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He is also a practicing pediatrics endocrinologist and father of three energetic children buy cheap super viagra on-line. Manuel Llins is an Assistant Professor of Molecular Biology and a member of the Lewis-Sigler Institute for Integrative Genomics at Princeton University cheap 160mg super viagra with mastercard. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease Ph cheap 160 mg super viagra amex. Llins laboratory studies the deadliest of the four human Plasmodium parasites, Plasmodium falciparum. The focus is predominantly on the red blood cell stage of development, which is the stage in which all of the clinical manifestations of the malaria disease occur. His research has focused on two major areas: the role of transcriptional regulation in orchestrating parasite development, and an in-depth characterization of the malaria parasite s unique metabolic network. These two approaches explore relatively virgin areas in the malaria field with the goal of identifying novel strategies for therapeutic intervention. He is also National Program Director for the Greenwall Faculty Scholars Program in Bioethics, a career development award for bioethics researchers. He is co-chair of the Standards Working Group of the California Institute of Regenerative Medicine, which recommends regulations for stem cell research funded by the state of California. He also serves on the Board of Directors of the Association for the Accreditation of Human Research Protection Programs. He has pioneered the field of genome cell biology by developing live-cell microscopy approaches to study the nuclear organization of the genome and gene expression in intact cells, and his laboratory aims to apply this knowledge to the development of novel diagnostic and therapeutic strategies for cancer and aging. Dr Misteli has received numerous awards for his work, and currently serves as Editor-in-Chief of The Journal of Cell Biology and of Current Opinion in Cell Biology. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 88 Sean J. Morrison, PhD, is the Director of the Children s Research Institute and the Mary McDermott Cook Chair in Pediatric Genetics at the University of Texas Southwestern Medical Center as well as an Investigator of the Howard Hughes Medical Institute. The Morrison laboratory is investigating the mechanisms that regulate stem cell function in the nervous and hematopoietic systems and the ways in which these mechanisms are hijacked by cancer cells to enable neoplastic proliferation and metastasis. The Morrison laboratory is particularly interested in the mechanisms that regulate stem cell self-renewal, stem cell aging, and the role these mechanisms play in cancer. Parallel studies of these mechanisms in two tissues reveals the extent to which different types of stem cells and cancer cells depend upon similar mechanisms to regulate their function. The Morrison laboratory has discovered a number of critical mechanisms that distinguish stem cell self-renewal from the proliferation of restricted progenitors. They have shown that stem cell self-renewal is regulated by networks of proto-oncogenes and tumor suppressors and that the balance between proto-oncogenic and tumor suppressor signals changes with age. This likely explains why the mutation spectrum changes with age in cancer patients, as different mechanisms become competent to hyper-activate self-renewal pathways in patients at different ages. The Morrison laboratory has further shown that in some cancers many tumor cells are capable of driving disease growth and progression while other cancers are driven by minority subpopulations of cancer cells that adopt stem cell characteristics. These insights into the cellular and molecular mechanisms of self-renewal have suggested new approaches for promoting normal tissue regeneration and cancer treatment. Morrison was at the University of Michigan where he Directed their Center for Stem Cell Biology. Morrison moved to the University of Texas Southwestern Medical Center where he is the founding Director of the new Children s Research Institute. Morrison has also been active in public policy issues surrounding stem cell research. For example, he has twice testified before Congress and was a leader in the successful Proposal 2 campaign to protect stem cell research in Michigan s state constitution. Nichols is a professor of anesthesiology/critical care medicine and pediatrics and the Mary Wallace Stanton Professor of Education. Since joining the School of Medicine faculty in 1984, he has held numerous leadership posts in both the Department of Anesthesiology and Critical Care Medicine and school-wide. