Certified reference materials (CRMs) traceable to national and international safeguards database are a critical prerequisite for ensuring that nuclear measurement systems are free of systematic ...biases. CRMs are used to validate measurement processes associated with nuclear analytical laboratories. Diverse areas related to nuclear safeguards are impacted by the quality of the CRM standards available to analytical laboratories. These include: nuclear forensics, radio-chronometry, national and international safeguards, stockpile stewardship, nuclear weapons infrastructure and nonproliferation, fuel fabrication, waste processing, radiation protection, and environmental monitoring. For the past three decades the nuclear community is confronted with the strange situation that improvements in measurement data quality resulting from the improved accuracy and precision achievable with modern multi-collector mass spectrometers could not be fully exploited due to large uncertainties associated with CRMs available from New Brunswick Laboratory (NBL) that are used for instrument calibration and measurement control. Similar conditions prevail for both plutonium and uranium isotopic standards and for impurity element standards in uranium matrices. Herein, the current status of U and Pu isotopic standards available from NBL is reviewed. Critical areas requiring improvement in the quality of the nuclear standards to enable the U. S. and international safeguards community to utilize the full potential of modern multi-collector mass spectrometer instruments are highlighted.
Schematic of a Thermal Ionization Mass Spectrometer (TIMS) Instrument.
ABSTRACT
Chronic abdominal pain, defined as long‐lasting intermittent or constant abdominal pain, is a common pediatric problem encountered by primary care physicians, medical subspecialists and ...surgical specialists. Chronic abdominal pain in children is usually functional‐that is, without objective evidence of an underlying organic disorder. The Subcommittee on Chronic Abdominal Pain of the American Academy of Pediatrics and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition has prepared this report based on a comprehensive, systematic review and rating of the medical literature. This report accompanies a clinical report based on the literature review and expert opinion.
The subcommittee examined the diagnostic and therapeutic value of a medical and psychologic history, diagnostic tests, and pharmacological and behavioral therapy. The presence of alarm symptoms or signs (such as weight loss, gastrointestinal bleeding, persistent fever, chronic severe diarrhea and significant vomiting) is associated with a higher prevalence of organic disease. There was insufficient evidence to state that the nature of the abdominal pain or the presence of associated symptoms (such as anorexia, nausea, headache and joint pain) can discriminate between functional and organic disorders. Although children with chronic abdominal pain and their parents are more often anxious or depressed, the presence of anxiety, depression, behavior problems or recent negative life events does not distinguish between functional and organic abdominal pain. Most children who are brought to the primary care physician's office for chronic abdominal pain are unlikely to require diagnostic testing. Pediatric studies of therapeutic interventions were examined and found to be limited or inconclusive.
Cell therapies such as tumor-infiltrating lymphocyte (TIL) therapy have shown promise in the treatment of patients with refractory solid tumors, with improvement in response rates and durability of ...responses nevertheless sought. To identify targets capable of enhancing the antitumor activity of T cell therapies, large-scale in vitro and in vivo clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens were performed, with the SOCS1 gene identified as a top T cell-enhancing target. In murine CD8+ T cell-therapy models, SOCS1 served as a critical checkpoint in restraining the accumulation of central memory T cells in lymphoid organs as well as intermediate (Texint) and effector (Texeff) exhausted T cell subsets derived from progenitor exhausted T cells (Texprog) in tumors. A comprehensive CRISPR tiling screen of the SOCS1-coding region identified sgRNAs targeting the SH2 domain of SOCS1 as the most potent, with an sgRNA with minimal off-target cut sites used to manufacture KSQ-001, an engineered TIL therapy with SOCS1 inactivated by CRISPR/Cas9. KSQ-001 possessed increased responsiveness to cytokine signals and enhanced in vivo antitumor function in mouse models. These data demonstrate the use of CRISPR/Cas9 screens in the rational design of T cell therapies.
