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By A. Sivert. Upper Iowa University. 2019.

A large stantially affect antiviral immune responses number of studies have been conducted on by interfering with the activity of cytokines purchase synthroid 75 mcg mastercard medicine 2 times a day, the use of phages in humans buy synthroid 125 mcg with mastercard medicine interactions, and of particular such as the production by adenoviruses and importance are studies that were carried out Epstein–Barr virus of proteins with activity in Georgia and Poland order 200 mcg synthroid amex treatment restless leg syndrome. However purchase synthroid 125 mcg free shipping medicine administration, it is modulatory activity have been identified essential to conduct formal clinical trials to (Ploegh, 1998). Thus, it is not unreasonable confirm the efficacy and safety of phage that phages infecting pathogenic and normal therapy before bacteriophages become flora bacteria would also be able to evolve widely available as therapeutic agents (see immunomodulating proteins to aid in their Burrowes and Harper, Chapter 14, this retention in the body. An understudied aspect of phage biology is their potential effects on the immune Prevalence of Bacteriophages and system. It is known that infections with the Safety of Phage Therapy pathogenic viruses – a category that does not include bacteriophages – are associated with Prevalence of bacteriophages in the activation of coordinated mechanisms of environment immune responses (Horst et al. At first, non-specific immune responses are induced There is a surprising abundance and following the recognition by immune cells of diversity of bacteriophages in the environ- pathogen-associated molecular paterns in ment. Primary immune responses to viral 104 and 108 phages ml–1 in water ecosystems infections are mediated by macrophages, (Weinbauer, 2004). Bacteriophages have also natural killer cells, granulocytes, complement been isolated from sewage (mean con- and interferons. Humoral in yogurt (Lactobacillus phages) and sauer- and cellular specific immune responses are kraut, where as many as 26 different phages induced, resulting in the neutralization of were found (Kiliç et al. Phages are however, many pathogenic viruses have particularly abundant in the intestines of developed mechanisms to avoid elimination mammals in view of the presence of by the immune system. This issue is can avoid recognition by the host immune discussed in detail by Letarov (Chapter 2, system as a result of high antigenic diversity, this volume). A lack of any deleterious considerations effects of phages on the microflora was found in a study by Brutin and Brüssow (2005). The omnipresence of bacteriophages in the They reported that oral administration of T4 environment implies constant exposure of phage at a titre of 103 or 105 plaque-forming humans to phages. Furthermore, no side effects effects of phage therapy are observed very atributable to the administration of phage rarely. This problem is discussed by endotoxin release following phage-mediated Christie et al. They showed that the administration preparations, which are released from the of phages to mice infected by Pseudomonas bacteria in which phages are propagated. However, so far, phage the treatment compared with the cor- lysates have been used for most treatment of responding values found in the patients prior humans, as purification of phage preparations to phage administration. Moreover, between from endotoxins is associated with a loss of days 9 and 32 of the treatment, significant active phage particles. These results suggest that orally or topically (Sulakvelidze and Kuter, lysis of bacteria by phages does not exert any 2005). Studies on using phage lysates in the pro-inflammatory effects; in fact, they treatment of chronic bacterial infections in indicate that phages could exert anti- humans have been conducted since 1952 at inflammatory activity (Międzybrodzki et al. A strong argument for the safety of No significant side effects of phage therapy phage therapy is the high specificity of the have been observed so far (Weber-Dąbrowska antibacterial activity of phages. Therefore, unlike antibiotics, they Preparations of phages specific to Gram- are less likely to disturb the balance of the positive bacteria can also contain some Phage Translocation, Safety and Immunomodulation 171 components of bacterial cells. There are data lysates and purified preparations of T4 phage in the literature, however, to show that it and staphylococcal phage A3/R induced only is possible to obtain safe preparations of a weak respiratory burst in human monocytes these phages. These species, including super- oxide, hydrogen peroxide, hydroxyl radicals Inactivation of phages by mechanisms of and singlet oxygen, exert bactericidal activity. When there are no host bacteria syndrome, atherosclerosis and neuro- in which phages could replicate, they are degenerative diseases, especially Alzheimer’s fairly rapidly removed from the blood and disease and Parkinson’s disease (Knight, the majority of internal organs. Kupffer cells within 30 min