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease guidelines; restructure graduate medical education; oversee the design of a new $50 million medical education building; and enhance diversity throughout Johns Hopkins Medicine. Nichols was associate director of the residency education program in the Department of Anesthesiology and Critical Care Medicine. Nichols became a full professor of anesthesiology/critical care medicine and pediatrics in 1998 and became the recipient of the Mary Wallace Stanton Professorship for Education in 2005. He has written more than 80 professional journal articles and abstracts, held 17 guest professorships, headed more than 20 symposia and delivered more than 115 guest lectures. He also has been editor in chief of the leading textbooks in pediatric critical care medicine and edited Rogers Textbook of Pediatric Intensive Care and Critical Heart Disease in Infants and Children. Maynard Olson is Professor Emeritus of Medicine and Genome Sciences, at the University of Washington. His research interests focus on studies of natural genetic variation in both bacteria and humans. Olson was involved in shaping scientific policy toward the Human Genome Project, serving on the National Research Council Committee on Mapping and Sequencing the Human Genome, the Program Advisory Committee of the National Center for Human Genome Research Institute. Charmaine Royal is an Associate Research Professor in the Institute for Genome Sciences & Policy and the Department of African and African American Studies at Duke University. She subsequently completed her postdoctoral training in the Bioethics and Special Populations Research Program at the National Human Genome Research Institute of the National Institutes of Health, and in the Division of Epidemiology and Behavioral Medicine at the Howard University Cancer Center. Royal was Assistant Professor of Pediatrics and Director of the GenEthics Unit in the National Human Genome Center at Howard University. She serves on the: Bioethics Advisory Committee of the March of Dimes Foundation; Social Issues Committee of the American Society of Human Genetics; Editorial Board of the American Journal of Bioethics; and various other professional Committees and boards. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease 90 ethnicity, and identity. She has taught, presented, published, and received funding in these and other related areas. A key objective of her research program is to advance a more holistic and ethical approach to understanding and improving human health and well-being through increased integration of genetic and genomic research with behavioral, social science, and humanities research. Yamamoto s research is focused on signaling and transcriptional regulation by intracellular receptors, which mediate the actions of several classes of essential hormones and cellular signals; he uses both mechanistic and systems approaches to pursue these problems in pure molecules, cells and whole organisms. Yamamoto was elected as a member of the American Academy of Arts and Sciences in 1988, the National Academy of Sciences in 1989, the Institute of Medicine in 2003, and as a fellow of the American Association for the Advancement of Sciences in 2002. Hook-Barnard is a program officer with the Board on Life Sciences of the National Research Council. She came to the National Academies from the National Institutes of Health where she was a Postdoctoral Research Fellow from 2003 to 2008. Her graduate research examined translational regulation and ribosome binding in Escherichia coli. Toward Precision Medicine: Building a Knowledge Network for Biomedical Research and a New Taxonomy of Disease she contributes to projects in a variety of topic areas. Much of her current work is related to issues of molecular biology, microbiology, biosecurity and genomics. She was study director for the 2010 report Sequence-Based Classification of Select Agents: A Brighter Line, and continues to direct the U. How would a New Taxonomy of human disease enable more cost effective and rapid development of new, effective and safe drugs in the pharma/biotech setting?

Cyproheptadine discount super viagra 160 mg without prescription, a piperidine generic 160mg super viagra, has the unique effect of causing weight gain in some patients (16) proven super viagra 160 mg. Intentional and accidental overdose, although uncommon, has been reported with these drugs ( 10,14). Even with normal doses, it is not unusual for children to experience a paradoxic excitatory reaction. Malignant cardiac arrhythmias have been known to occur with overdoses, emphasizing the need to act expeditiously to counteract the toxic effect of these agents ( 10,14,99). Because these agents are secreted in breast milk, caution should be exercised using these agents in lactating women to avoid adverse effects in the newborn ( 99). Sedation and the side effects associated with first-generation agents have been noted to occur, but to no greater extent than with placebo ( 10,14,101). Astemizole, like cyproheptadine, was associated with increased appetite and weight gain ( 10). Loratadine and fexofenadine have similar side effect profiles and have not been found to cause cardiotoxicity ( 3). Cetirizine is considered a low sedating antihistamine but is generally well tolerated by most patients. This phenomenon has been speculated to occur because of autoinduction of hepatic metabolism, resulting in an accelerated clearance rate of the antihistamine ( 103). Short-term studies evaluating tolerance to second-generation agents have found no change