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The presence of oxygen in soil controls the occurrence and rates of biogeochemical processes underlying soil nutrient transformations and greenhouse gas dynamics. Oxygen (O2) levels within the rhizosphere are heavily modulated by both root and microbial respiration. Thus, a microscopic environment near the root may be a microbial hotspot and not well represented by broader, non-rhizosphere soil. Here we examine the millimeter-scale oxygen consumption or loss processes in the rhizosphere of sorghum, how they are influenced by irrigation practices, and the relationship between oxygen dynamics and nitrification in the rhizosphere.In a field study at a research farm at the University of Illinois Urbana-Champaign, sorghum was grown under a rainout shelter with plants undergoing one of 2 irrigation treatments. Soil O2 concentration and isotopic ratios, nitrous oxide (N2O), and carbon dioxide (CO2) were measured in the rhizosphere of the sorghum via an array of novel microvolume probes coupled to an Aerodyne TILDAS (Tunable Infrared Laser Direct Absorption Spectrometer). Probes were placed within the rhizosphere or outside the root zone with the aid of root windows installed at the site.We collected continuous, real-time, in situ measurements of O2, O2 isotopes, CO2 and N2O over the 2022 sorghum growing season. The high spatial and temporal resolution of the measurements allowed us to observe spatiotemporal heterogeneity of biogeochemical activity in the rhizosphere as a function of agricultural activity. We will also report on controlled laboratory incubations to quantify the impact of soil microbial oxygen consumption on 18O enrichment as compared to water displacement in the soil; and controlled greenhouse experiments to measure fine scale gradients of oxygen concentrations and isotopic composition near roots.The novel microvolume sampling system coupled with the O2 detection method can provide insights into fine scale gradients driven by higher microbial activity in microbial hotspots within the rhizosphere. Measurements on this mm-scale have further applications for monitoring other trace soil gases and their spatial and temporal heterogeneity in soil systems.

Pressed by the accumulating knowledge in genomics and the proven success of the translation of cancer genomics to clinical practice in oncology, the Obama administration unveiled a $215 million commitment for the Precision Medicine Initiative (PMI) in 2016, a pioneering research effort to improve health and treat disease using a new model of patient-powered research. The objectives of the initiative include more effective treatments for cancer and other diseases, creation of a voluntary national research cohort, adherence to privacy protections for maintaining data sharing and use, modernization of the regulatory framework, and forging public–private partnerships to facilitate these objectives. Specifically, the DoD Military Health System joined other agencies to execute a comprehensive effort for PMI. Of the many challenges to consider that may contribute to the implementation of genomics—lack of familiarity and understanding, poor access to genomic medicine expertise, needs for extensive informatics and infrastructure to integrate genomic results, privacy and security, and policy development to address the unique requirements of military medical practice—we will focus on the need to establish education in genomics appropriate to the provider’s responsibilities. Our hypothesis is that there is a growing urgency for the development of educational experiences, formal and informal, to enable clinicians to acquire competency in genomics commensurate with their level of practice. Several educational approaches, both in practice and in development, are presented to inform decision-makers and empower military providers to pursue courses of action that respond to this need.

Introduction Studies have reported higher risks of mortality for patients with schizophrenia, compared to the general population. This study aimed to evaluate the risk of all-cause, sudden death, and cardiovascular mortality among patients with schizophrenia in terms of types of antipsychotics. Methods A retrospective cohort study assessed the risk of mortality among antipsychotic-treated patients with schizophrenia. The study linked the Taiwan National Health Insurance (NHI) claims and National Register of Death databases from 2001 to 2015. Patients were hierarchically assigned to the following index antipsychotic treatment groups: atypical long acting injection (LAI), typical LAI, atypical oral, and typical oral. Results A total of 68,159 antipsychotic-treated patients with schizophrenia were analyzed. Under the hierarchical grouping, the largest percentages of patients were on atypical oral antipsychotic regimens (65.51%), followed by typical oral (14.00%), typical LAI (12.84%), and atypical LAI (7.65%). Typical oral patients had the highest incidence of all-cause mortality of 27.48 per 1000 patient-years and the atypical LAI group had the lowest incidence (13.95 per 1000 patient-years). Compared to typical oral users, there were lower risks of all-cause mortality for users of atypical LAI (aHR = 0.62, 95% CI: 0.47–0.81), typical LAI (aHR = 0.65, 95% CI: 0.55–0.78), and atypical orals (aHR = 0.55, 95% CI: 0.49–0.62). Conclusion Compared to typical oral users, we found a lower risk of all-cause mortality, sudden death, and cardiovascular mortality among schizophrenia users of LAIs and oral atypicals. Further research is warranted to characterize the risk of mortality among users of more recently available LAIs in the Asia Pacific region and elsewhere.

