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A signed graph is a graph with a sign attached to each edge. This article extends some fundamental concepts of the Laplacian matrices from graphs to signed graphs. In particular, the largest Laplacian eigenvalue of a signed graph is investigated, which generalizes the corresponding results on the largest Laplacian eigenvalue of a graph. [ABSTRACT FROM AUTHOR]

The 18 th Workshop on Recent Issues in Bioanalysis (18 th WRIB) took place in San Antonio, TX, USA on May 6-10, 2024. Over 1100 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 18 th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines.Moreover, in-depth workshops on "IVDR Implementation in EU & Changes for LDT in the US" and on "Harmonization of Vaccine Clinical Assays Validation" were the special features of the 18 th edition.As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and Regulatory Agencies experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues.This 2024 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2024 edition of this comprehensive White Paper has been divided into three parts for editorial reasons.This publication (Part 3) covers in the Part 3A the recommendations on Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity and in Part 3B the Regulatory Inputs on these topics. Part 1 (Mass Spectrometry Assays and Regulated Bioanalysis/BMV) and Part 2 (Biomarkers/BAV, IVD/CDx, LBA and Cell-Based Assays) are published in volume 17 of Bioanalysis, issues 4 and 5 (2025), respectively.

Background and Objective: As the population and life expectancy of people with Down syndrome increases, identifying common skin conditions throughout the lifespan will help inform clinical care and research. We sought to evaluate dermatologic conditions diagnosed in pediatric and adult patients with Down syndrome., Methods: This multicenter retrospective study analyzed demographic and outpatient visit International Classification of Diseases codes of patients with Down syndrome evaluated at outpatient dermatology clinics in the United States or Canada between 2011 and 2021., Results: A total of 1529 patients with Down syndrome were identified from eight academic medical centers: 50.8% were children (0-12 years), 25.2% were adolescents (13-17 years), and 24% were adults (18 years and older). Eczematous dermatitis was the most common diagnosis overall (26%), followed by folliculitis (19.3%) and seborrheic dermatitis (15.6%). Other notable diagnoses included dermatophyte infections (13%), alopecia areata (11.6%), and psoriasis (6.7%). About 4.3% of visits included a code for high-risk medication use. Eczematous dermatitis, alopecia areata, and folliculitis were the most common diagnoses observed in children; folliculitis, hidradenitis suppurativa, and eczematous dermatitis in adolescents; and seborrheic dermatitis, eczematous dermatitis, and folliculitis in adults., Conclusions: Dermatologic conditions in patients with Down syndrome vary by age, but are most often eczematous, adnexal, and cutaneous autoimmune disorders. This multicenter retrospective review identifies skin diseases that should be prioritized for clinical care guideline development and research in the Down syndrome community., (© 2024 Wiley Periodicals LLC.)