in their therapeutic efficacy after 6 to 8 weeks of regular use ( 108,109). Studies up to 12 weeks found no evidence that second-generation agents cause autoinduction of hepatic metabolism leading to rapid excretion rates and drug tolerance ( 42). The clinical efficacy of these agents in the skin and treatment of allergic rhinitis does not decrease with chronic use. The decongestants used in most preparations today predominantly include phenylpropanolamine hydrochloride, phenylephrine hydrochloride, and pseudoephedrine hydrochloride. These agents have saturated benzene rings without 3- or 4-hydroxyl groups, which is the reason for their weak a-adrenergic effect, improved oral absorption, and duration of action. The early agents, which were developed for their gastric acid inhibitory properties, were either not strong enough for clinical use or hazardous because of serious associated side effects (e. Cimetidine (Tagamet) was introduced to the United States in 1982 and has been proved safe and effective in the treatment of peptic ulcer disease (15). For example, ranitidine (Zantac) has a furan ring, whereas famotidine (Pepcid) and nizatidine (Axid) are composed of thiozole rings ( 15). H2 antagonists act primarily by competitive inhibition of the H 2 receptors, with the exception of famotidine, which works noncompetitively (15). The four available H2 antagonists all have potent H2 antagonistic properties, varying mainly in their pharmacokinetics, and adverse effects such as drug interactions. Numerous studies have been undertaken to examine the clinical utility of H 2 antagonists in allergic and immunologic diseases. Generally, H2 antagonists have limited or no utility in treating allergen-induced and histamine-mediated diseases in humans ( 118,119,120 and 121). One notable exception to this rule may be their use in combination with H 1 antagonists in the treatment of chronic idiopathic urticaria ( 122). The studies evaluating the clinical efficacy of H 2 antagonists in allergic and immunologic disorders are extensively reviewed elsewhere ( 3,117). These actions by histamine could not be suppressed by H 1 or H2 antagonists, leading researchers to postulate the existence of a third class of histamine receptors. They both have demonstrated H 3 receptor selectivity but remain strictly for experimental use (9). Chemical modifications of these early agents have yielded the second-generation antihistamines, which are of equal antagonistic efficacy but have fewer side effects because of their lipophobic structures. Newer nonsedating antihistamines, which are metabolites or isomers of existing agents, are now under development. H 2 receptor antagonists have been found extremely useful in the treatment of peptic ulcer disease. However, they have been disappointing in the treatment of allergic and immunologic disorders in humans. Newer selective nonsedating H1 antagonists and dual-action antihistamines, because of their lower side-effect profiles, have provided therapeutic advantages over first-generation agents for long-term management of allergic rhinitis. Because there are virtually dozens of antihistamine preparations available with or without decongestants, it is recommended that physicians become familiar with all aspects of a few agents from each structural class. Analysis of triggering events in mast cells for immunoglobulin E-mediated histamine release. Blockade of histamine-mediated increased in microvascular permeability by H 1- and H2-receptor antagonists. Medicinal chemistry and dynamic structure-activity analysis in the discovery of drugs acting as histamine H 2-receptors. The pharmacokinetics and antihistaminic of the H 1 receptor antagonist hydroxyzine. Inhibition of histamine release from human lung in vitro by antihistamines and related drugs. Evaluation of sustained-action chlorpheniramine-pseudoephedrine dosage form in humans. In vitro and in vivo binding characteristics of a new long-acting histamine H1 antagonist, astemizole. Dose-proportionality, bioavailability and steady-state kinetics of astemizole in man. Pharmacoclinical investigation of cetirizine, a new potent and well tolerated anti-H 1. Cetirizine: a pharmacokinetic and pharmacodynamic evaluation in children with seasonal allergic rhinitis. Grapefruit juice alters the systemic bioavailability and cardiac repolarization of terfenadine in poor metabolizers of terfenadine. Inhibition by azelastine of nonallergic histamine release from rat peritoneal mast cells. Inhibition of IgE-mediated allergic histamine release from rat peritoneal mast cells by azelastine and selected anti-allergic drugs. Intracellular calcium release induced by histamine releasers and its inhibition by antiallergic drugs. A comparison of the in vivo effects of ketotifen, clemastine, chlorpheniramine and sodium cromoglycate on histamine and allergen induced wheals in human skin. The modification by ketotifen of respiratory responses to histamine and antigen in guinea pigs. Preliminary data on antiserotonin effects of oxatomide, a novel antiallergic compound. Pharmacologic and toxicological properties of azelastine, a novel antiallergic agent.