Agriculture contributes nearly a quarter of global greenhouse gas (GHG) emissions, which is motivating interest in certain farming practices that have the potential to reduce GHG emissions or sequester carbon in soil. The related GHG emission (including N2O and CH4) and changes in soil carbon stock are defined here as “agricultural carbon outcomes”. Accurate quantification of agricultural carbon outcomes is the basis for achieving emission reductions for agriculture, but existing approaches for measuring carbon outcomes (including direct measurements, emission factors, process-based modeling) fall short of achieving the required accuracy and scalability necessary to support credible, verifiable, and cost-effective measurement and improvement of these carbon outcomes. Here we propose a foundational and scalable framework to quantify field-level carbon outcomes for farmland, which is based on the holistic carbon balance of the agroecosystem: Agroecosystem Carbon Outcomes = Crops (C) × Management (M) × Environment (E). Following a comprehensive review of the scientific challenges associated with existing approaches, as well as their tradeoffs between cost and accuracy, we propose that the most viable path for the quantification of field-level carbon outcomes in agricultural land is through an effective integration of various approaches (e.g. diverse observations, sensor/in-situ data, modeling), defined as the “system- of-systems” solution. Such a “system-of-systems” solution should simultaneously comprise the following components: (1) scalable collection of ground truth data and cross-scale sensing of crop conditions (C), management practices (M), and environment (E) at the local field level; (2) advanced modeling with necessary processes to support the quantification of carbon outcomes; (3) systematic Model-Data Fusion (MDF), i.e. robust and efficient methods to integrate sensing data and models at each local farmland level; (4) high computation efficiency and artificial intelligence (AI) to scale to millions of individual fields with low cost; and (5) robust and multi-tier validation systems and infrastructures to ensure solution fidelity and true scalability, i.e. the ability of a solution to perform robustly with accepted accuracy on all targeted fields. In this regard, we provide here the detailed scientific rationale, current progress, and future R&D priorities to achieve different components of the “system-of-systems” solution, thus accomplishing the Crop×Management×Environment framework to quantify field-level agricultural carbon outcomes.

ObjectiveTo assess the association between clinical integration and financial integration, quality-focused care delivery processes, and beneficiary utilization and outcomes.Data sourcesMultiphysician practices in the 2017-2018 National Survey of Healthcare Organizations and Systems (response rate 47%) and 2017 Medicare claims data.Study designCross-sectional study of Medicare beneficiaries attributed to physician practices, focusing on two domains of integration: clinical (coordination of patient services, use of protocols, individual clinician measures, access to information) and financial (financial management and planning across operating units). We examined the association between integration domains, the adoption of quality-focused care delivery processes, beneficiary utilization and health-related outcomes, and price-adjusted spending using linear regression adjusting for practice and beneficiary characteristics, weighting to account for sampling and nonresponse.Data collection/extraction methods1604580 fee-for-service Medicare beneficiaries aged 66 or older attributed to 2113 practices. Of these, 414209 beneficiaries were considered clinically complex (frailty or 2+chronic conditions).Principal findingsFinancial integration and clinical integration were weakly correlated (correlation coefficient=0.19). Clinical integration was associated with significantly greater adoption of quality-focused care delivery processes, while financial integration was associated with lower adoption of these processes. Integration was not generally associated with reduced utilization or better beneficiary-level health-related outcomes, but both clinical integration and financial integration were associated with lower spending in both the complex and noncomplex cohorts: (clinical complex cohort: -$2518, [95% CI: -3324, -1712]; clinical noncomplex cohort: -$255 [95% CI: -413, -97]; financial complex cohort: -$997 [95% CI: -$1320, -$679]; and financial noncomplex cohort: -$143 [95% CI: -210, -$76]).ConclusionsHigher levels of financial integration were not associated with improved care delivery or with better health-related beneficiary outcomes. Nonfinancial forms of integration deserve greater attention, as practices scoring high in clinical integration are more likely to adopt quality-focused care delivery processes and have greater associated reductions in spending in complex patients.

