-protein abundance, bacterial killing, and the global pattern of gene expression with the GMSI was determined. RESULTS:We validated 18 potentially damaging missense mutations in CSF2RA and CSF2RB. CSF2RA A17G carriage increased from 10% in those with intact neutrophil GMSI to 32% in those with low GMSI (P = 0.02). The frequency of reduced Staphylococcus aureus killing increased from 17% in those with intact neutrophil GMSI to 35% in GMSI-Lo neutrophils (P = 0.043). Crohn's disease neutrophils with low GMSI exhibited specific alterations in phospho-protein networks and genes regulating cytokine production, wound healing, and cell survival and proliferation. Stricturing behavior increased from 7% in patients with both low GMAb and intact GMSI to 64% in patients with both elevated GMAb and low GMSI (P l 0.0001). CONCLUSIONS:Low/normal neutrophil-intrinsic GM-CSF signaling is associated with CSF2RA missense mutations, alterations in gene expression networks, and higher rates of disease complications in pediatric CD.

Background & aimsIndividuals with monogenic disorders of phagocyte function develop chronic colitis that resembles Crohn's disease (CD). We tested for associations between mutations in genes encoding reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, neutrophil function, and phenotypes of CD in pediatric patients.MethodsWe performed whole-exome sequence analysis to identify mutations in genes encoding NADPH oxidases (such as CYBA, CYBB, NCF1, NCF2, NCF4, RAC1, and RAC2) using DNA from 543 pediatric patients with inflammatory bowel diseases. Blood samples were collected from an additional 129 pediatric patients with CD and 26 children without IBD (controls); we performed assays for neutrophil activation, reactive oxygen species (ROS) production, and bacteria uptake and killing. Whole-exome sequence analysis was performed using DNA from 46 of the children with CD to examine associations with NADPH gene mutations; RNA sequence analyses were performed using blood cells from 46 children with CD to test for variations in neutrophil gene expression associated with ROS production.ResultsWe identified 26 missense mutations in CYBA, CYBB, NCF1, NCF2, and NCF4. Patients with CD who carried mutations in these genes were 3-fold more likely to have perianal disease (P= .0008) and stricturing complications (P= .002) than children with CD without these mutations. Among patients withCD with none of these mutations, 9% had undergone abdominal surgery; among patients with mutations in these NADPH oxidase genes, 31% had undergone abdominal surgery (P=.0004). A higher proportion of neutrophils from children with CD had low ROS production (47%) than from controls (15%) among the 129 patients tested for ROS (P= .002). Minor alleles of the NADPH genes were detected in 7% of children with CD whose neutrophils produced normal levels of ROS vs 38% of children whose neutrophils produced low levels of ROS (P= .009). Neutrophils that produced low levels of ROS had specific alterations in genes that regulate glucose metabolism and antimicrobial responses.ConclusionsWe identified missense mutations in genes that encode NADPH oxidases in children with CD; these were associated with a more aggressive disease course and reduced ROS production by neutrophils from the patients.

Background: Yttrium-90 (90Y) radioembolization involves the intra-arterial delivery of radioactive microspheres to treat hepatic malignancies. Though this therapy involves careful pre-treatment planning and imaging, little is known about the precise location of the microspheres once they are administered. Recently, there has been growing interest post-radioembolization imaging using positron-emission tomography (PET) for quantitative dosimetry and identifying lesions that may benefit from additional salvage therapy. In this study, we aim to measure the inter-center variability of 90Y PET measurements as measured on PET/MRI in preparation for a multi-institutional prospective phase I/II clinical trial. Eight institutions participated in this study and followed a standardized phantom filling and imaging protocol. The NEMA NU2-2012 body phantom was filled with 3 GBq of 90Y chloride solution. The phantom was imaged for 30 min in listmode on a Siemens Biograph mMR non-TOF PET/MRI scanner at five time points across 10 days (0.3–3.0 GBq). Raw PET data were sent to a central site for image reconstruction and data analysis. Images were reconstructed with optimal parameters determined from a previous study. Volumes of interest (VOIs) matching the known sphere diameters were drawn on the vendor-provided attenuation map and propagated to the PET images. Recovery coefficients (RCs) and coefficient of variation of the RCs (COV) were calculated from these VOIs for each sphere size and activity level. Results: Mean RCs ranged from 14.5 to 75.4%, with the lowest mean RC coming from the smallest sphere (10 mm) on the last day of imaging (0.16 MBq/ml) and the highest mean RC coming from the largest sphere (37 mm) on the first day of imaging (2.16 MBq/ml). The smaller spheres tended to exhibit higher COVs. In contrast, the larger spheres tended to exhibit lower COVs. COVs from the 37 mm sphere were 25%. Conclusions: Post-radioembolization dosimetry of lesions or other VOIs ≥ 22 mm in diameter can be consistently obtained (