The objective of this scoping review is to provide a summary of the current literature regarding adolescents and young adults with histories of cloacal anomalies. Preferred Reporting Items for Systematic Reviews and Meta-analysis Extension for Scoping Reviews were used. Data were categorized into four domains-urologic, colorectal, gynecologic/obstetric, and sexual/psychosocial. The current literature has poor study quality and mostly consists of retrospective studies of small cohorts with varying definitions of outcomes. Women with cloacal anomalies are at high risk for urologic dysfunction but can maintain kidney health and achieve social continence with medical and surgical management. Sexual function and adult healthcare transition are areas ripe for improved future research., Competing Interests: Declaration of Competing Interest All authors declare no disclosure., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Standard-of-care systemic chemotherapies for pancreatic ductal adenocarcinoma (PDAC) currently have limited clinical benefits, in addition to causing adverse side effects in many patients. One factor known to contribute to the poor chemotherapy response is the poor drug diffusion into PDAC tumors. Novel treatment methods are therefore drastically needed to improve targeted delivery of treatments. Here, we evaluated the efficacy of the 3DNA® Nanocarrier (3DNA) platform to direct delivery of therapeutics to PDAC tumors in vivo., Materials and Methods: A panel of PDAC cell lines and a patient tissue microarray were screened for established tumor-specific proteins to identify targeting moieties for active targeting of the 3DNA. NRG mice with or without orthotopic MIA PaCa-2-luciferase PDAC tumors were treated intraperitoneally with 100 μl of fluorescently labeled 3DNA., Results: Folic acid and transferrin receptors were significantly elevated in PDAC compared to normal pancreas. Accordingly, both folic acid- and transferrin-conjugated 3DNA treatments significantly increased delivery of 3DNA specifically to tumors in comparison to unconjugated 3DNA treatment. In the absence of tumors, there was an increased clearance of both folic acid-conjugated 3DNA and unconjugated 3DNA, compared to the clearance rate in tumor-bearing mice. Lastly, delivery of siLuciferase by folic acid-conjugated 3DNA in an orthotopic model of luciferase-expressing PDAC showed significant and prolonged suppression of luciferase protein expression and activity., Conclusion: Our study progresses the 3DNA technology as a reliable and effective treatment delivery platform for targeted therapeutic approaches in PDAC., Competing Interests: Declaration of Competing Interest All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. This work and G.A.M. were supported Code Biotherapeutics through a Sponsored Research Agreement. Materials for 3DNA were supplied by Code Biotherapeutics. A.S., S.Z.B., L.G., and R.G. are all employees of Code Biotherapeutics., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: Cochlear implantation is indicated for pediatric patients with bilateral severe to profound sensorineural hearing loss. The literature reports large variability in cochlear implant (CI) device survival and rates of explantation and reimplantation. This retrospective chart review summarizes CI survival and rates of explantation and reimplantation in pediatric CI recipients at a Canadian tertiary pediatric hospital over 32 years., Methods: A retrospective chart review of all pediatric patients who received a Cochlear Corporation® CI between April 1988 and June 2020 was undertaken. Rates of explantation/reimplantation were collected and categorized based on device type and reason for failure (medical, device, and inconclusive failure). Device survival analysis based on implant model was also completed utilizing Kaplan-Meier curves., Results: 512 CIs were implanted over the 32-year period by four surgeons (77.1%, 18.16%, 4.49%, and 0.20%, respectively). Patient age ranged from seven months to 20.4 years. The overall explantation and reimplantation rate was 3.32% (17/512 implants), with seven as a result of device failure (1.37%), nine events of medical failure (1.76%), and one inconclusive failure (0.20%). Cumulative CI survival rates at 5, 10, 15, and 20 years were 98.15%, 96.33%, 95.53%, and 94.39%., Conclusion: The overall institutional CI failure, explantation, and reimplantation rates are lower than the average reported rates in the literature., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier B.V.)

Malignant melanoma is the deadliest form of skin cancer. Despite significant efforts in sun protection education, melanoma incidence is still rising globally, drawing attention to other socioenvironmental risk factors for melanoma. Ethanol and acetaldehyde (AcAH) are ubiquitous in our diets, medicines, alcoholic beverages, and the environment. In the liver, ethanol is primarily oxidized to AcAH, a toxic intermediate capable of inducing tumors by forming adducts with proteins and DNA. Once in the blood, ethanol and AcAH can reach the skin. Although, like the liver, the skin has metabolic mechanisms to detoxify ethanol and AcAH, the risk of ethanol/AcAH-associated skin diseases increases when the metabolic enzymes become dysfunctional in the skin. This review highlights the evidence linking cutaneous ethanol metabolism and melanoma. We summarize various sources of skin ethanol and AcAH and describe how the reduced activity of each alcohol metabolizing enzyme affects the sensitivity threshold to ethanol/AcAH toxicity. Data from the Gene Expression Omnibus database also show that three ethanol metabolizing enzymes (alcohol dehydrogenase 1B, P450 2E1, and catalase) and an AcAH metabolizing enzyme (aldehyde dehydrogenase 2) are significantly reduced in melanoma tissues.

Sarcopenia, an age-associated skeletal muscle disorder characterized by muscle loss, is associated with disability in elderly populations. This literature review summarizes the impact of protein intake and supplementation on the indicators of severe sarcopenia-muscle mass, muscle strength, and physical function in community-dwelling older adults. We performed a literature search on PubMed, EMBASE, and MedLine, and included studies that evaluated the effects of protein intake with or without exercise intervention and on sarcopenia in community-dwelling older adults. Information regarding study participants, protein intervention, and sarcopenia-related outcomes were collected. Protein supplementation with or without exercise positively improves muscle mass, and aspects of muscle strength and physical function in sarcopenic and pre-frail older adults, while it elicited inconclusive effects in healthy populations. Greater dietary animal-based and soy-based protein diets can improve muscle mass in older adults. In conclusion, protein supplementation can improve muscle mass and reduce the risk of sarcopenia in sarcopenia and pre-frail older adults, while future studies should continue to investigate the effects of protein supplementation on indicators of sarcopenia in healthy older adults., Competing Interests: CONFLICT OF INTEREST DISCLOSURES We have read and understood the Canadian Geriatrics Journal’s policy on conflicts of interest disclosure and declare there are none., (© 2022 Author(s). Published by the Canadian Geriatrics Society.)