Key Points Question How does low-value care use vary across health systems? Findings This cohort study measured and reported the use of 41 individual low-value services and a composite measure of 28 services for 556 health systems serving a total of 11 637 763 Medicare beneficiaries across the US. Systems varied widely in the provision of low-value care; those with a smaller proportion of primary care physicians, without a major teaching hospital, serving a larger proportion of non-White patients, headquartered in the South and West, and serving areas with higher health care spending delivered more low-value care. Meaning This study suggests that claims-based definitions can be used to measure low-value care within systems, providing granular, actionable feedback to promote health care quality and affordability., Importance Low-value health care remains prevalent in the US despite decades of work to measure and reduce such care. Efforts have been only modestly effective in part because the measurement of low-value care has largely been restricted to the national or regional level, limiting actionability. Objectives To measure and report low-value care use across and within individual health systems and identify system characteristics associated with higher use using Medicare administrative data. Design, Setting, and Participants This retrospective cohort study of health system–attributed Medicare beneficiaries was conducted among 556 health systems in the Agency for Healthcare Research and Quality Compendium of US Health Systems and included system-attributed beneficiaries who were older than 65 years, continuously enrolled in Medicare Parts A and B for at least 12 months in 2016 or 2017, and eligible for specific low-value services. Statistical analysis was conducted from January 26 to July 15, 2021. Main Outcomes and Measures Use of 41 individual low-value services and a composite measure of the 28 most common services among system-attributed beneficiaries, standardized to distance from the mean value. Measures were based on the Milliman MedInsight Health Waste Calculator and published claims-based definitions. Results Across 556 health systems serving a total of 11 637 763 beneficiaries, the mean (SD) use of each of the 41 low-value services ranged from 0% (0.01%) to 28% (4%) of eligible beneficiaries. The most common low-value services were preoperative laboratory testing (mean [SD] rate, 28% [4%] of eligible beneficiaries), prostate-specific antigen testing in men older than 70 years (mean [SD] rate, 27% [8%]), and use of antipsychotic medications in patients with dementia (mean [SD] rate, 24% [8%]). In multivariable analysis, the health system characteristics associated with higher use of low-value care were smaller proportion of primary care physicians (adjusted composite score, 0.15 [95% CI, 0.04-0.26] for systems with less than the median percentage of primary care physicians vs −0.16 [95% CI, –0.27 to –0.05] for those with more than the median percentage of primary care physicians; P 20% of non-White beneficiaries vs −0.06 [95% CI, –0.16 to 0.03] for systems with ≤20% of non-White beneficiaries; P = .04), headquartered in the South or West (adjusted composite, 0.28 [95% CI, 0.14-0.43] for the South and 0.22 [95% CI, 0.02-0.42] for the West compared with −0.09 [95% CI, –0.26 to 0.08] for the Northeast and −0.44 [95% CI, –0.60 to –0.28] for the Midwest; P, This cohort study uses Medicare data to measure and report low-value care use across and within individual health systems and identify system characteristics associated with higher use.

Background Understanding immunogenicity and effectiveness of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines is critical to guide rational use. Methods We compared the immunogenicity of mRNA-1273, BNT-162b2, and Ad26.COV2.S in healthy ambulatory adults. We performed an inverse-variance meta-analysis of population-level effectiveness from public health reports in > 40 million individuals. Results A single dose of either mRNA vaccine yielded comparable antibody and neutralization titers to convalescent individuals. Ad26.COV2.S yielded lower antibody concentrations and frequently undetectable neutralization titers. Bulk and cytotoxic T-cell responses were higher in mRNA1273 and BNT162b2 than Ad26.COV2.S recipients. Regardless of vaccine, Conclusions Variation in the immunogenicity correlates with variable effectiveness of the 3 vaccines deployed in the United States.