of their This result suggests that lysis of bacteria by intravenous administration. As well as phages is not likely to induce oxidative stress Kupffer cells, spleen macrophages can also in cells, arguing for the safety of phage eliminate phages, but their activity in this therapy. Consequently, phage titre in the liver which suggests that the presence of decreases rapidly, while in the spleen phages neutralizing antibodies does not always remain at high titre for up to 5–7 days afer result in a lower therapeutic efficacy. It has been suggested that phages entrapped in the Immunogenic properties of X174 phage spleen can be a source of antigen necessary for antibody generation (Geier et al. The immunogenic properties of phages have found use in the diagnosis of immune system diseases and monitoring of humoral immune responses. Concentration of evaluate the effects of rituximab, a B cell- these antibodies depends, among other depleting antibody, on the production of things, on the route of phage administration antibodies in patients with type I diabetes. It (topical and oral administration result in only was found that this assay is a sensitive a slight increase in the generation of indicator of antibody production that enables antibodies) and dosage protocol (the level of the evaluation of humoral immune responses. In healthy individuals, Neutralizing antibodies can limit the intravenous administration of X174 results efficacy of phage therapy. It was observed that a was slower in B cell-deficient mice compared long presence of phages in the circulation with wild-type mice. Phage X174 was selected Antibodies against Staphylococcus aureus for diagnostic use because it is a strong phages were detected in 12 out of 57 patients antigen and does not cause any side effects in with staphylococcal infections (Kucharewicz- humans. During phage clearance from blood is relatively simple therapy, these antibodies were detected in (Ochs et al. Further analysis of the results obtained in 30 patients revealed that phage therapy was ineffective in two out of five Anti-phage cellular immunity patients in whom anti-phage antibodies were detected prior to therapy (Kucharewicz- Apart from non-specific immune responses Krukowska and Ślopek, 1987). Interestingly, and humoral immunity, cellular immunity the clinical state of the remaining three also plays an important role in combating patients improved following the treatment, viral infections. Some of the first authors to Phage Translocation, Safety and Immunomodulation 173 show that phages can induce cellular immune Moreover, phages were found to relieve the responses were Langbeheim et al. They found that subcutaneous granulocytes and monocytes and had no injection of phages resulted in a strong effect on the intracellular killing of bacteria hypersensitivity reaction in all animals. On the other hand, the results of days 7 and 8 post-transplantation (Górski et Srivastava et al. They showed that the clearance of T7 phage in T cell-deficient mice Influence of phages on phagocytosis is similar to that found in T cell-proficient mice. Thus, the data are conflicting, and Our studies have shown that phages also can further studies are needed in this regard. A similar effect was noted when phagocytic cells were Effects of phages on granulocytes incubated with E. The first cells to migrate (F8), resulted in an increase in the phago- to the site of infection are macrophages and cytosis of bacteria by both neutrophils and granulocytes, especially neutrophils. It appears been shown that, in patients subjected to that homologous phages can coat bacteria phage therapy, clearance of infection was (‘phage opsonization’), thus facilitating their accompanied by a decrease in the number of phagocytosis (Górski et al. T4 phage, mature neutrophils and an increase in the however, had no effect on the in vitro number of neutrophil precursors in the phagocytosis of bacteria by monocytes and peripheral blood (Weber-Dąbrowska et al. Stimulatory effects of phage preparations on the generation of neutrophil Effects of phages on T cells and precursors appear to be beneficial because platelets – practical implications they result in the enhancement of non-specific immune responses. Integrins comprise a family of cell-surface It was also shown that bacteriophages receptors that, by interacting with extra- can affect the migration of phagocytic cells. We also showed that phages can decrease the production of cytokines induced reduce the adhesion of platelets and, to a by bacterial infections in animals. For lesser extent, of T cells, to fibrinogen (Kniotek example, in a murine model of lung infection et al. In a inflammatory cytokines in bronchoalveolar study on the role of bacteriophages in the lavage samples collected at 20 h afer development of transplantation tolerance, intranasal administration of bacteria. It was also found that a purified T4 logical examination revealed that damage of phage preparation significantly decreased pulmonary tissue was more pronounced in alloantigen-driven in vitro humoral responses untreated mice compared with phage-treated (Kniotek et al.