While fatty acid metabolism is altered under physiological conditions, alterations can also be maladaptive in diseases such as diabetes and heart failure. Peroxisome Proliferator Activated Receptor α (PPARα) is a transcription factor that regulates fat metabolism but its role in regulating lipid storage in the heart is unclear. The aim of this study is to improve our understanding of how cardiac PPARα regulates cardiac health and lipid accumulation. To study the role of cardiac PPARα, tamoxifen inducible cardiac-specific PPARα knockout mouse (cPPAR-/-) were treated for 5 days with tamoxifen and then studied after 1-2 months. Under baseline conditions, cPPAR-/- mice appear healthy with normal body weight and mortality is not altered. Importantly, cardiac hypertrophy or reduced cardiac function was also not observed at baseline. Mice were fasted to elevate circulating fatty acids and induce cardiac lipid accumulation. After fasting, cPPAR-/- mice had dramatically lower cardiac triglyceride levels than control mice. Interestingly, cPPAR-/- hearts also had reduced Plin2, a key protein involved in lipid accumulation and lipid droplet regulation, which may contribute to the reduction in cardiac lipid accumulation. Overall, this suggests that a decline in cardiac PPARα may blunt cardiac lipid accumulation by decreasing Plin2 and that independent of differences in systemic metabolism a decline in cardiac PPARα does not seem to drive pathological changes in the heart., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Over 300 million people in the world live with asthma, resulting in 500,000 annual global deaths with future increases expected. It is estimated that around 50-80% of asthma exacerbations are due to viral infections. Currently, a combination of long-acting beta agonists (LABA) for bronchodilation and glucocorticoids (GCS) to control lung inflammation represent the dominant strategy for the management of asthma, however, it is still sub-optimal in 35-50% of moderate-severe asthmatics resulting in persistent lung inflammation, impairment of lung function, and risk of mortality. Mechanistically, LABA/GCS combination therapy results in synergistic efficacy mediated by intracellular cyclic adenosine monophosphate (cAMP)., Hypothesis: Increasing intracellular cAMP during LABA/GCS combination therapy via inhibiting phosphodiesterase 4 (PDE4) and/or blocking the export of cAMP by ATP Binding Cassette Transporter C4 (ABCC4), will potentiate anti-inflammatory responses of mainstay LABA/GCS therapy., Methods: Expression and localization experiments were performed using in situ hybridization and immunohistochemistry in human lung tissue from healthy subjects, while confirmatory transcript and protein expression analyses were performed in primary human airway epithelial cells and cell lines. Intervention experiments were performed on the human airway epithelial cell line, HBEC-6KT, by pre-treatment with combinations of LABA/GCS with PDE4 and/or ABCC4 inhibitors followed by Poly I:C or imiquimod challenge as a model for viral stimuli. Cytokine readouts for IL-6, IL-8, CXCL10/IP-10, and CCL5/RANTES were quantified by ELISA., Results: Using archived human lung and human airway epithelial cells, ABCC4 gene and protein expression were confirmed in vitro and in situ. LABA/GCS attenuation of Poly I:C or imiquimod-induced IL-6 and IL-8 were potentiated with ABCC4 and PDE4 inhibition, which was greater when ABCC4 and PDE4 inhibition was combined. Modulation of cAMP levels had no impact on LABA/GCS modulation of Poly I:C-induced CXCL10/IP-10 or CCL5/RANTES., Conclusion: Modulation of intracellular cAMP levels by PDE4 or ABCC4 inhibition potentiates LABA/GCS efficacy in human airway epithelial cells challenged with viral stimuli. The data suggest further exploration of the value of adding cAMP modulators to mainstay LABA/GCS therapy in asthma for potentiated anti-inflammatory efficacy., (© 2021. The Author(s).)