Background: Video-assisted thoracoscopic bullectomy with pleurodesis is widely used to treat spontaneous pneumothorax. However, 1%–3% of patients experience postoperative complications that may require reoperation, such as bleeding or prolonged air leaks, and 3%–7% of patients require a repeat thoracoscopic bullectomy due to recurrence. Therefore, a modified procedure with improved outcomes is required. Methods: Between January 1, 2011 and December 31, 2015, 196 patients with spontaneous pneumothorax underwent thoracoscopic bullectomy and pleurodesis with or without fixation of the lung apex to the chest wall. In patients in the fixation group, the lung apex was fixed to the chest wall with two non-absorbable sutures after bullectomy and pleurodesis. The treatment of each lung was considered an independent operation in patients with bilateral spontaneous pneumothorax. Results: The patients in each group had comparable backgrounds. In the fixation group, 67 patients underwent 87 operations, four of which (in three patients) led to recurrences (recurrence rate, 4.60%). There were no readmissions or reoperations within 30 days in this group. In the non-fixation group, 128 patients underwent 161 operations, 14 of which (in nine patients) led to recurrences (recurrence rate, 8.7%). In addition, three patients in this group required reoperation and two were readmitted within 30 days. Conclusions: Modified thoracoscopic bullectomy with fixation of the lung apex is a safe procedure that provides better outcomes with lower complication rates. Key Words: spontaneous pneumothorax, thoracoscopic bullectomy, video-assisted thoracoscopic surgery (VATS), lung apex fixation

Specifications in the U.S. Code of Federal Regulations for the color additive D&C Red No. 17 (R17, Colour Index No. 26100) limit the levels of the dye’s intermediates, aniline (AN), 2-naphthol (β-naphthol, BN), and 4-aminoazobenzene (4AAB), to 0.2, 0.2, and 0.1%, respectively. The present work reports the development and application of an ultra-HPLC method for the quantitative determination of these impurities in R17. A 1.7 μm particle size C-18 column was used with 0.2 M ammonium acetate and acetonitrile as the eluents. AN, BN, and 4AAB were quantified by using six-point calibration curves with data points (w/w) ranging from 0.01 to 0.25% for AN, 0.01 to 0.24% for BN, and 0.01 to 0.19% for 4AAB. The correlation coefficients ranged from 0.9992 to 0.9999. Limits of detection for the analytes ranged from 0.002 to 0.01%. Recoveries of the analytes ranged from 99.5 to 102%. Relative standard deviations ranged from 0.482 to 1.262%. The new method was applied to analyze portions from 22 batches of R17 submitted to the U.S. Food and Drug Administration for certification. It was found to be simpler to implement, faster, and more sensitive than the older gravity-elution column chromatography method, which it has replaced.

SUMMARY The development and function of epithelia depend on the establishment and maintenance of cell-cell adhesion and intercellular junctions, which operate as mechanosensor hubs for the transduction of biochemical signals regulating cell proliferation, differentiation, survival, and regeneration. Here, we show that αE-catenin, a key component of adherens junctions, functions as a positive regulator of pancreatic islet cell lineage differentiation by repressing the sonic hedgehog pathway (SHH). Thus, deletion of αE-catenin in multipotent pancreatic progenitors resulted in (1) loss of adherens junctions, (2) constitutive activation of SHH, (3) decrease in islet cell lineage differentiation, and (4) accumulation of immature Sox9+ progenitors. Pharmacological blockade of SHH signaling in pancreatic organ cultures and in vivo rescued this defect, allowing αE-catenin-null Sox9+ pancreatic progenitors to differentiate into endocrine cells. The results uncover crucial functions of αE-catenin in pancreatic islet development and harbor significant implications for the design of β cell replacement and regeneration therapies in diabetes., Graphical abstract Jimenez-Caliani et al. examine a regulatory function for αE-catenin in the endocrine differentiation of pancreatic progenitors. Ablation of αE-catenin in multipotent Pdx1+ progenitors disrupts cell-cell adhesion and leads to constitutive activation of SHH signaling that precludes endocrine differentiation and leads to the accumulation of proliferating Sox9+ cells. Pharmacological blockade of SHH rescues the competency of αE-cateninnullSox9+ progenitors to acquire an endocrine phenotype.

Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap disorders characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, interleukin-3, and stem cell factor in a NOD/SCID-IL2Rγnull background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML. Xenotransplantation of CD34+ cells (n = 8 patients) or unfractionated bone marrow (BM) or peripheral blood mononuclear cells (n = 10) resulted in robust engraftment of CMML in BM, spleen, liver, and lung of recipients (n = 82 total mice). Engrafted cells were myeloid-restricted and matched the immunophenotype, morphology, and genetic mutations of the corresponding patient. Similar levels of engraftment were seen upon serial transplantation of human CD34+ cells in secondary NSGS recipients (2/5 patients, 6/11 mice), demonstrating the durability of CMML grafts and functionally validating CD34+ cells as harboring the disease-initiating compartment in vivo. Successful engraftments of JMML primary samples were also achieved in all NSGS recipients (n = 4 patients, n = 12 mice). Engraftment of CMML and JMML resulted in overt phenotypic abnormalities and lethality in recipients, which facilitated evaluation of the JAK2/FLT3 inhibitor pacritinib in vivo. These data reveal that NSGS mice support the development of CMML and JMML disease-initiating and mature leukemic cells in vivo, allowing creation of genetically accurate preclinical models of these disorders.

A new practical and time-saving ultra-high performance liquid chromatography (UHPLC) method has been developed for determining the organic impurities in the anthraquinone color additives D&C Violet No. 2 and D&C Green No. 6. The impurities determined are p-toluidine, 1-hydroxyanthraquinone, 1,4-dihydroxyanthraquinone, and two subsidiary colors. The newly developed UHPLC method uses a 1.7-μ particle size C-18 column, 0.1 M ammonium acetate and acetonitrile aseluents, and photodiode array detection. For the quantification of the impurities, six-point calibration curves were used with correlation coefficients that ranged from 0.9974 to 0.9998. Recoveries of impurities ranged from 99 to 104%. Relative standard deviations ranged from 0.81 to 4.29%. The limits of detection for the impurities ranged from 0.0067% to0.216%. Samples from sixteen batches of each color additive were analyzed, and the results favorably compared with the results obtained by gravity-elution column chromatography, thin-layer chromatography, and isooctane extraction. Unlike with those other methods, use of the UHPLC method permits all of the impurities to be determined in a single analysis, while also reducing the amount of organic waste and saving timeand labor. The method is expected to be implemented by the U.S. Food and Drug Administration for analysis of color additive samples submitted for batch certification.

BACKGROUND Hirschsprung's disease (HSCR) is a congenital disorder with the absence of myenteric and submucosal ganglion cells within distal gut. Due to multigenic inheritance and interactions, we employed next-generation sequencing (NGS) to investigate genetic backgrounds of long-segment HSCR (L-HSCR) in Taiwan. METHODS Genomic DNA extracted from peripheral blood of L-HSCR patients was subjected to capture-based NGS, based on a 31-gene panel. The variants with allele frequency

Systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE) of the skin are autoimmune diseases characterized by inappropriate immune responses against self-proteins; the key elements that determine disease pathogenesis and progression are largely unknown. Here, we show that mice lacking immune inhibitory receptor VISTA or programmed death-1 homolog (PD-1H KO) on a BALB/c background spontaneously develop cutaneous and systemic autoimmune diseases resembling human lupus. Cutaneous lupus lesions of PD-1H KO mice have clustering of plasmacytoid dendritic cells (pDCs) similar to human DLE. Using mass cytometry, we identified proinflammatory neutrophils as critical early immune infiltrating cells within cutaneous lupus lesions of PD-1H KO mice. We also found that PD-1H is highly expressed on immune cells in human SLE, DLE lesions, and cutaneous lesions of MRL/lpr mice. A PD-1H agonistic monoclonal antibody in MRL/lpr mice reduces cutaneous disease, autoantibodies, inflammatory cytokines, chemokines, and immune cell expansion. Furthermore, PD-1H on both T cells and myeloid cells including neutrophils and pDCs could transmit inhibitory signals, resulting in reduced activation and function, establishing PD-1H as an inhibitory receptor on T cells and myeloid cells. On the basis of these findings, we propose that PD-1H is a critical element in the pathogenesis and progression of lupus, and PD-1H activation could be effective for treatment of systemic and cutaneous lupus.

Precision oncology embodies the targeted and rational treatment of cancer according to the specific molecular alterations underlying an individual patient’s disease. It is now well-established that cancer is primarily a genetic disease caused by inherited and acquired genomic aberrations [1]. Each cancer carries a unique set of “driver” genomic aberrations that work together to promote cancer initiation and maintenance. It is also understood that cancer genomes are inherently unstable, and the accumulation of new driver genomic aberrations can lead to cancer progression and drug resistance [2]. The promise of precision oncology postulates that each cancer can be treated more effectively, and even possibly cured, through understanding and targeting key driver genomic aberrations. This requires first identifying key oncogenic genomic aberrations in cancer cells, enabled via molecular diagnostics, to guide the rational selection of molecular therapeutic agents specifically targeting these alterations. Thus, cancer molecular diagnostics are a fundamental and integral component of precision oncology.