Fluorodeoxyglucose (FDG) positron emission tomography-magnetic resonance (PET/MR) is useful for the evaluation of cognitively-impaired patients. This study aims to assess two different attenuation correction (AC) methods (Dixon-MR and atlas-based) versus index-standard computed tomography (CT) AC for the visual interpretation of regional hypometabolism in patients with cognitive impairment. Two board-certified nuclear medicine physicians blindly scored brain region FDG hypometabolism as normal versus hypometabolic using two-dimensional (2D) and 3D FDG PET/MR images generated by MIM software. Regions were quantitatively assessed as normal versus mildly, moderately, or severely hypometabolic. Hypometabolism scores obtained using the different methods of AC were compared, and interreader, as well as intra-reader agreement, was assessed. Regional hypometabolism versus normal metabolism was correctly classified in 16 patients on atlas-based and Dixon-based AC map PET reconstructions (vs. CT reference AC) for 94% (90%–96% confidence interval [CI]) and 93% (89%–96% CI) of scored regions, respectively. The averaged sensitivity/specificity for detection of any regional hypometabolism was 95%/94% (P = 0.669) and 90%/91% (P = 0.937) for atlas-based and Dixon-based AC maps. Interreader agreement for detection of regional hypometabolism was high, with similar outcome assessments when using atlas- and Dixon-corrected PET data in 93% (Κ =0.82) and 93% (Κ =0.84) of regions, respectively. Intrareader agreement for detection of regional hypometabolism was high, with concordant outcome assessments when using atlas- and Dixon-corrected data in 93%/92% (Κ =0.79) and 92/93% (Κ =0.78). Despite the quantitative advantages of atlas-based AC in brain PET/MR, routine clinical Dixon AC yields comparable visual ratings of regional hypometabolism in the evaluation of cognitively impaired patients undergoing brain PET/MR and is similar in performance to CT-based AC. Therefore, Dixon AC is acceptable for the routine clinical evaluation of dementia syndromes.

Objectives Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are characterized by an aberrant host response to intestinal microbiota causing mucosal inflammation and gastrointestinal symptoms. Patient reported outcome measures (PROs) are increasingly utilized in clinical care and research. Our study aim was to determine if fecal microbial shifts were associated with PROs in children and young adults with IBD. Methods A longitudinal prospective single center study of 93 patients tested for association between fecal microbial shifts, mucosal inflammation as measured by fecal calprotectin, and self-reported symptoms including diarrhea, rectal bleeding, and abdominal pain. For CD, abdominal pain and diarrhea determined disease activity or overall PRO. For UC, diarrhea and rectal bleeding were used. Fecal calprotectin and shotgun metagenomic sequencing were performed on all samples. Demographic and clinical characteristics (Table 1) were incorporated into a negative binomial mixed-effects model in “R” to identify differentially abundant species by PRO and fecal calprotectin. Metabolic pathways were mapped using the HUMAnN2 pipeline and compared to overall PRO, individual symptoms and fecal calprotectin level. Results In 70 CD patients with 244 stool samples, there was no association between symptoms and fecal calprotectin. In 23 UC patients with 76 stool samples, increased fecal calprotectin was associated with rectal bleeding (OR 4.93 [1.18, 20.64], p=0.03). Examination of differentially abundant species in those with self-reported active UC showed increased Klebsiella species and reduced Bacteroides. Conversely, UC patients with fecal calprotectin < 100 µg/gm had reduction in Klebsiella and increase in Bifidobacteria and Bacteroides (Figure 1). Analysis of differentially abundant species in those with abdominal pain in CD showed increase in Haemophilus and reduction in Bacteroides. No microbial shifts were identified in CD patients in association with overall PRO, diarrhea, nor with fecal calprotectin < 250 µg/gm. Metabolic pathway analysis showed no differences in those with CD. In UC patients, increases in sulfoglycolysis and ornithine biosynthesis were associated with overall PROs. Conclusions Fecal microbial shifts including decreased commensals such as Bacteroides correlate with UC patient symptoms. Increased fecal calprotectin level was associated with rectal bleeding in these patients, but not diarrhea. In CD, there was no association with fecal calprotectin and symptoms, and microbial shifts were detected in association with abdominal pain. Similarly, metabolic pathways differed relative to patient-reported symptoms in UC, but not in CD. Data suggests that microbial shifts may directly contribute to symptoms in children and young adults with IBD.

AIM To determine the vaccination rates in pediatric immunosuppression-dependent inflammatory bowel disease (IBD) and review the safety and efficacy of vaccinations in this population. METHODS The electronic medical records from October 2009 to December 2015 of patients diagnosed with IBD at 10 years of age or younger and prescribed anti-tumor necrosis factor alpha (anti-TNF-α) therapy were reviewed for clinical history, medication history, vaccination history, and hepatitis B and varicella titers. Literature discussing vaccination response in IBD patients were identified through search of the MEDLINE database and reviewed using the key words “inflammatory bowel disease”, “immunization”, “vaccination”, “pneumococcal”, “varicella”, and “hepatitis B”. Non-human and non-English language studies were excluded. Search results were reviewed by authors to select articles that addressed safety and efficacy of immunizations in inflammatory bowel disease. RESULTS A total of 51 patients diagnosed with IBD prior to the age of 10 and receiving anti-TNF-α therapy were identified. Thirty-three percent of patients (17/51) had incomplete or no documentation of vaccinations. Sixteen case reports, cohort studies, cross-sectional studies, and randomized trials were determined through review of the literature to describe the safety and efficacy of hepatitis B, pneumococcal, and varicella immunizations in adult and pediatric patients with IBD. These studies showed that patients safely tolerated the vaccines without significant adverse effects. Importantly, IBD patients receiving immunosuppressive medications, particularly anti-TNF-α treatment, have decreased vaccine response compared to controls. However, the majority of patients are still able to achieve protective levels of specific antibodies. CONCLUSION Immunizations have been shown to be well-tolerated and protective immunity can be achieved in patients with IBD requiring immunosuppressive therapy.