Background: We aimed to investigate the prognostic role of examined (dissected) lymph nodes (ELNs), negative LNs (NLNs), and positive (metastatic) LNs (PLNs) counts and LN ratio (LNR = PLNs/ELNs×100) in patients with major salivary gland cancer (SGC)., Methods: Data were retrieved for major SGC patients diagnosed between 1988 and 2011 from Surveillance, Epidemiology, and End Results program., Results: We have included 5446 patients with major SGC. Most patients had parotid gland cancer (84.61%). Patients having >18 ELNs, >4 PLNs, and >33.33% LNR were associated with a worse survival. Moreover, older age, male patients, grade IV, distant stage, unmarried patients, submandibular gland cancer, and received chemotherapy but not received surgery were significantly associated with a worse survival., Conclusions: We demonstrated that patients with >18 ELNs and >4 PLNs counts, and >33.33% LNR were high-risk group patients. We strongly suggest adding the ELNs and PLNs counts and/or LNR into the current staging system., (© 2019 Wiley Periodicals, Inc.)

Chronic inflammation drives the progression of colorectal cancer (CRC). Increased expression of interleukin (IL)-17A is associated with poor prognosis, and IL-17A blockade curbs tumor progression in preclinical models of CRC. Here we examined the impact of IL-1 signaling, a key regulator of the IL-17 pathway, in different cell types within the CRC microenvironment. Genetic deletion of the IL-1 receptor (IL-1R1) in epithelial cells alleviated tumorigenesis in the APC model of CRC, demonstrating a cell-autonomous role for IL-1 signaling in early tumor seed outgrowth. T cell specific ablation of IL-1R1 decreased tumor-elicited inflammation dependent on IL-17 and IL-22, thereby reducing CRC progression. The pro-tumorigenic roles of IL-1 were counteracted by its effects on myeloid cells, particularly neutrophils, where IL-1R1 ablation resulted in bacterial invasion into tumors, heightened inflammation and aggressive CRC progression. Thus, IL-1 signaling elicits cell-type-specific responses, which, in aggregate, set the inflammatory tone of the tumor microenvironment and determine the propensity for disease progression., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The superior carrier mobility of SiGe alloys make them a highly desirable channel material in complementary metal-oxide-semiconductor (CMOS) transistors. Passivation of the SiGe surface and the associated minimization of interface defects between SiGe channels and high- k dielectrics continues to be a challenge for fabrication of high-performance SiGe CMOS. A primary source of interface defects is interfacial GeO x . This interfacial oxide can be decomposed using an oxygen-scavenging reactive gate metal, which nearly eliminates the interfacial oxides, thereby decreasing the amount of GeO x at the interface; the remaining ultrathin interlayer is consistent with a SiO x -rich interface. Density functional theory simulations demonstrate that a sub-0.5 nm thick SiO x -rich surface layer can produce an electrically passivated HfO 2 /SiGe interface. To form this SiO x -rich interlayer, metal gate stack designs including Al/HfO 2 /SiGe and Pd/Ti/TiN/nanolaminate (NL)/SiGe (NL: HfO 2 -Al 2 O 3 ) were investigated. As compared to the control Ni-gated devices, those with Al/HfO 2 /SiGe gate stacks demonstrated more than an order of magnitude reduction in interface defect density with a sub-0.5 nm SiO x -rich interfacial layer. To further increase the oxide capacitance, the devices were fabricated with a Ti oxygen scavenging layer separated from the HfO 2 by a conductive TiN diffusion barrier (remote scavenging). The Pd/Ti/TiN/NL/SiGe structures exhibited significant capacitance enhancement along with a reduction in interface defect density.