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Disease management becomes creased physical activity buy cheap synthroid 100mcg line treatment chronic bronchitis, and decreased alcohol intake); one of several means towards the end goal buy 25 mcg synthroid with visa treatment xdr tb, rather than purchase synthroid 75 mcg on line medications side effects prescription drugs, as preventive services (e buy generic synthroid 100mcg on line medicine 1700s. In the disease model, the patient’s tions such as aspirin, statins, calcium, vitamin D, and “chief complaint” leads to the creation of a differential bisphosphonates, which are all predicated on preventing diagnosis. Under a more individually tailored cillary tests help to determine which diseases most likely model, preventive decision making is based on a patient’s explain the patient’s symptoms or complaints. Treatment articulation of preferred trade-offs between long-term then is aimed at this underlying disease. In the integrated, outcomes such as survival or functioning and short-term individually tailored model, the patient’s complaints ini- acceptance of testing burden, lifestyle changes, and the tiate three sets of questions. The first set asks in what ways inconvenience, costs, and side effects of daily medica- the complaints are bothersome—what is the effect on the tions. The details of how clinical encounters will be struc- patient’s physical, psychological, and social functioning? What trade-offs are the patient willing The need to ascertain and incorporate individual pri- to make? In the case of prevention, does the patient value orities, to address multiple contributing factors simulta- “down the road” benefits more or does the patient have neously, and to prescribe and monitor multifaceted in- more immediate concerns about the side effects of daily terventions will make clinical decision making more medications? The third set of questions explores the non- iterative, interactive, individualized, and complex. For example, are psy- ative use of information technologies should facilitate the chological or social factors further impeding health and organization, presentation, and integration of this infor- functioning? The answers to these questions are integral mation to arrive at individualized yet systematic clinical to constructing the treatment plan. Examples of clinical decision making predicated on individual patient priori- decision making under these contrasting models are ties. To accomplish its goals, health care must be- The integrated, individually tailored approach also ap- come more interdisciplinary. Clinical Decision Making with the Disease-Oriented and Integrated, Individually Tailored Models for a 44-Year-Old Obese Man Reporting Decreased Activity Tolerance Disease-Oriented Model Integrated, Individually Tailored Model Collect clinical data Collect patient-specific data ● History (e. The increased emphasis on psychological, so- will be needed in the training of other health profession- cial, environmental, and other factors will raise concerns als. Al- Research, along with clinical care, has shaped the de- though necessitating a delineation of the components of partmental structure of medical schools, which in turn health, the debate should revolve not around medicaliza- has influenced the organization of clinical practice. Re- tion or interdisciplinary “boundaries,” but around efforts search is, however, already restructuring along method- to coordinate and pay for efficient and effective interdis- ological and technological lines, and away from an organ- ciplinary care, whether it is provided within or outside and specialty-based configuration. Medical education, for example, which can thus evolve unencumbered by the need to artificially has been organized around pathophysiologic mecha- fit into a research-driven paradigm. These changes are primarily in re- coverage and payment decisions should follow logically sponse to time constraints and information overload and from a clear articulation of the goals and structure of care. Nevertheless, it is worth taking advan- nity, perhaps for the first time, to articulate coverage de- tage of this transition to train the next generation of phy- cisions based on evidence of effectiveness and on trans- sicians, who are not yet wedded to the disease model, in a parent societal and personal priorities. Clinical Decision Making with the Disease-Oriented and Integrated, Individually Tailored Models for a 76-Year-Old Woman with Fatigue and Weight Loss Disease-Oriented Model Integrated, Individually Tailored Model Collect clinical data Collect patient-specific data ● History (e. Determining the boundaries of which both biologic and nonbiologic factors operate. The organization, Paradoxically, two anticipated arguments against payment, and quality assessment of medical care remain change will be that “this is nothing new, we already do firmly entrenched in disease-specific, episodic care. Dizziness among older adults: a the benefits that accrue from targeting the basic mecha- possible geriatric syndrome. The relative influence of perceived pain nisms of disease, it is na¨ıve to think that this strategy alone control, anxiety, and functional self-efficacy on spinal function will obviate the need for a more individualized, interdis- among patients with chronic low back pain. Acute myocardial infarction: number of persons with a heavy burden of illness and psychosocial and cardiovascular risk factors in men. What will be the impetus for tors on the pathogenesis of cardiovascular disease and implications embarking on the daunting task of transforming the for therapy. Neighborhood of resi- possible scenario is that with diverse motivations, medi- dence and incidence of coronary heart disease. The ever expanding array of expen- den death by