Field windbreaks can increase crop yield within a protected zone. However, they also take land out of crop production and compete with adjacent crops. Although the beneficial aspects are generally ...recognized, the question arises whether the windbreak will increase crop revenue enough to offset costs over time. Achieving additional yields to offset windbreak costs might be a sufficient incentive for a producer to plant a windbreak. Additional maize (Zea mays) yields necessary to break even with costs are calculated for four typical Midwestern USA field windbreaks: poplar (Populus spp.), mixed tree/shrubs (Populus spp., Acer saccharinum L./Physocarpus spp., Viburnum spp., Cornus spp.), and two and four-row spruce (Picea spp.) windbreaks. Five lifespans, two management and two cost scenarios, and three protected zone widths to account for changing sheltering effects are evaluated. Greatest additional yields are for a 4-row spruce windbreak with intensive management at high cost and a 10-year lifespan: 15.38 Mg ha–1 yr–1 within 6H, 7.69 Mg ha–1 yr–1 within 12H and 6.15 Mg ha–1 yr–1 within 15H. If a 50-year lifespan is implemented, the additional yields are about 11% of those in 10-year lifespan. Smallest additional yields are for a mixed tree/shrubs windbreak with extensive management at low cost and a 50-year lifespan: 0.56 Mg ha–1 yr–1, 0.28 Mg ha–1 yr–1 and 0.22 Mg ha–1 yr–1, respectively. The mixed windbreak is likely to have actual maize yield increases comparable to the added maize yields required to break even as long as the lifespan is 30 years or longer with a minimum protected zone of 12H.
Hypoxemia and hypotension are common complications during endotracheal intubation of critically ill adults. Verbal performance of a written, preintubation checklist may prevent these complications. ...We compared a written, verbally performed, preintubation checklist with usual care regarding lowest arterial oxygen saturation or lowest systolic BP experienced by critically ill adults undergoing endotracheal intubation.
A multicenter trial in which 262 adults undergoing endotracheal intubation were randomized to a written, verbally performed, preintubation checklist (checklist) or no preintubation checklist (usual care). The coprimary outcomes were lowest arterial oxygen saturation and lowest systolic BP between the time of procedural medication administration and 2 min after endotracheal intubation.
The median lowest arterial oxygen saturation was 92% (interquartile range IQR, 79-98) in the checklist group vs 93% (IQR, 84-100) with usual care (P = .34). The median lowest systolic BP was 112 mm Hg (IQR, 94-133) in the checklist group vs 108 mm Hg (IQR, 90-132) in the usual care group (P = .61). There was no difference between the checklist and usual care in procedure duration (120 vs 118 s; P = .49), number of laryngoscopy attempts (one vs one attempt; P = .42), or severe life-threatening procedural complications (40.8% vs 32.6%; P = .20).
The verbal performance of a written, preprocedure checklist does not increase the lowest arterial oxygen saturation or lowest systolic BP during endotracheal intubation of critically ill adults compared with usual care.
ClinicalTrials.gov; No.: NCT02497729; URL: www.clinicaltrials.gov.
Partial hepatectomy triggers hepatocyte proliferation, hepatic matrix remodeling, and hepatocyte apoptosis, all of which are important processes in the regenerating liver. Previous studies have shown ...an increase in the levels of matrix metalloproteinases gelatinase A (MMP‐2) and gelatinase B (MMP‐9) after partial hepatectomy. The goal of this study was to investigate the role of MMP‐9 in liver regeneration after partial hepatectomy. A 70% hepatectomy or sham laparotomy was performed in wild‐type or MMP‐9–deficient (MMP‐9−/−) mice. Hepatic regeneration was determined by liver weight/total body weight ratios and BrdU staining, which was used to a calculate mitotic index at several times postoperatively. Cytokine and growth factor expression was evaluated by Luminex™ bead–based ELISA and Western blots. Finally, the effect of MMP‐9 on apoptosis was measured using TUNEL and caspase expression. The MMP‐9−/− animals had a delayed hepatic regenerative response when compared with wild‐type controls. The MMP‐9–deficient animals expressed significantly less VEGF, HGF, and TNF‐α between days 2 and 3 post‐hepatectomy. Apoptosis, as measured by TUNEL staining and caspase expression, was decreased in the MMP‐9−/−. In conclusion, MMP‐9 plays an important role in liver regeneration after partial hepatectomy by affecting matrix remodeling, as well as cytokine, growth factor, and caspase expression. (HEPATOLOGY 2006;44:540–549.)