The tumor microenvironment offers multiple targets for cancer therapy, including pro-tumorigenic inflammation. Natural compounds represent an enormous source of new anti-inflammatory and anticancer agents. We previously showed that the styryl lactone goniothalamin (GTN) has promising antiproliferative and anti-inflammatory activities. Because inflammation is a major driver of colorectal cancer (CRC), we therefore evaluated the therapeutic and preventive potentials of GTN in colitis, colitis-associated cancer (CAC) and spontaneous CRC. First, in a simplistic model of inflammation in vitro, GTN was able to inhibit cytokine production in bone marrow-derived macrophages induced by lipopolysaccharide. Next, in dextran sulfate sodium (DSS) induced-colitis model, mice treated with GTN displayed restored tissue architecture, increased cell proliferation in the colonic crypts and reduced epithelial damage. Moreover, colon tissue from GTN-treated mice had significantly less expression of the inflammatory genes interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), S100A9, interleukin 23A (IL-23A), IL-22 and IL-17A In the azoxymethane/DSS model of CAC, GTN reduced tumor multiplicity, load and size. Additionally, GTN suppressed production of IL-6, IL-17 and TNF-α in tumor tissue, as well as abrogated stromal immune cell activation and nuclear translocation of NF-κB. Finally, in a tamoxifen inducible model of sporadic CRC, GTN-treated mice had significantly fewer tumors and decreased levels of IL-17A, IL-6, S100A9 and TNF-α protein within the tumors. These results suggest that GTN possesses anti-inflammatory and antitumor activities and represents a preventive and therapeutic agent modulating the inflammatory environment in the colon during colitis as well as CAC and CRC development., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: To use multiplane en face Doppler optical coherence tomography (OCT) to measure the change in total retinal blood flow (TRBF) in response to hyperoxia., Methods: One eye of each healthy human participant (n = 8) was scanned with a commercial high-speed (70-kHz) spectral OCT system. Three repeated scans were captured at baseline and after 10 minutes of oxygen (hyperoxia) by open nasal mask. The procedure was performed twice on day 1 and once more on day 2. Blood flow of each vein was estimated using Doppler OCT at an optimized en face plane. The TRBF was summed from all veins at the optic disc. The TRBF hyperoxic response was calculated as the TRBF percent change from baseline., Results: Participants experienced a 23.6% ± 10.7% (mean ± standard deviation [SD]) decrease (P < 0.001, paired t-test) in TRBF during hyperoxia. The within-day repeatability of baseline TRBF was 4.1% and the between-day reproducibility was 10.9% coefficient of variation (CV). Between-grader reproducibility was 3.9% CV. The repeatability and reproducibility (pooled SD) of hyperoxic response were 6.1% and 6.4%, respectively., Conclusions: The multiplane en face Doppler OCT algorithm was able to detect, in all participants, a decreased TRBF in response to hyperoxia. The response magnitude for each participant varied among repeated trials, and the averaging of multiple trials was helpful in establishing the individual response. This technique shows good potential for the clinical investigation of vascular autoregulation.

Inflammatory bowel diseases (IBDs) are debilitating conditions that result in intestinal damage due to chronic inflammation. In addition, the perpetual state of inflammation predisposes individuals to the development of colitis-associated cancer. Because of the immense immune cell infiltration into colon, cytokines produced by immune cells are major players in the initiation and progression of IBD and colitis-associated cancer. In this review, we will explore the functions of many key cytokines and their roles in IBD and colitis-associated cancer, as well as their influences on the immune system and stromal cells. Finally, we will briefly discuss current therapies and current clinical trials targeting cytokines in IBD.

Inflammation has long been suspected to play a major role in the pathogenesis of cancer. Only recently, however, have some mechanisms of its tumor promoting effects become known. Microbes, both commensal and pathogenic, are critical regulators of the host immune system and, ultimately, of inflammation. Consequently, microbes have the potential power to influence tumor progression as well, through a wide variety of routes, including chronic activation of inflammation, alteration of tumor microenvironment, induction of genotoxic responses, and metabolism. In this review, we will provide a general overview of commensal microbiota, inflammation, and cancer, as well as how microbes fit into this emerging field.

We report a case of a patient who used multiple aliases as part of a medical fraud scheme. As a consequence, the surgical team was unaware of a left-sided adrenal mass that had been documented for this patient under another name. In the operating room, severe hypertension from the undiagnosed pheochromocytoma led to a ventricular fibrillation cardiac arrest. This case demonstrates the importance of physician awareness of medical identity fraud and its potential consequences.

The number of molecular species suitable for multispectral fluorescence imaging is limited due to the overlap of the emission spectra of indicator fluorophores, e.g., dyes and nanoparticles. To remove fluorophore emission cross-talk in wide-field multispectral fluorescence molecular imaging, we evaluate three different solutions: (1) image stitching, (2) concurrent imaging with cross-talk ratio subtraction algorithm, and (3) frame-sequential imaging. A phantom with fluorophore emission cross-talk is fabricated, and a 1.2-mm ultrathin scanning fiber endoscope (SFE) is used to test and compare these approaches. Results show that fluorophore emission cross-talk could be successfully avoided or significantly reduced. Near term, the concurrent imaging method of wide-field multispectral fluorescence SFE is viable for early stage cancer detection and localization in vivo. Furthermore, a means to enhance exogenous fluorescence target-to-background ratio by the reduction of tissue autofluorescence background is demonstrated.