a multifactorial intervention programme after myo- sive technologies available for an increasing number of cardial infarction. A meta-analysis of psy- boomers who will rapidly overwhelm a health care system choeducational programs for coronary heart disease patients. Psychosocial interventions for pa- tients with diverse health priorities to participate in clin- tients with coronary artery disease: a meta-analysis. A report of the American College of Cardi- Perhaps the greatest barrier will be that the disease ology/American Heart Association Task Force on Practice Guide- model is so entrenched that most clinicians and patients lines. Comparison of two model, developed as a means of translating emerging sci- aspirin doses on ischemic stroke in post myocardial infarction pa- tients in the warfarin (Coumadin) aspirin reinfarction study. The sixth report of the Joint National Commission on prevention, grated model based on the health care needs of patients in detection, evaluation and treatment of high blood pressure. Treatmentofdysthymiaand ment-tradeoff method to elicit preferences for the treatment of lo- minor depression in primary care: a randomized controlled trial in callyadvancednon-small-celllungcancer. A patient-centered approach to investigations to diagnose the cause of dizziness in elderly people: a advance medical planning in the nursing home. Shared risk factors for falls, incon- decision aid for patients with atrial fibrillation who are considering tinence, and functional dependence. Gastrointestinal illness and the biopsychosocial measuring clinically important changes in the frail elderly. Immunisation contacts and resources Specifc questions on immunisation should be directed to your immunisation provider (doctor or child health nurse), your local public health unit, or to the Central Immunisation Clinic on telephone 9321 1312. A range of publications and information on immunisation can be accessed and/or ordered through: Department of Health www. While every reasonable effort has been made to ensure the accuracy of the information in these guidelines, no guarantee is given that the guidelines are free from error or omission. The information provided is not a substitute for medical care and so specifc questions about a person’s health status should be directed to their health care provider. Notifable diseases outlined in this book may be followed up by a public health unit staff member. While it is often diffcult to prevent the transmission of common respiratory (colds/fu) and gastroenteritis infections that occur, every effort should be made to minimise the spread of infection by encouraging: * staff and children attending school or childcare should stay at home in the early stages of illness as they are likely to be more infectious and transmit the virus/bacteria to others, via coughing, sneezing and, contaminating surfaces that others touch * staff working in schools or childcare organisations, including the children, should remain absent until they are symptom free if they have a cold or fu; and for at least 24 hours if they have had gastroenteritis * parents to seek medical advice if their child has ongoing symptoms of illness * follow up by the local public health unit for other important infections, including measles, whooping cough, meningococcal and typhoid infections (telephone numbers on page 3). Many childhood infectious diseases require students/staff to be excluded from day care or school for a recommended period of time; if they are unable to provide evidence of immunisation against specifc diseases that are known to be highly transmissible they will be excluded. If unsure about what action to take, contact your local public health unit (telephone numbers on page 3). Strategies to prevent transmission of infection: * Hand washing with soap and water for at least 15 seconds before preparing or eating food, after using the toilet, changing nappies, after blowing your nose with a hanky or tissue (disposable tissues are preferred), and after any contamination of the hands with body fuids such as blood and vomit. Symptoms include fever, malaise, chills, headache, muscle pain, sore throat, cough and diarrhoea. Symptoms include fever, fatigue, and a generalised rash characterised by small vesicles (blisters) that rupture to form crusts. Transmission Airborne or droplet; direct or indirect contact with fuid from vesicles of an infected person Incubation Average 10–21 days period Infectious From 2 days before rash appears to period 5 days after, when vesicles have formed crusts. See Appendix 1 for immunisation recommendations Exclusion Exclude for at least 5 days after vesicles (rash) appear and until vesicles have formed crusts. Note that crusts alone do not warrant exclusion Treatment Antiviral treatment available Contacts Refer any immunosuppressed children (e. Do not exclude other contacts Immunisation Non-immune pregnant women should see their doctor urgently as immunisation may prevent chickenpox in contacts within 5 days of exposure. Post exposure immunisation can also be offered to other non-immune contacts to prevent disease 9 Communicable disease guidelines 2017 Edition Conjunctivitis C (various viruses and bacteria) A common, acute, viral or bacterial infection of the eyes. Transmission Direct or indirect contact with secretions from infected eyes Incubation 24–72 hours period Infectious While eye discharge is present period Exclusion Exclude until discharge from eyes has ceased Treatment Treatment as recommended by doctor – refer to doctor Contacts Do not exclude Immunisation None available 10 Communicable disease guidelines 2017 Edition Cryptosporidiosis C Notifable – discuss with your local public health unit staff. When present, symptoms include vomiting, loss of appetite, stomach pain and foul smelling diarrhoea.