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If possible discount super viagra 160 mg visa, treatment should be with agents with little or no mineralocorticoid activity order super viagra 160mg on-line. This strategy is based in part on recent advances in our knowledge about the mechanisms of asthma order generic super viagra on-line. Studies show differences in potencies and levels of adverse systemic effects, but these need to be interpreted with caution because adverse effects can be measured in several ways, and the results of different measurements do not always correspond. Comparisons are further complicated by a choice of inhaler delivery systems for one or more of the drugs (Table 34. Comparison factors for risk/benefit ratios of glucocorticoids and delivery systems The ratio of doses producing undesirable effects to doses producing desirable effects (therapeutic index) is the most relevant measurement for comparing various inhaled steroids or a single drug in different formulations. Desirable topical effects depend on potency, the amount of drug delivered to the lungs, and probably also the local pharmacokinetics in target tissues and cells. Undesirable systemic effects derive from mineralocorticoid activity, rate of clearance from the body, and the bioavailability of the steroid after lung or gastrointestinal absorption and first-pass metabolism of the swallowed fraction of the dose ( 45). Devices that are easier to use lead to better compliance, as does less frequent dosing. Dose-Response Considerations Although studies consistently demonstrate a clinical benefit of inhaled steroids, the dose-response curve for this benefit is apparently relatively flat in large population studies; in individual patients, the dose-response curve may be linear. In measurements of improved lung function, there seem to be few differences among doses, and most of the benefit appears to be obtained at the lowest doses used ( 34). In contrast, there is a much steeper dose-response curve relative to systemic effects. From this, we might infer that the slight improvement in lung function with higher doses would not be justified in light of a disproportionately greater increase in the risk for adverse side effects. Patients with very mild asthma have relatively minimal airflow obstruction and little room for improvement, so that low doses potentially provide maximal improvement. Patients with unstable or more severe asthma have significantly greater airflow obstruction and therefore may show a greater response to increasing doses. Clinical Use of Inhaled Corticosteroid Therapy Inhaled corticosteroid therapy is recommended as first-line treatment for all patients with persistent symptoms. Once control is achieved, the dose should be stepped down to the lowest possible dose necessary for optimal control, which is defined as best or normal lung function and only occasional need for a b2-agonist inhaler. Twice-daily dosing is standard for older preparations, but in unstable asthma, four-times-daily dosing achieves better control ( 52), and once-daily dosing does not reduce efficacy for doses of 400 g or less ( 53). There are no data to suggest that one compound is more efficacious than another in comparable doses (54), but there are differences in side effects and costs. For acutely ill asthmatic adults, 10 to 15 mg/kg per 24 hours intravenously of hydrocortisone (or its equivalent) is generally appropriate. This would equate to a comparable dose of 600 to 900 mg of hydrocortisone (4 to 6 mg/kg in children), 150 to 225 mg of prednisone (1 to 1. For maximum therapeutic benefit, treatment should be maintained for 36 to 48 hours depending on the clinical response. Dosing intervals depend on the clinical condition of the acutely ill asthmatic patient. When signs and symptoms improve, doses can be tapered to twice daily, then to a single morning daily dose. The total duration of intravenous therapy is dependent on both subjective and objective improvement in respiratory status and responsiveness to adrenergic bronchodilator therapy ( 54). In most hospitalized patients without risk for impending ventilatory failure, oral prednisone, prednisolone, or methylprednisolone are as effective as intravenous treatments ( 17). Prednisone, 40 to 60 mg/day (1 to 2 mg/kg/day in children), or methylprednisolone, 7. The clinician should attempt to reduce the dose by 5 to 10 mg every 2 weeks until the lowest clinically effective dose is reached. Pharmacologically, it would appear that newer compounds have substantially higher lipophilicity and topical potencies and lower systemic bioavailability than compounds developed earlier. Studies suggest that patients treated prophylactically before the allergy season have a significantly higher proportion of symptom-free days, and they experience reduced symptoms compared with placebo-treated groups. Local adverse effects on the nasal mucosa include epistaxis, which occurs in up to 5% to 8% of patients and is usually