OBJECTIVES Exocrine pancreatic insufficiency (EPI) can have a significant impact on a child's growth and nutrition. Our aim was to evaluate the utility of direct endoscopic pancreatic function testing (ePFT) in pediatrics. METHODS A single-center retrospective chart review was performed of children who underwent ePFT from December 2007 through February 2015. Endoscopic pancreatic function testings were performed by 1 of 2 methods: (1) intravenous cholecystokinin, followed by the collection of a single duodenal aspirate at 10 minutes, or (2) intravenous cholecystokinin or secretin, followed by the collection of 3 duodenal aspirates at a 5, 10, and 15 minutes. Samples were tested for pH and enzyme activities. RESULTS A total of 508 ePFTs were performed (481 single-sample tests, 27 multiple-sample tests). Based on the multiple-sample group, enzyme levels for chymotrypsin, amylase, and lipase peaked at 5 minutes, followed by a decrease in activity over time. Exocrine pancreatic sufficiency was identified in 373 (73.4%) and EPI in 93 (18.3%). Exocrine pancreatic sufficiency analysis found all pancreatic enzyme activities significantly increase with age: trypsin, chymotrypsin, amylase, and lipase, (P < 0.05). CONCLUSIONS Endoscopic pancreatic function testing can be used in the evaluation of EPI in children. Normative data suggest that pancreatic enzyme activities mature with age.

This report describes what professional experiences and other characteristics the general and flag officers in each of the military services tend to share as a result of each service's approach to personnel management and other related factors, such as service culture, and how these approaches might influence the ways in which general and flag officers lead, manage, and advise.

Background Clostridioides difficile infection and colonization are common in pediatric Crohn’s disease (CD). Our aims were to test the relationship between C. difficile positivity and bowel resection surgery and to characterize microbial shifts associated with C. difficile carriage and surgery. Methods A retrospective single-center study of 75 pediatric CD patients tested for association between C. difficile carriage and bowel resection surgery. A prospective single-center study of 70 CD patients utilized C. difficile testing and shotgun metagenomic sequencing of fecal samples to define microbiota variation stratified by C. difficile carriage or history of surgery. Results The rate of bowel resection surgery increased from 21% in those without C. difficile to 67% in those with (P = 0.003). From a Kaplan-Meier survival model, the hazard ratio for time to first surgery was 4.4 (95% CI, 1.2–16.2; P = 0.00) in patients with positive C. difficile testing in the first year after diagnosis. Multivariable logistic regression analysis confirmed this association (odds ratio 16.2; 95% CI, 2.2–120; P = 0.006). Larger differences in microbial abundance and metabolic pathways were observed in patients with prior surgery than in those with C. difficile carriage. Depletion of Alistipes and Ruminococcus species and reduction in methionine biosynthesis were noted in patients with both C. difficile carriage and past surgery. Conclusions A positive C. difficile test during the first year after diagnosis is associated with decreased time to first bowel resection surgery in pediatric Crohn’s disease. Depletion of beneficial commensals and methionine biosynthesis in patients with C. difficile carriage may contribute to increased risk for surgery.

Background We hypothesized that elevations of plasma Oncostatin M (OSM) would be associated with infliximab nonresponse. Methods Plasma OSM was measured in Crohn disease patients pre-infliximab with biochemical response (>50% reduction in fecal calprotectin) as the primary outcome. Results The median OSM in biochemical responders was 86 (69–148) pg/mL compared with 166 (74–1766) pg/mL in nonresponders (P = 0.03). Plasma OSM > 143.5 pg/mL was 71% sensitive and 78% specific for biochemical nonresponse (area under the curve 0.71). Early biochemical nonremission was also associated with an elevated neutrophil CD64 expression (odds ratio 8.9, P = 0.011). Conclusions Elevated preinfliximab plasma OSM and nCD64 surface expression were both associated with poor biochemical outcomes., Pretreatment elevations in plasma Oncostatin M and whole blood neutrophil CD64 are associated with unfavorable early and late treatment outcomes to infliximab in patients with Crohn disease.

Purpose Diffusion-weighted imaging (DWI) and 18F-fluorodeoxyglucose–positron emission tomography (18F-FDG–PET) independently correlate with malignancy in breast cancer, but the relationship between their structural and metabolic metrics is not completely understood. This study spatially correlates diffusion, perfusion, and glucose avidity in breast cancer with simultaneous PET/MR imaging and compares correlations with clinical prognostics. Methods In this Health Insurance Portability and Accountability Act-compliant prospective study, with written informed consent and approval of the institutional review board and using simultaneously acquired FDG-PET and DWI, tissue diffusion (Dt), and perfusion fraction (fp) from intravoxel incoherent motion (IVIM) analysis were registered to FDG-PET within 14 locally advanced breast cancers. Lesions were analyzed using 2D histograms and correlation coefficients between Dt, fp, and standardized uptake value (SUV). Correlations were compared with prognostics from biopsy, metastatic burden from whole-body PET, and treatment history. Results SUV||Dt correlation coefficient significantly distinguished treated (0.11 ± 0.24) from nontreated (−0.33 ± 0.26) patients (P = 0.005). SUV||fp correlations were on average negative for the whole cohort (−0.17 ± 0.13). Conclusion Simultaneously acquired and registered FDG-PET/DWI allowed quantifiable descriptions of breast cancer microenvironments that may provide a framework for monitoring and predicting response to treatment. Magn Reson Med, 2016. © 2016 International Society for Magnetic Resonance in Medicine