Background: Verorab was licensed in 1985 for both pre- and post-exposure prophylaxis of rabies. The next generation purified Vero cell rabies vaccine (PVRV-NG) is a highly purified vaccine. We performed a phase II clinical study in adults in France to assess its immunological non-inferiority and clinical safety for pre-exposure prophylaxis., Methods: In a randomized phase-II trial, 384 healthy adult subjects were randomized (2:1) to receive a three-dose primary series of PVRV-NG or Verorab. One year later, the PVRV-NG group received a PVRV-NG booster while the Verorab group participants were randomized to receive a booster of PVRV-NG or Verorab for. Rabies virus neutralizing antibodies (RVNA) were evaluated on days 0, 28 (subgroup), 42, months 6, 12 and 12+14 days. Safety was evaluated for seven days after each dose. Adverse event between doses, until 28 days after the final dose was recorded. Serious adverse events were recorded up to 6 months after the last dose., Results: The criterion for non-inferiority was met in the per-protocol analysis set and confirmed in the full analysis set (FAS). In the FAS, 99.6% and 100% of subjects had RVNA titers ≥0.5 IU/mL in PVRV-NG and Verorab groups, respectively. While RVNA levels gradually decreased over the 12-month period, at 6 and 12 months after vaccination >89% and >77%, respectively, in both groups had RVNA titers ≥0.5 IU/mL. The PVRV-NG booster induced a strong response, irrespective of the vaccine given for the primary series. PVRV-NG was safe and well tolerated and its safety profile was similar to Verorab for unsolicited adverse events and solicited systemic reactions. The incidence of solicited injection-site reactions was lower with PVRV-NG than with Verorab after the primary series and the booster dose., Conclusions: PVRV-NG was shown to be at least as immunogenic as Verorab and to present a similar safety profile., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

We developed a stable, reproducible three-dimensional optical phantom for the evaluation of a wide-field endoscopic molecular imaging system. This phantom mimicked a human esophagus structure with flexibility to demonstrate body movements. At the same time, realistic visual appearance and diffuse spectral reflectance properties of the tissue were simulated by a color matching methodology. A photostable dye-in-polymer technology was applied to represent biomarker probed "hot-spot" locations. Furthermore, fluorescent target quantification of the phantom was demonstrated using a 1.2 mm ultrathin scanning fiber endoscope with concurrent fluorescence-reflectance imaging.