Low-grade chronic inflammation plays an important role in the pathogenesis of obesity-induced insulin resistance. ABCA1 is essential for reverse cholesterol transport and HDL synthesis, and protects against macrophage inflammation. In the present study, the effects of ABCA1 deficiency in hematopoietic cells on diet-induced inflammation and insulin resistance were tested in vivo using bone marrow transplanted (BMT)-WT and BMT-ABCA1(-/-) mice. When challenged with a high-fat high-carbohydrate diabetogenic diet with added cholesterol (HFHSC), BMT-ABCA1(-/-) mice displayed enhanced insulin resistance and impaired glucose tolerance as compared with BMT-WT mice. The worsened insulin resistance and impaired glucose tolerance in BMT-ABCA1(-/-) mice were accompanied by increased macrophage accumulation and inflammation in adipose tissue and liver. Moreover, BMT-ABCA1(-/-) mice had significantly higher hematopoietic stem cell proliferation, myeloid cell expansion, and monocytosis when challenged with the HFHSC diet. In vitro studies indicated that macrophages from ABCA1(-/-) mice showed significantly increased inflammatory responses induced by saturated fatty acids. Taken together, these studies point to an important role for hematopoietic ABCA1 in modulating a feed-forward mechanism in obesity such that inflamed tissue macrophages stimulate the production of more monocytes, leading to an exacerbation of inflammation and associated disease processes.

Summary Efficient stem cell differentiation into pancreatic islet cells is of critical importance for the development of cell replacement therapies for diabetes. Here, we identify the expression pattern of connexin 43 (Cx43), a gap junction (GJ) channel protein, in human embryonic stem cell (hESC)-derived definitive endoderm (DE) and primitive gut tube cells, representing early lineages for posterior foregut (PF), pancreatic progenitors (PP), pancreatic endocrine progenitors (PE), and islet cells. As the function of GJ channels is dependent on their gating status, we tested the impact of supplementing hESC-derived PP cell cultures with AAP10, a peptide that promotes Cx43 GJ channel opening. We found that this treatment promotes the expression of DE markers FoxA2 and Sox17, leads to a more efficient derivation of DE, and improves the yield of PF, PP, and PE cells. These results demonstrate a functional involvement of GJ channels in the differentiation of embryonic stem cells into pancreatic cell lineages., Graphical Abstract, Highlights • Cx43 is upregulated during hESC differentiation into definitive endoderm (DE) • siRNA-mediated knockdown of Cx43 prevents hESC differentiation into DE cells • AAP10-mediated gating of Cx43 gap junctions promotes the expression of FoxA2 and Sox17 • Cx43 gap junction communication supports DE and pancreatic progenitors development, Cell Biology; Stem Cells Research; Specialized Functions of Cells

Background: Nowadays, volumetric data acquisition has allowed for the accurate quantification of volumetric tumor burden. However, few studies have focused on the relationship between neuroblastoma tumor volume and relevant clinical parameters. Objectives: The purpose of this study was to investigate the relationship of initial computed tomography - measured primary tumor volume (CTPTV) with 24 - hour urine vanillylmandelic acid (VMA) level and stage in patients with neuroblastoma. Patients and Methods: This retrospective study included 24 patients. The patients’ age, gender, urine VMA levels and stage at diagnosis were collected, and the CTPTVs were calculated. The correlation between urine VMA level and CTPTV was assessed. The differences in CTPTVs with respect to age of the patients (≤ 1.5 and > 1.5 years old), gender, urine VMA levels (≤ 9.8 and > 9.8 mg/24 hours) and stage (stage 4 and non - stage 4) were analyzed. Multivariate linear regression was conducted to estimate the effect of age, gender, urine VMA level, and stage at diagnosis for CTPTV. Finally, a comparison of demographic characteristics and stage between various CTPTV ranges ( 9.8 mg (P = 0.03) and in patients who were diagnosed with stage 4 (P = 0.002). The most effective variable for CTPTV was urine VMA level. When the urine VMA level increases 1 mg every 24 hours, the CTPTV will increase 4.85 cm3. Among the patients with a CTPTV ≥ 35 cm3, the median age was significantly higher (P = 0.011), and median urine VMA level was significantly higher (P = 0.001) than in patients with a CTPTV < 35 cm3. Additionally, all patients with a CTPTV ≥ 35 cm3 had stage 4 disease at the time of diagnosis (P = 0.001). Conclusion: A moderate positive quantitative correlation was observed between 24 - hour urine VMA levels and initial CTPTV. A CTPTV ≥ 35 cm3 may therefore be used as an indicator of advanced tumor stage in neuroblastoma.