Messenger RNA profiling for body fluid identification (bfID) is a useful approach to collect contextual information associated with a crime. Current methods require costly fluorescent probes, lengthy amplification protocols and/or time-consuming sample preparation. To simplify this process, we developed a bfID method that has the potential to be rapid in analysis time, inexpensive and fluorescence-free, combining a universal operating procedure with a high-throughout (microwell plate) platform for simultaneous detection of mRNA markers from whole blood, semen, saliva, and vaginal fluid. Full bfID sample preparation and analysis of 23 samples was completed in under 3 h using smart phone optical detection and analysis and show efficacy of the method in a validated blind study. The results provide an efficient, sensitive and specific approach to supplement the current biochemical tests in a forensic laboratory.

U.S. security-sector assistance has a mixed record in Africa. RAND experts offer recommendations to promote the success of such assistance in Africa. The recommendations focus on strategies, programs, and their assessment, monitoring, and evaluation.

From September 2011 through May 2012, icarusLabs competed in the UAVForge Competition, sponsored by the United States Defense Advanced Research Projects Agency (DARPA). The objective of the competition was to design and build a small unmanned aerial vehicle (UAV) that could complete a local surveillance mission. A unique feature of the competition was an experimental crowdsourcing model, in which competing teams were able to provide technical feedback to each other as part of the design process. The icarusLabs team's solution to the challenge combined a tricopter and blended wing body aircraft into a single hybrid airframe. This paper presents the rationale and theory behind the design as well as the lessons learned from the technical and logistical challenges faced. In addition, the authors reflect on the crowdsourcing aspect of the challenge from a competitor's perspective. Overall, incentives for individual teams' success directly conflicted with the essence of crowdsourcing, but the competition was successful at stimulating interest to fill a void in current UAV solutions, bringing together passionate individuals from the global unmanned systems community, and generating a broad range of novel approaches to address the presented challenges.

This report describes the likely evolution of Islamic State of Iraq and the Levant (ISIL) finances under three specific scenarios: a continuation of the current campaign, a negotiated settlement in Syria and political accommodation in Iraq, and military victory without negotiated settlement or political accommodation. Discussion of these scenarios offered ways to counter fundraising in ISIL territory and use financial information to damage ISIL.

The aim of this study was to conduct a prospective pilot study comparing the diagnostic performance of MRI alone and F-FDG simultaneous PET/MRI using a diuresis protocol in bladder cancer patients.Twenty-two bladder cancer patients underwent F-FDG PET/MRI, using intravenous furosemide and oral hydration for bladder clearance. A radiologist scored probability of tumor in 3 locations (urinary bladder, pelvic lymph nodes, nonnodal pelvis) using 1- to 3-point scale (1 = negative, 2 = equivocal, 3 = definite tumor). A nuclear medicine physician reviewed fused PET/MRI images, after which scores were reassigned based on combined findings. Follow-up pathologic and imaging data served as reference. Performances of MRI alone and PET/MRI were compared.Of these patients, 82%, 38%, and 18% were positive for bladder, pelvic nodal, and nonnodal pelvic tumor, respectively. At a score of 3, PET/MRI exhibited greater accuracy for detection of bladder tumor (86% vs 77%), metastatic pelvic lymph nodes (95% vs 76%), and nonnodal pelvic malignancy (100% vs 91%). In the bladder, PET changed the level of suspicion in 36% of patients (50% increased suspicion, 50% decreased suspicion), with 75% of these changes deemed correct based on reference standard. For pelvic lymph nodes, PET changed suspicion in 52% (36% increase, 64% decrease), with 95% of changes deemed correct. For nonnodal pelvis, PET changed suspicion in 9% (100% increase), with 100% deemed correct.Additional PET information helped to appropriately determine level of suspicion in multiple anatomic sites for otherwise equivocal findings on MRI alone. Although requiring larger studies, findings suggest a possible role for simultaneous PET/MRI to assist bladder cancer management.

We have previously shown that CD64 surface expression on circulating neutrophils is significantly elevated in children with newly diagnosed Crohn's disease (CD). Our primary aim was to investigate whether elevations in neutrophil CD64 in asymptomatic patients could be used to predict treatment failure during maintenance infliximab.Pediatric CD subjects receiving maintenance infliximab in clinical remission (short pediatric CD activity index [shPCDAI]15) were enrolled. We measured neutrophil CD64 expression (CD64 index, Trillium Diagnostics, LLC) and infliximab trough concentrations. Infliximab failure was defined as an shPCDAI15 on 2 consecutive infusions, discontinuation of infliximab, hospitalization, endoscopic ulcerations, or surgery during the following year of maintenance infliximab.We enrolled 36 subjects, 22/36 were male and 29/36 were white. Mean (SD) age at study entry was 15 (4) years with a median of 14 (5-20) infusions before study entry. 4/36 were receiving a concurrent immunomodulator. Over 1 year, 15/36 subjects were classified as infliximab failures. Asymptomatic subjects with a neutrophil CD64 index1 at study entry had a higher probability of treatment failure compared with asymptomatic subjects with a CD64 index1 (log-rank = 0.002). We found only neutrophil CD64 index1 and nonwhite race were risk factors for treatment failure by univariate regression analysis. We found no difference in the mean infliximab trough concentration at study entry between treatment failures (2.8 μg/mL, SD, 1.2) and subjects remaining in remission on infliximab (4.2 μg/mL, SD, 3.4; P = 0.17).Neutrophil CD64 index1 is a significant risk factor for treatment failure during infliximab maintenance therapy.