Background: Pneumococcal vaccines based on protein antigens may provide expanded protection against Streptococcus pneumoniae., Objective: To evaluate safety and immunogenicity in adults of pneumococcal vaccine candidates comprising S. pneumoniae pneumococcal histidine triad protein D (PhtD) and pneumococcal choline-binding protein A (PcpA) in monovalent and bivalent formulations., Methods: This was a phase I, randomized, observer-blinded, placebo-controlled, step-wise dose-escalation study. Following a pilot safety study in which participants received one intramuscular injection of either aluminum hydroxide (AH)-adjuvanted PcpA (25 μg) or PhtD-PcpA (10 μg each), participants in the main study received AH-adjuvanted PcpA (25 μg), AH-adjuvanted PhtD-PcpA (10, 25, or 50 μg each), unadjuvanted PhtD-PcpA (25 μg each), or placebo as 2 injections 30 days apart. Assignment of successive dose cohorts was made after blinded safety reviews after each dose level. Safety endpoints included rates of solicited injection site and systemic reactions, unsolicited adverse events (AEs), serious AEs (SAEs), and safety laboratory tests. Immunogenicity endpoints included levels of anti-PhtD and anti-PcpA antibodies (ELISA)., Results: Six adults 18-50 years of age were included in the pilot study and 125 in the main study. No obvious increases in solicited reactions or unsolicited AEs were reported with escalating doses (adjuvanted vaccine) after either injection, or with repeated administration. Adjuvanted vaccine candidates were associated with a higher incidence of solicited reactions (particularly injection site reactions) than unadjuvanted vaccine candidates. However, no SAE or discontinuation due to an AE occurred. Geometric mean concentrations of anti-PhtD IgG and anti-PcpA IgG increased significantly after injection 2 compared with injection 1 at each dose level. No enhancement of immune responses was shown with adjuvanted vaccine candidates compared with the unadjuvanted vaccine candidate. In the dose-escalating comparison, a plateau effect at the 25 μg dose was observed as measured by geometric mean concentrations and by fold increases., Conclusions: Promising safety profiles and immunogenicity of these monovalent and bivalent protein vaccine candidates were demonstrated in an adult population (ClinicalTrials.gov registry no. NCT01444339)., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Background: Quadrivalent meningococcal conjugate vaccine (Menactra [MenACWY-D]), was licensed in the United States in 2005 to prevent meningococcal disease in adolescents and adults. The license was extended to children aged 2-10 years in 2007 and extended again in 2011 to infants aged 9 months and older based, in part, on results from 3 phase III studies presented herein., Methods: The safety and immunogenicity of 2 doses of MenACWY-D was assessed in study-eligible children: dose 1 was administered at 9 months of age and dose 2 was administered 3 months later with or without routine childhood vaccines., Results: Thirty days after vaccination, protective serum bactericidal assay-human complement titers ≥1:8 for meningococcal serogroups A, C, Y and W-135 were achieved by 86-100% of children receiving 2 doses of MenACWY-D. When MenACWY-D was concomitantly administered with measles, mumps, rubella and varicella or heptavalent pneumococcal conjugate vaccine, 81-98% of participants achieved protective responses (serum bactericidal assay-human complement titers ≥1:8 for all serogroups). All seroprotection rates were >91% when the protective titer was defined as serum bactericidal assay-human complement ≥1:4. MenACWY-D did not interfere with measles, mumps, rubella or varicella vaccine responses (98-100% achieved protective titers). When heptavalent pneumococcal conjugate vaccine was given concomitantly with MenACWY-D, antipneumococcal antibody levels, although decreased, were protective for all serotypes by enzyme-linked immunosorbent assay (98-100% ≥ 0.35 μg/mL) and opsonophagocytic assay (99-100% ≥ 1:8). Adverse events were generally mild and similar across groups. Serious adverse events were uncommon., Conclusions: MenACWY-D was safe and immunogenic when given in 2 doses to infants and toddlers; this vaccine can be given with other common childhood immunizations.

Background: Cardiac transplantation, a procedure nearly abandoned in the 1970s, has evolved into the standard of care for appropriate patients with end-stage heart failure. Much of this success has been due to improvements in immunosuppression, including the introduction of a triple-drug regimen. Retrospective reports suggested that single-drug immunosuppression with tacrolimus was feasible. As such, a prospective, randomized trial was conducted to test this approach., Methods and Results: One hundred fifty adult de novo heart transplant recipients were enrolled in a prospective, randomized, controlled, open-label trial comparing tacrolimus monotherapy (MONO) with tacrolimus and mycophenolate mofetil therapy (COMBO). Corticosteroids were used in the early postoperative period but discontinued in all patients over 8 to 9 weeks. The primary end point was the composite biopsy score at 6 months after transplant. Patients were followed for 1 to 5 years. The composite biopsy score was similar between groups at 6 and 12 months: 6-month MONO, 0.70 ± 0.44 (95% confidence interval, 0.60 to 0.80) versus COMBO, 0.65 ± 0.40 (95% confidence interval, 0.55 to 0.74; P=0.44). Allograft vasculopathy was assessed by angiography and intravascular ultrasound, with no significant differences noted. Three-year survival was also similar (92.4% MONO versus 97% COMBO; P=0.58, log-rank)., Conclusions: Addition of mycophenolate to single-agent immunosuppression did not provide an advantage over single-agent immunosuppression in terms of rejection, allograft vasculopathy, or 3-year survival. Corticosteroids, which have traditionally been a mainstay of therapy, were successfully discontinued in all patients. These conclusions are tempered by the limited statistical power associated with a sample size of only 150 patients. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00299221.