Specifications in the U.S. Code of Federal Regulations for the color additive D&C Green No. 8 (Colour Index No. 59040) limit the levels of the subsidiary colors 1,3,6-pyrenetrisulfonic acid trisodium salt (P3S) and 1,3,6,8-pyrenetetrasulfonic acid tetrasodium salt (P4S). The present paper describes a comparative study of two possible methods to replace the currently used multi-step TLC/spectrophotometry method of separating and quantifying the minor components P3S and P4S in G8. One of the new approaches uses conventional high-performance liquid chromatography (HPLC) and the other, derivative spectrophotometry. While the derivative spectrophotometric method was shown to be inadequate for the analysis of minor components overwhelmed by components of much higher concentration, the HPLC method was proven highly effective. The closely related, very polar compounds P3S and P4S were separated by the new HPLC method in less than 4 min using a conventional HPLC instrument. P3S and P4S were quantified by using five-point calibration curves with data points that ranged from 0.45 to 7.63% and from 0.13 to 1.82%, by weight, for P3S and P4S, respectively. The HPLC method was applied to the analysis of test portions from 20 batches of D&C Green No. 8 submitted to the U.S. Food and Drug Administration for certification.

Background Huntington's disease (HD) is a neurological disorder caused by mutations in the huntingtin (HTT) gene, the product of which leads to selective and progressive neuronal cell death in the striatum and cortex. Transcriptional dysregulation has emerged as a core pathologic feature in the CNS of human and animal models of HD. It is still unclear whether perturbations in gene expression are a consequence of the disease or importantly, contribute to the pathogenesis of HD. Objective To examine if transcriptional dysregulation can be ameliorated with antisense oligonucleotides that reduce levels of mutant Htt and provide therapeutic benefit in the YAC128 mouse model of HD. Methods Quantitative real-time PCR analysis was used to evaluate dysregulation of a subset of striatal genes in the YAC128 mouse model. Transcripts were then evaluated following ICV delivery of antisense oligonucleotides (ASO). Rota rod and Porsolt swim tests were used to evaluate phenotypic deficits in these mice following ASO treatment. Results Transcriptional dysregulation was detected in the YAC128 mouse model and appears to progress with age. ICV delivery of ASOs directed against mutant Htt resulted in reduction in mutant Htt levels and amelioration in behavioral deficits in the YAC128 mouse model. These improvements were correlated with improvements in the levels of several dysregulated striatal transcripts. Conclusions The role of transcriptional dysregulation in the pathogenesis of Huntington's disease is not well understood, however, a wealth of evidence now strongly suggests that changes in transcriptional signatures are a prominent feature in the brains of both HD patients and animal models of the disease. Our study is the first to show that a therapeutic agent capable of improving an HD disease phenotype is concomitantly correlated with normalization of a subset of dysregulated striatal transcripts. Our data suggests that correction of these disease-altered transcripts may underlie, at least in part, the therapeutic efficacy shown associated with ASO-mediated correction of HD phenotypes and may provide a novel set of early biomarkers for evaluating future therapeutic concepts for HD.