Objectives The aim of this study was to determine if comprehensive genetic testing was useful to identify genetic variants that discriminate chronic pancreatitis (CP) from acute recurrent pancreatitis (ARP) in a pediatric population. Methods We conducted a retrospective review of 50 patients enrolled in our institutional pancreatitis registry between April 2013 and January 2015. Genetic analysis of PRSS1, CFTR, SPINK1, and CTRC classified variants as mutations or variants of unknown clinical significance and the minor allele frequency of variants in our cohort was obtained. Results Genetic testing was obtained in 16/16 (100%) of CP and 29/34 (85%) of ARP patients. A total of 39 genetic variants were found in 27 (60%) of 45 subjects tested with 5 (11%) subjects having 2 different genes affected. Variant frequency was greatest in patients for CFTR (17/45, 38%) followed by SPINK1 (11/44, 25%), CTRC (2/27, 7%), and PRSS1 (2/44, 4%). CFTR variants were more likely in those with CP compared to ARP (63% and 24%, P = 0.01). Conclusions This study is the first to find a higher rate of CFTR mutations in CP versus ARP groups using comprehensive genetic testing in a pediatric population.

We developed a microfluidic scanner-based profile exploration system, μSCAPE, capable of generating high resolution 3D profiles of microstructure architecture in a variety of transparent substrates. The profile is obtained by scanning the dye-filled microstructure followed by absorbance calculation and the reconstruction of the optical length at each point. The power of the method was demonstrated in (1) the inspection of the variation of the cross-section of laser-ablated PDMS channel; (2) the volume of PeT chamber; and (3) the population distribution of the volumes of the micro wells in HF-etched glass and laser-ablated PDMS. The reported methods features low equipment-cost, convenient operation and large field of view (FOV) and has revealed unreported quality parameters of the tested microstructures.

The development of Unmanned Vehicles (UVs) with increasing autonomy has enabled a transition from teleoperation to Human Supervisory Control (HSC). In this demonstration, participants can test three innovative operator interfaces for HSC of UVs. The first system allows users to control a Micro Air Vehicle (MAV) via a hand-held device, such as an iPhone®, through high-level waypoint commands and fine-grained nudge controls. The second system enables a single operator to collaborate with an automated planner to control multiple heterogeneous UVs from a laptop-sized display for searching for, tracking and engaging moving ground targets. The third system is designed to aid in planning on naval aircraft carrier decks, serving as a decision support tool for a supervisor overseeing and scheduling the activity of people, vehicles and unmanned vehicles working in this complex and uncertain environment.

With recent regulatory efforts to reduce restrictions placed on the operation of Micro Air Vehicles (MAVs) in the United States, it is likely that in the next few years, these vehicles will become commonplace in the commercial marketplace as they are in military environments. In order to reduce the barrier to entry for operations of MAVs, customers of these systems will require ease of operation as well as minimal training time in order to reduce costs. To this end, a smartphone application was developed to control a quadrotor remotely in the exploration of an unknown environment, and tested for users with only three minutes of training. Initial motion capture room tests produced encouraging results for localization and target identification tasks, however, such environments are inherently artificial and the extensibility of such results is limited. A follow-on outdoor field study was conducted in order to compare the indoor and outdoor results and to assess operator performance in a realistic environment. Performance on the outdoor localization tasks was comparable to the indoor study, however, participants generally performed slightly worse on the target identification task in the outdoor experiment, attributed to camera image quality and GPS localization issues. Other issues such as wind and flight safety considerations are discussed.

Most major medical organizations recommend routine screening for breast, cervical, and colorectal cancers. Screening can lead to early detection of these cancers, resulting in reduced mortality. Yet, not all people who should be screened are screened regularly or, in some cases, ever. This report presents results of systematic reviews of effectiveness, applicability, economic efficiency, barriers to implementation, and other harms or benefits of provider reminder/recall interventions to increase screening for breast, cervical, and colorectal cancers. These interventions involve using systems to inform healthcare providers when individual clients are due (reminder) or overdue (recall) for specific cancer screening tests. Evidence in this review of studies published from 1986 through 2004 indicates that reminder/recall systems can effectively increase screening with mammography, Pap, fecal occult blood tests, and flexible sigmoidoscopy. Additional research is needed to determine if provider reminder/recall systems are effective in increasing colorectal cancer screening by colonoscopy. Specific areas for further research are also suggested.

Many post-9/11 horror films are particularly brutal in their portrayal of the fragmentation of the nuclear family and the larger patriarchal structure that it supports.1 In such films, patriarchs are often absent or violently dispatched, and a host of feminine figures and children are left to pick up the pieces. In this chapter, I examine four of these contemporary horror films in which fathers and sons function as mediums for vengeful ghosts: M. Night Shyamalan’s The Sixth Sense (1999), David Koepp’s Stir of Echoes (1999), and James Wan’s Insidious (2010) and Insidious: Chapter 2 (2013). The time gap between the first two films and the latter two is significant, as horror-film critics have identified certain shifts in the horror genre after 9/11 and the cultural anxieties the events of that day induced.2 All four of these films on the surface seem to champion the relationships between fathers and sons and thereby reinforce the patriarchal line. The first two films, however, suggest in the end that the next generation has seen too much to take on the mantle of the father. Particularly in The Sixth Sense, it is the child’s relationship to the mother that offers the possibility of a future free of the haunting presence of the dethroned patriarch and all of those who have suffered in his wake.