self-limiting. In severe cases of atopic dermatitis, oral steroids may be used sparingly ( 75,76). Allergic contact dermatitis that fails to respond to topical treatment may improve with once-daily, then alternate-day oral prednisone at doses of 30 to 60 mg for 1 to 2 weeks. Treatments for vernal keratoconjunctivitis, a severe but transient form of ocular allergy, include fluorometholone 0. Ocular corticosteroids should be managed by an ophthalmologist experienced in their use. Because it potentiates the tendency for paclitaxel (Taxol) to induce full-thickness skin necrosis, fluorometholone should not be used in patients receiving treatment with paclitaxel (81). Idiopathic Anaphylaxis Idiopathic anaphylaxis in both adults and children has been successfully treated with systemic prednisone, hydroxyzine, and albuterol to control symptoms and induce remission (82). Potential adverse effects of glucocorticoids Steroid-induced osteoporosis has been treated with alendronate, an antiresorptive agent ( 89), and ideally it is important to limit systemic steroid use as much as possible. The risk for bone loss increases with concomitant use of some medications, notably excessive thyroid replacement treatment. This is a medical emergency that requires prompt diagnosis and rapid treatment with intravenous hydrocortisone (2 mg/kg followed by 1. All adrenally suppressed individuals should receive hydrocortisone at the time of any surgical procedure or at times of acute stress. A review conducted by the Expert Panel Report 2 found that most studies did not demonstrate an effect on growth, but others did find growth delay ( 15). Because asthma itself appears to delay growth in some children ( 93,94), this issue remains controversial. Oral candidiasis is directly related to dose frequency, and both it and hoarseness appear to be dose dependent. A spacer may alleviate both oral candidiasis and hoarseness, and the former responds to oral antifungal preparations, such as nystatin. An alternative steroid could alleviate hoarseness, but simply resting the voice may help. Much more commonly, patients require large oral or inhaled doses to control their asthma. Further studies may reveal more about the mechanisms involved in steroid resistance or dependence. Methotrexate has both immunosuppressive and antiinflammatory mechanisms, but there is little evidence of immunosuppressive effects at low doses, and its benefit for asthma has not been confirmed. Oral gold also has a history of use for steroid-resistant or steroid-dependent asthma but can cause proteinuria and a skin rash. These treatments all have adverse effects that can cause problems of their own, so they have been recommended for treatment in asthma patients only when there is no alternative.

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These terms are not strictly correct in that they imply a mechanism that has not been proved cheap super viagra 160 mg online. Desensitization applies to clinical situations in which antigens are administered in a few hours in sufficient quantity to neutralize available immunoglobulin E (IgE) antibody rapidly ( 27) quality 160mg super viagra. This type of true desensitization may be necessary in treating patients with allergy to an antibiotic purchase cheap super viagra line. Immunotherapy, a term introduced by Norman and co-workers (28), does not imply a mechanism. It consists of injections of increasing amounts of allergen to which the patient has type I immediate hypersensitivity. As a result of these injections, the patient is able to tolerate exposure to the allergen with fewer symptoms. The mechanism by which this improvement occurs has not been definitely established. However, over the years, several mechanisms have been postulated to account for the improvement. Immunotherapy was first used by Noon and Freeman, who observed that pollen was the etiologic agent of seasonal rhinitis and that immunization was effective in the treatment of various infectious diseases, including tetanus and diphtheria. Cooke ( 29) observed that cutaneous reactivity was not obliterated by allergy injections. Cooke also discovered a serum factor, which he called blocking antibody, in the serum of patients receiving immunotherapy ( 30). This serum factor could inhibit the passive transfer of allergic antibody described by Prausnitz and Kstner. However, there was not a constant relationship between blocking antibody titers and symptom relief. The first controlled study of the efficacy of immunotherapy was published in 1949 ( 31). Within a short time in vitro techniques were developed to assess objectively the immunologic results of immunotherapy. Immunologic changes with immunotherapy In general, immunotherapy is indicated for clinically significant disease when the usual methods of avoidance and medication are inadequate to control symptoms ( 34) (Table 10. It is considered to be effective in ameliorating symptoms of allergic rhinitis, allergic asthma, and Hymenoptera sensitivity. Assessment