CONTEXT: Laparoscopic surgery is commonly used for the treatment of many pediatric surgical diseases at our department. Single-incision laparoscopic surgery (SILS) is well-known for its cosmetic benefit. We, hereby, present our experience of SILS and evaluate its efficacy. MATERIALS AND METHODS: From July 2012 to June 2014, 78 patients aged less than 18 years who underwent SILS were retrospectively evaluated. There were 44 males and 34 females, with a mean age of 10.3 years. The procedures included appendectomy (n = 64), reduction of intussusception (n = 8), removal of an intestinal foreign body (n = 3), and Meckel's diverticulectomy (n = 3). We compared the patients who underwent SILS with those who underwent conventional laparoscopic surgery (CLS), regarding these procedures. The parameters for analysis included the patient's demographic data, surgical indication, complications, operative time, and length of hospital stay. CONCLUSION: SILS is comparable to CLS regarding two major procedures, namely, appendectomy and reduction of intussusception. There were no significant differences between the two groups regarding the patients' demographic data, complications, and length of hospital stay. According to our experience of SILS, it could be a feasible and safe procedure for the treatment of various pediatric surgical diseases. However, large prospective randomized studies are needed to identify the differences between SIL and CLS.

Background There are no well-established indications for the surgical management of acute necrotizing pneumonitis in children. This study presents our experience regarding this challenging topic. Methods Between 2002 and 2009, 56 necrotizing pneumonitis patients with empyema were treated surgically. The outcomes were analyzed retrospectively. Computed tomography findings of massive lung necrosis or large cavities involving more than 50% of the involved lobe were deemed to be complicated necrotizing pneumonitis. Patients without the above indications were considered uncomplicated. Results Thirty-one cases were uncomplicated and 25 were complicated. Operative procedures included 38 decortications (31 uncomplicated and seven complicated), 14 wedge resections, and four lobectomies (complicated only). Preoperatively, patients with complicated necrotizing pneumonia had a higher incidence of pneumothorax (32% vs. 14.3%; p = 0.001), endotracheal intubation (44% vs. 9.7%; p = 0.008), and hemolytic uremic syndrome (20% vs. 3.2%; p = 0.01). These patients also had higher incidences of intraoperative transfusion (68% vs. 9.7%; p = 0.03), major postoperative complications (16% vs. 0%; p = 0.02), reoperations (16% vs. 0%; p = 0.02), and longer postoperative stay (19.8 ± 24.2 days vs. 11.2 ± 5.8 days; p = 0.03). Four complicated patients, who initially had decortications and limited resections, underwent reoperations. Compared with uncomplicated patients, those who underwent decortications and wedge resection required longer postoperative stays (23.6 ± 9.9 days, p p = 0.04, respectively), whereas patients who had lobectomy had a similar duration of recovery (9.0 ± 2.1 days, p = 0.23). All patients improved significantly at follow-up. Conclusion Children with complicated necrotizing pneumonitis have more preoperative morbidities, more major postoperative complications, and require longer postoperative stays. Aggressive surgical treatment results in significant clinical improvement. Lobectomy in patients with complicated necrotizing pneumonitis may shorten the postoperative course and avoid subsequent surgery.

Fibrotic disorders involve replacement of normal parenchyma with myofibroblasts, which deposit connective tissue, leading to obliteration of the function of the underlying organ. The treatment options are inadequate and reflect the fact that signaling targets in myofibroblasts are unknown. Here we identify the hyperactive Lyn signaling in myofibroblasts of patients with chronic pancreatitis-induced fibrosis. Lyn activation coexpress with markers of activated myofibroblasts, and is increased ~11-fold in chronic pancreatitis compared to normal tissue. Inhibition of Lyn with siRNA or INNO-406 leads to the substantial decrease of migration and proliferation of human chronic pancreatitis myofibroblasts in vitro, while leaving migration and proliferation of normal myofibroblasts only slightly affected. Furthermore, inhibition of Lyn prevents synthesis of procollagen and collagen in myofibroblasts in a mouse model of chronic pancreatitis-induced fibrosis. We conclude that Lyn, as a positive regulator of myofibroblast migration, proliferation, and collagen production, is a key target for preventing fibrosis.

Studies show that in the US alone, approximately 8 million people are affected by Peripheral Vascular Disease and approximately 26.6 million have cardiovascular disease. This report will discuss the usage of lab-on-a-chip devices and artificial blood vessels as vascular prostheses and compare the strengths and weaknesses of the two methods to measure relative efficacy and possible applications in the fields of angiology and cardiology. Lab-ona- chip devices, machines which operate on a liquid scale of micro- or nano-meters and manipulate blood flow and shear stress, may be used as long-term, compact prostheses for smaller blood vessels. Artificial, man-made blood vessels, made either from cells or synthetic material, are become increasingly effective when they are made larger. Both methods may someday be instrumental in saving lives and eliminating vascular disease.