The leading cause of perioperative morbidity and mortality after major noncardiac surgery is cardiovascular complications. Clinical trials of lipid-lowering 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have shown improved cardiovascular outcomes; therefore, statins have become a mainstay in the prevention of cardiovascular disease. Retrospective trials and a small number of prospective randomized trials indicate that statin use may be beneficial during the perioperative period. In addition to the effects on serum lipid levels, statins influence inflammatory, thrombotic, and vasodilatory cellular pathways; and thus, their beneficial effects are not limited to patients with hypercholesterolemia. This review will (1) examine the evidence for using perioperative statin therapy in the noncardiac surgical patient (2) explore the possible consequences of statin withdrawal, and (3) revisit the evidence for the safety of statin use. Further studies are still needed to establish the optimal dosage as well as timing and length of statin therapy perioperatively.

Alternative splicing plays a major role in regulating tissue-specific expression of cytoskeletal protein 4.1R isoforms. In particular, expression of the protein's functionally critical spectrin-actin binding domain, essential for maintenance of red cell membrane mechanical properties, is governed by a developmentally regulated splicing switch involving alternative exon 16. Using a model 3-exon 4.1R pre-messenger RNA (pre-mRNA), we explored the sequence requirements for excision of the introns flanking exon 16. These studies revealed that splicing of this alternative exon occurs preferentially in an ordered fashion. The first step is excision of the downstream intron to join exons 16 and 17, followed by excision of the upstream intron. Constructs designed to test the converse pathway were spliced less efficiently and with less fidelity, in part due to activation of a cryptic 5' splice site in exon 16. This downstream-first model for ordered splicing is consistent with the hypothesis that regulated alternative splicing requires cooperation between multiple exonic and/or intronic regulatory elements whose spatial organization is critical for recruitment of appropriate splicing factors. Our results predict that exon 16 splicing is regulated at the first step-excision of the downstream intron-and that cells unable to catalyze this step will exhibit exon 16 skipping. In cells that include exon 16, adherence to an ordered pathway is important for efficient and accurate production of mature 4.1R mRNA encoding an intact spectrin-actin binding domain. (Blood. 2000;95:692-699)

Background: Neuromuscular relaxants such as pancuronium bind to M2 and M3 muscarinic receptors as antagonists. Blockade of muscarinic receptors in atria of the M2 subtype mediates tachycardia. In the lung, blockade of M2 receptors on parasympathetic nerves potentiates vagally induced bronchospasm, whereas blockade of M3 receptors on bronchial smooth muscle inhibits bronchospasm. The current study was designed to quantify the affinity of a series of neuromuscular relaxants for the M2 and M3 muscarinic receptors, which were individually stably transfected in Chinese hamster ovary cell lines., Methods: Competitive radioligand binding assays determined the relative binding affinities of the neuromuscular relaxants pancuronium, succinylcholine, mivacurium, doxacurium, atracurium, rocuronium, gallamine, and pipecuronium for the muscarinic receptor in the presence of a muscarinic receptor antagonist (3H-QNB) in membranes prepared from cells individually expressing either the M2 or M3 muscarinic receptor., Results: All muscle relaxants evaluated displaced 3H-QNB from muscarinic receptors. The relative order of potency for the M2 muscarinic receptor (highest to lowest) was pancuronium, gallamine, rocuronium, atracurium, pipecuronium, doxacurium, mivacurium, and succinylcholine. The relative order of potency for the M3 muscarinic receptor (highest to lowest) was pancuronium, atracurium, pipecuronium, rocuronium, mivacurium, gallamine, succinylcholine, and doxacurium., Conclusions: All neuromuscular relaxants studied had affinities for the M2 and M3 muscarinic receptor, but only pancuronium and gallamine had affinities within the range of concentrations achieved with clinical use. The high affinities of gallamine and pancuronium for the M2 muscarinic receptor are consistent with a mechanism of M2 receptor blockade in relaxant-induced tachycardia.

Three cats were raised with monocular deprivation for 5.2-7.2 years, and ganglion-cell densities and soma sizes were measured in their flat-mounted retinae. The retinae were Nissl-stained so that ganglion cells could be measured whether or not they maintained normal central projections. Measurements were made in the area centralis, peripheral binocular segment, and monocular segment of the retinae. There were no significant differences between the deprived and non-deprived retinae in the densities or soma-sizes of alpha cells or other (non-alpha) ganglion cells at any of these retinal locations. These results support the view that the most distal effects of monocular deprivation occur at the retino-geniculate contact, and they suggest that even after long-term monocular deprivation, effects in the lateral geniculate nucleus do not produce secondary, retrograde changes in the retina.