This chapter offers further commentary on the return of the archaic mother in the horror genre, examining the use of myth and fairy tale in Jaume Collet-Serra’s Orphan (2009), Andres Muschietti’s Mama (2013), and Mike Flanagan’s Oculus (2014). It also serves as a bookend for chapter 1 in that it offers alternate mythic formulae through which the feminine might free itself from the fetters of the past and begin to redefine itself The films treated in this chapter take the focus off of the patriarchal line almost entirely, focusing instead on mothers and daughters and on mythic paradigms other than the oedipal drama. The earliest of the three films, Orphan offers the most pessimistic vision of the future of the nuclear family. As the title indicates, Orphan is linked to the Orpheus myth, but like the other films in this study, the myth has been rewritten to include a female protagonist and antagonist. While mother and daughter survive their struggle with an infernal antagonist, their ultimate fate remains highly uncertain in the end, and it is unclear if they will ever be free of the monstrous feminine fury she unleashed. Elements of myth and fairy tale are much more overt in Mama and Oculus, and perhaps it is this conscious return to origins that allows the later films to envision an alternate ending to the tragic struggle against patriarchal oppression.

Dixon-based MR is acquired for attenuation correction of brain PET during PET/MR. Early adopters of PET/MR have noted variability in the performance of Dixon-based tissue segmentation, and questions exist regarding potential impacts on quantitative accuracy in dual-time-point studies. Ten patients injected with 10 mCi FDG underwent dual-time-point clinical brain PET/MR on a Siemens mMR, with image reconstructions based on data acquired at 45 – 60 and 75 – 90 minutes. Dixon μmaps were obtained the time of FDG injection and at 75 minutes. 8 cc of Gadavist was injected for post-contrast MR at 30 minutes. Subjects were removed from the table and re-positioned prior to the 75 minute scan. The delayed μmap was registered to the original μmap using MIMneuro. The aligned image data was copied onto the original μmap DICOM file using Matlab. Early time-point PET data was reconstructed using both the early and delayed μmaps. Atlas-based segmentation was performed to compare regional SUV values. When comparing the delayed versus original μmap reconstructions, regional SUV values varied on average by +1.9% for both SUVmax and SUVmean. For large brain structures, SUVmax and SUVmean varied by -0.5% to +5.6% and -0.2 to +4.7%, respectively. For deep brain structures, SUVmax using the delayed reconstruction varied by -0.5% to +3.7% and SUVmean varied by -0.3% to +3.6%. Most differences in SUV were higher when using the delayed μmap. There is variability in regional SUV values for brain PET data reconstructed using two different aligned Dixon acquisitions performed on subjects undergoing repeat same-day PET/MR imaging, with SUV values ~2% higher using the delayed μmap. This variability may impact results in dual-time-point brain PET/MR.

Bladder cancer is a common malignancy, with an estimate of nearly 75,000 new diagnoses in the United States in 2014.1 Although CT and MRI are the most widely used imaging modalities for bladder cancer evaluation, both of these modalities share common limitations. Mural inflammation from a series of interventions commonly applied in these patients, including transurethral bladder tumor resections, biopsies, and intravesical Bacillus Calmette-Guerin therapy, can contribute to misinterpretations on imaging in terms of the presence and stage of residual tumor as well as the differentiation of recurrent tumor from chronic reactive changes.2–4 In addition, both CT and MRI, including MRI with diffusion-weighted imaging (DWI), are limited in determining the presence of metastatic lymph nodes.5,6 Although PET has also received attention for bladder cancer evaluation,7,8 standard 18F-FDG PET is limited by free excretion of FDG into the urine and subsequent high accumulation within the bladder lumen.9 This accumulation obscures, if not entirely masks, focal bladder lesions. In addition, alignment of the bladder between the PET and CT acquisitions in PET/CT is recognized to be suboptimal.10 Therefore, FDG PET has historically had a very limited role in bladder cancer evaluation in clinical practice.9 Recent protocol advances suggest that FDG PET may in fact have greater potential for bladder cancer assessment than previously considered. A number of investigations have explored a forced diuresis protocol entailing, most commonly, oral hydration, IV diuretic administration, and subsequent voiding, performed between radiotracer administration and PET imaging.9,11,12 This approach is intended to achieve clearance of excreted FDG from the bladder lumen while allowing for persistent uptake within the bladder wall itself. Recent studies of PET/CT using this approach have shown that bladder tumors indeed are consistently FDG avid and can be well visualized by PET.12,13 In addition, small metastatic pelvic lymph nodes have been reported to exhibit increased activity using 18F-FDG PET/CT, further supporting the potential value of PET for bladder cancer assessment.14,15 Although such methodological advances are encouraging, the ability to fully characterize bladder cancer is inherently limited using PET/CT. First, using the forced diuresis protocol, the bladder is actively reexpanding at the time of imaging, thus undergoing changes in shape and volume over time. Given that PET and CT are performed in sequential, rather than truly simultaneous, fashion using PET/CT, these dynamic changes of the bladder likely contribute to the recognized misregistration of the bladder between PET and CT acquisitions, even when obtained consecutively during a single examination.10 Patient motion may interfere with accurate coregistration as well, not just of the bladder itself, but also of other important pelvic structures such as small lymph nodes. Finally, the muscularis propria, a critical anatomic landmark in the staging of bladder cancer, is not well visualized as a distinct layer within the bladder wall on CT, further hindering comprehensive tumor evaluation by PET/CT.16 The advent of integrated PET/MRI scanners provides a novel imaging approach that may further improve upon recent advances in PET/CT in numerous respects.17 In PET/MRI, the acquisitions are spatially and temporal simultaneous, such that the degree of bladder filling and consequent bladder volume and shape are essentially identical between the PET and MRI image sets. This truly simultaneous acquisition is likely to also help compensate for the impact of patient motion on registration of the bladder and other pelvic structures. In addition, the higher contrast resolution of MRI, as compared with CT, allows improved delineation of the muscularis propria of the bladder wall and thereby improved local staging.16 Moreover, MRI offers a multiparametric approach that provides, along with anatomic assessment, quantitative metrics, including measures derived from DWI and dynamic contrast-enhanced (DCE) MRI. Such metrics have shown significant associations with bladder cancer aggressiveness in past studies.18,19 Furthermore, simultaneous PET allows for determination of SUV as an additional metric that can be incorporated into a multiparametric panel for bladder cancer assessment. Although integrated PET/MRI systems have generated a large amoun of interest, these systems entail a large financial investment and are only being used clinically at a small number of centers. Centers may instead elect to separately perform conventional PET and MRI scans, with subsequent retrospective fusion. Therefore, the benefit of simultaneous imaging, as is only achievable with an integrated system, is important to investigate in order to ascertain such a system’s true value. Bladder cancer provides an appropriate setting for such an investigation given the dynamic changes in bladder size and shape during short time intervals over the course of a single scan. In this study, our aim was to compare the accuracy of coregistration of the bladder wall, bladder lesions, and pelvic lymph nodes between sequential and simultaneous acquisitions obtained during 18F-FDG PET/MRI performed using a forced diuresis protocol in bladder cancer patients.