of efficacy in these studies is difficult because the diseases being treated are chronic and have variations based on geography, climate, and individuals. Assessments are generally made from subjective daily symptom and medication reports by the patient. In some studies, objective clinical evaluation by physicians or by nasal or bronchial challenge was also a part of the assessment. In one study, children who were monosensitized to house dust mite and who received allergen immunotherapy developed fewer new sensitivities than those who did not receive immunotherapy ( 38). A metaanalysis of immunotherapy studies in asthma concluded that immunotherapy was efficacious ( 46). Examples of double-blind placebo-controlled allergen immunotherapy studies reporting efficacy There is no indication for immunotherapy in food allergy or chronic urticaria, nor is there sufficient evidence to support the use of bacterial vaccine ( 18,47). However, it is a potent allergen in the southern United States, where people often vacation. In the allergic evaluation, a patient undergoes skin testing with various allergens. For example, a patient having a positive grass skin test, rhinorrhea, and palatal itching in May and June in the Midwest will benefit from grass pollen immunotherapy. In contrast, a patient with an isolated positive grass skin test and with perennial symptoms of rhinorrhea and nasal congestion probably has vasomotor rhinitis and will not benefit from immunotherapy. Many patients have allergic rhinitis or allergic asthma from various types of animal dander. In rare instances, avoidance is unacceptable; for example, a blind person with a seeing-eye dog or a veterinarian whose livelihood depends on animal exposure cannot be expected to avoid these animals. Patients who are very sensitive to dander extracts may have difficulties with local or systemic reactions, such that it is difficult to attain clinically efficacious doses ( 50). Technical Aspects Allergen Extract Potency and Dosage Schedules The preparation and distribution of allergen extracts, also called vaccines, is regulated by the U. This agency has developed reference standards for a number of allergen vaccines and reference serum pools to be used by manufacturers to standardize their vaccines. Short ragweed and cat extracts (both hair and pelt) are standardized by major allergen content, unit per milliliter of Amb a 1 or unit per milliliter of Fel d 1, respectively. Other aeroallergen preparations made in the United States are not required to be standardized. Potency can be measured practically in various ways: cutaneous end-point titration, radioimmunoassay inhibition, or content of a known major allergen like antigen E ( Amb a 1) in ragweed, or Fel d 1 in cat extracts (51). Standard extracts, including short ragweed and Dermatophagoides pteronyssinus, have been developed by the Allergen Standardization Subcommittee of the International Union of Immunologic Societies ( 53,54). Until reference standards and exact quantitation of potency can be established for all extracts, less exact methods such as W/V will continue to be used. That is, a patient receiving immunotherapy to grass pollen and tree pollen could receive two injections, one of grass and one of tree, or could receive one injection containing both grass and tree pollens. Because mold extracts contain proteases that may influence other extracts like pollens and dust mite, some recommend giving mold as a separate injection (51). Most clinicians in the United States administer allergen immunotherapy subcutaneously, beginning with weekly or twice-weekly injections ( 55). Current evidence suggests that treatment with higher doses of pollen extracts results in better long-term reduction of clinical symptoms and greater immunologic changes than low-dose therapy. There is evidence that dosage based on the Rinkel technique, a low-dose protocol, is not effective ( 56). There are no clear data on the optimal length of time immunotherapy should be continued. Most patients who are maintained on immunotherapy and show improvement through three annual pollen seasons continue to maintain improvement even when their injections are discontinued ( 57). Patients who do not respond after receiving maintenance doses of immunotherapy for 1 year are unlikely to improve with further treatment. Therefore, immunotherapy should be discontinued in patients who have not had appreciable improvement after an entire year of maintenance doses. The most common method of administering perennial immunotherapy is subcutaneously using a dose schedule similar to that in Table 10. The injections are given weekly until the patient reaches the maintenance dose of 0. At that point, the interval between injections may be gradually increased to 2 weeks, 3 weeks, and ultimately monthly. When a new vial of extract is given to a patient receiving a maintenance dose of 0.

By B. Basir. Loyola Marymount University.

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