Cell therapies such as tumor-infiltrating lymphocyte (TIL) therapy have shown promise in the treatment of patients with refractory solid tumors, with improvement in response rates and durability of ...responses nevertheless sought. To identify targets capable of enhancing the antitumor activity of T cell therapies, large-scale in vitro and in vivo clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screens were performed, with the SOCS1 gene identified as a top T cell-enhancing target. In murine CD8.sup.+ T cell-therapy models, SOCS1 served as a critical checkpoint in restraining the accumulation of central memory T cells in lymphoid organs as well as intermediate (Tex.sup.int) and effector (Tex.sup.eff) exhausted T cell subsets derived from progenitor exhausted T cells (Tex.sup.prog) in tumors. A comprehensive CRISPR tiling screen of the 50C57-coding region identified sgRNAs targeting the SH2 domain of SOCS1 as the most potent, with an sgRNA with minimal off-target cut sites used to manufacture KSQ-001, an engineered TIL therapy with SOCS1 inactivated by CRISPR/Cas9. KSQ-001 possessed increased responsiveness to cytokine signals and enhanced in vivo antitumor function in mouse models. These data demonstrate the use of CRISPR/Cas9 screens in the rational design of T cell therapies.
A large hexanucleotide (GGGGCC) repeat expansion in the first intron of C9ORF72, a gene located on chromosome 9p21, has been recently reported to be responsible for ~40% of familial amyotrophic ...lateral sclerosis cases of European ancestry. The aim of the current article was to describe the phenotype of amyotrophic lateral sclerosis cases carrying the expansion by providing a detailed clinical description of affected cases from representative multi-generational kindreds, and by analysing the age of onset, gender ratio and survival in a large cohort of patients with familial amyotrophic lateral sclerosis. We collected DNA and analysed phenotype data for 141 index Italian familial amyotrophic lateral sclerosis cases (21 of Sardinian ancestry) and 41 German index familial amyotrophic lateral sclerosis cases. Pathogenic repeat expansions were detected in 45 (37.5%) patients from mainland Italy, 12 (57.1%) patients of Sardinian ancestry and nine (22.0%) of the 41 German index familial amyotrophic lateral sclerosis cases. The disease was maternally transmitted in 27 (49.1%) pedigrees and paternally transmitted in 28 (50.9%) pedigrees (P = non-significant). On average, children developed disease 7.0 years earlier than their parents children: 55.8 years (standard deviation 7.9), parents: 62.8 (standard deviation 10.9); P = 0.003. Parental phenotype influenced the type of clinical symptoms manifested by the child: of the 13 cases where the affected parent had an amyotrophic lateral sclerosis-frontotemporal dementia or frontotemporal dementia, the affected child also developed amyotrophic lateral sclerosis-frontotemporal dementia in nine cases. When compared with patients carrying mutations of other amyotrophic lateral sclerosis-related genes, those with C9ORF72 expansion had commonly a bulbar onset (42.2% compared with 25.0% among non-C9ORF72 expansion cases, P = 0.03) and cognitive impairment (46.7% compared with 9.1% among non-C9ORF72 expansion cases, P = 0.0001). Median survival from symptom onset among cases carrying C9ORF72 repeat expansion was 3.2 years lower than that of patients carrying TARDBP mutations (5.0 years; 95% confidence interval: 3.6-7.2) and longer than those with FUS mutations (1.9 years; 95% confidence interval: 1.7-2.1). We conclude that C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry. Together with mutation of SOD1, TARDBP and FUS, mutations of C9ORF72 account for ~60% of familial amyotrophic lateral sclerosis in Italy. Patients with C9ORF72 hexanucleotide repeat expansions present some phenotypic differences compared with patients with mutations of other genes or with unknown mutations, namely a high incidence of bulbar-onset disease and comorbidity with frontotemporal dementia. Their pedigrees typically display a high frequency of cases with pure frontotemporal dementia, widening the concept of familial amyotrophic lateral sclerosis.
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