Purpose: Radiomics involves the extraction of texture features from different imaging modalities with the purpose of developing models to predict patient treatment outcomes. The purpose of this study is to investigate texture feature reproducibility across [18F]FDG PET/CT and [18F]FDG PET/MR imaging in patients with primary malignancies. Methods: Twenty five prospective patients with solid tumors underwent clinical [18F]FDG PET/CT scan followed by [18F]FDG PET/MR scans. In all patients the lesions were identified using nuclear medicine reports. The images were co-registered and segmented using an in-house auto-segmentation method. Fifty features, based on the intensity histogram, second and high order matrices, were extracted from the segmented regions from both image data sets. One-way random-effects ANOVA model of the intra-class correlation coefficient (ICC) was used to establish texture feature correlations between both data sets. Results: Fifty features were classified based on their ICC values, which were found in the range from 0.1 to 0.86, in three categories: high, intermediate, and low. Ten features extracted from second and high-order matrices showed large ICC ≥ 0.70. Seventeen features presented intermediate 0.5 ≤ ICC ≤ 0.65 and the remaining twenty three presented low ICC ≤ 0.45. Conclusion: Features with large ICC values could be reliable candidates for quantification as they lead to similar results from both imaging modalities. Features with small ICC indicates a lack of correlation. Therefore, the use of these features as a quantitative measure will lead to different assessments of the same lesion depending on the imaging modality from where they are extracted. This study shows the importance of the need for further investigation and standardization of features across multiple imaging modalities.

Purpose The purpose of this study was to examine the effects of Active Steps for Diabetes (ASD), a self-management education (DSME) program for aging adults with diabetes and frailty, on blood glucose control (A1C) and level of frailty of participants. Methods Fifty females (62.2 ± 10.1 years old) with type 2 diabetes and frailty completed the program; 16 used a walking aid. Outcome measures included A1C and the modified Physical Performance Test (mPPT). Repeated measures analysis of variance was used to compare outcomes before and after the program and between participants who did and did not use a walking aid. Results ASD was effective in reducing A1C and frailty in participants who did and did not use a walking aid. The reduction in A1C was similar for the 2 groups. The reduction in frailty was greater for the group that used a walking aid. Conclusion Physical activity, a keystone for blood glucose control, is difficult for older adults who are frail. ASD provides a model for DSME that may reduce frailty of participants and increase their capacity for physical activity.

The purpose of this study was to assess the correlation between standardized uptake value (SUV) and apparent diffusion coefficient (ADC) of neoplastic lesions in the use of a simultaneous PET/MRI hybrid system.Twenty-four patients with known primary malignancies underwent FDG PET/CT. They then underwent whole-body PET/MRI. Diffusion-weighted imaging was performed with free breathing and a single-shot spin-echo echo-planar imaging sequence with b values of 0, 350, and 750 s/mm(2). Regions of interest were manually drawn along the contours of neoplastic lesions larger than 1 cm, which were clearly identified on PET and diffusion-weighted images. Maximum SUV (SUVmax) on PET/MRI and PET/CT images, mean SUV (SUVmean), minimum ADC (ADCmin), and mean ADC (ADCmean) were recorded on PET/MR images for each FDG-avid neoplastic soft-tissue lesion with a maximum of three lesions per patient. Pearson correlation coefficient was used to asses the following relations: SUVmax versus ADCmin on PET/MR and PET/CT images, SUVmean versus ADCmean, and ratio of SUVmax to mean liver SUV (SUV ratio) versus ADCmin. A subanalysis of patients with progressive disease versus partial treatment response was performed with the ratio of SUVmax to ADCmin for the most metabolically active lesion.Sixty-nine neoplastic lesions (52 nonosseous lesions, 17 bone metastatic lesions) were evaluated. The mean SUVmax from PET/MRI was 7.0 ± 6.0; SUVmean, 5.6 ± 4.6; mean ADCmin, 1.10 ± 0.58; and mean ADCmean, 1.48 ± 0.72. A significant inverse Pearson correlation coefficient was found between PET/MRI SUVmax and ADCmin (r = -0.21, p = 0.04), between SUVmean and ADCmean (r = -0.18, p = 0.07), and between SUV ratio and ADCmin (r = -0.27, p = 0.01). A similar inverse Pearson correlation coefficient was found between the PET/CT SUVmax and ADCmin. Twenty of 24 patients had previously undergone PET/CT; five patients had a partial treatment response, and six had progressive disease according to Response Evaluation Criteria in Solid Tumors 1.1. The ratio between SUVmax and ADCmin was higher among patients with progressive disease than those with a partial treatment response.Simultaneous PET/MRI is a promising technology for the detection of neoplastic disease. There are inverse correlations between SUVmax and ADCmin and between SUV ratio and ADCmin. Correlation coefficients between SUVmax and ADCmin from PET/MRI were similar to values obtained with SUVmax from the same-day PET/CT. Given that both SUV and ADC are related to malignancy and that the correlation between the two biomarkers is relatively weak, SUV and ADC values may offer complementary information to aid in determination of prognosis and treatment response. The combined tumoral biomarker, ratio between SUVmax and ADCmin, may be useful for assessing progressive disease versus partial treatment response.

This chapter will focus specifically on the relationship between image technology and the nuclear family, eventually pinpointing the themes of maternity and technological reproduction, particularly as they relate to memory. As in The Blair Witch Project and the Paranormal Activity series, the position of paternal authority is challenged in Joseph Ruben’s The Forgotten (2004) and Walter Salles’s Dark Water (2005). Both films involve absent fathers and single mothers attempting to save their children from a seemingly destructive technological foe. As in Cloverfield, technologically produced images and archives seem to be parasitic on internal, psychic memory, pulling memories out of the mind, destroying and/or manipulating them. The relationship between past and present, absence and presence is disturbed in the process, and the future is radically uncertain, as these technological forces threaten the lives of the children in each film. Paradoxically, it is through the very same technology that appears to be threatening the mother-child relation that that relation will be preserved and the children saved.

In this chapter I extend my discussion of the demonology of the image, addressing a recent trend in supernatural horror—cinema verite-style filming—that was popularized with the success of The Blair Witch Project (Myrick and Sanchez, 1999) and continued in Cloverfield (Reeves, 2008) and the Paranormal Activity series (Peli, 2007; Williams, 2010; Schulman and Joost, 2011 and 2012). In all of these films, there is a sense that turning on the camera sets the events in motion, that the camera does not merely record events but actually makes things happen. Control over the camera and the events it films passes from the human subjects to a force emanating from the film/image itself, so that the filming seems to create the monsters that plague their human counterparts. These monsters turn the eye of the viewer back upon him or her in a violent way, ultimately killing the cameraman in Cloverfield, violently dispatching them in The Blair Witch Project and all of the Paranormal films, and often threatening to swallow the image itself. This violent reversal of the viewer-viewed relation calls into question its traditionally gendered characterization: on one side the male, active subject/gaze and on the other the female, passive object/image. In these films, the image is active, and the one behind the camera often becomes the passive victim.

In this paper we present a method for estimating wind gusts and a corresponding display for increasing the situational awareness of a minimally trained operator controlling a Micro Aerial Vehicle (MAV). Our method utilizes statistical correlations between MAV controller output and prior wind conditions to predict the presence of a gust in the current flight environment. The findings show that the effect of wind gusts on the MAV are significantly correlated to the rate of increase and duration of a gust rather than the magnitude of the gust. The primary benefit of this method is the simplicity of identifying wind gusts without additional sensors and without performing additional maneuvers. This technique enables existing vehicles to incorporate wind conditions into their operator displays without vehicle modification and without dedicating computation resources to flight modeling. In contrast to traditional wind indicators, our display presents wind information in the form of a warning metric rather than a wind velocity vector.

Study objective: To determine the safety of lumbar puncture in patients with hemophilia who are pretreated with clotting factor. Design: Retrospective analysis of medical records between 1980 and 1990. Setting: Three hospitals, each serving as a regional hemophilia center. Participants: Thirty-three patients with hemophilia A or B who received one or more lumbar puncture. Intervention: All patients received replacement of deficient factor before the lumbar puncture. Serious post-lumbar puncture complications were defined as motor or sensory deficits, incontinence, or documented intraspinal hemorrhage. Results: Thirty-three patients with hemophilia A or B received a total of 52 lumbar punctures during the study period. Thirty of 33 patients (91%) had severe baseline factor deficiency, two (6%) had moderate deficiency, and one (3%) had mild deficiency. There were no serious complications reported as a result of the lumbar puncture. The 95% confidence interval for the risk of a serious complication was 0% to 5.8%. Conclusion: With adequate factor replacement, a lumbar puncture can be done safely in patients with hemophilia.