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Many of the digestive enzymes and enzymes concerned with blood coagulation are in this group Examples: Pepsinogen - This zymogen is from gastric juice generic 100 mcg synthroid with mastercard symptoms uterine prolapse. When required Pepsinogen converts to Pepsin Trypsinogen - This zymogen is found in the pancreatic juice cheap 25mcg synthroid amex symptoms xeroderma pigmentosum, and when it is required gets converted to trypsin cheap synthroid 25 mcg on line pretreatment. Isoenzymes (Isozymes) These are enzymes having similar catalytic activity synthroid 100mcg with amex treatment table, act on the same substrate and produces the same product but originated at different site and exhibiting different physical and chemical characteristics such as electrophoretic mobilities, amino acid composition and immunological behavior. The international union of Biochemistry and Molecular Biology developed a system of nomenclature on which enzymes are divided in to six major classes, each with numerous sub groups. Each enzyme is characterized by a code number comprising four digits separated by points. The four digits characterize class, sub-class, sub-sub-class, and serial number of a particular enzyme. Transferases: Enzymes catalyzing a transfer of a group other than hydrogen (methyl, acyl, amino or phosphate groups) Example: Enzymes catalyzing transfer of phosphorus containing groups. Hydrolases: Enzymes catalyzing hydrolysis of ester, ether, peptido, glycosyl, acid-anhydride, C-C, C-halide, or P-N-bonds by utilizing water. Lyases: Enzymes that catalyze removal of groups from substances by mechanisms other than hydrolysis, leaving double bonds. Isomerases: Includes all enzymes catalyzing interconversion of optical, geometric, or positional isomers. Example: Enzymes catalyzing interconversion of aldose and ketoses D - Glyceraldehyde-3- phosphate ketoisomerase (triosephosphate isomerase) D - Glyceraldehyde-3phosphate Dihydroxyacetone phosphate. Lock: Key model of enzyme action implies that the active site of the enzyme is complementary in shape to that of its substrate, i. Figure: Models of enzyme- substrate interactions Mechanism of Enzyme Action (1913) Michaels and Menten have proposed a hypothesis for enzyme action, which is most acceptable. Enzyme once dissociated from the complex is free to combine with another molecule of substrate and form product in a similar way. The transition state is the top of the energy barrier separating the reactants and products. The rate of a given reaction will vary directly as the number of reactant molecules in the transition state. The “energy of activation is the amount of energy required to bring all the molecules in 1 gram-mole of a substrate at a given temperate to the transition state A rise in temperature, by increasing thermal motion and energy, causes an increase in the number of molecules on the transition state and thus accelerates a chemical reaction. The enzyme combines transiently with the substrate to produce a transient state having c lower energy of activation than that of substrate alone. Once the products are formed, the enzyme (or catalyst) is free or regenerated to combine with another molecule of the substrate and repeat the process. Activation energy is defined as the energy required to convert all molecules in one mole of reacting substance from the ground state to the transition state. Themperature Starting from low temperature as the temperature increases to certain degree the activity of the enzyme increases because the temperature increase the total energy of the chemical system. Above this the reaction rate decreases sharply, mainly due to denaturation of the enzyme by heat. The temperature at which an enzyme shows maximum activity is known as the optimum temperature for the enzyme. For most body enzymes the optimum 0 temperature is around 37 c, which is body temperature. First, the catalytic process usually requires that the enzyme and substrate have specific chemical groups in an ionized or unionized sate in order to interact. Extreme pH can also lead to denaturation of the enzyme, because the structure of the catalytically active protein molecule depends on the ionic character of the amino acid chains. The pH at which maximum enzyme activity is achieved is different for different + enzymes, and after reflects the pH ] at which the enzyme functions in the body. For example, pepsin, a digestive enzyme in the stomach, has maximum action at pH 2, where as other enzymes, designed to work at neutral pH, are denatured by such an acidic environment. Concentration of substrate At fixed enzyme concentration pH and temperature the activity of enzymes is influenced by increase in substrate concentration. An increase in the substrate concentration increases the enzyme activity till a maximum is reached. This condition shows that as concentration of substrate is increased, the substrate molecule combine with all available enzyme molecules at their active site till not more active sites are available (The active Sites become saturated). Relationship between [S] and Km Km shows the relationship between the substrate concentration and the velocity of the enzyme catalyzed reaction. Take the point in which 50% of the active site of the enzyme will be saturated by substrate, Assume that at ½ Vmax-50% of the active site of enzyme becomes saturated. Therefore: 11 Vo = ½ Vmax, at 50% saturation ½ Vmax = Vmax[S] Km + [S] 2[S] = Km + [S] Km= [S] Figure: Relationship between [S] and Km Characteristics of Km Km- can defined as the concentration of the substrate at which a given enzyme yields one-half its max. Km- values varies from enzyme to enzyme and used to characterized different enzymes. Km- values of an enzyme helps to understand the nature and speed of the enzyme catalysis. Small Km - A numerically small (Low) km reflects a high affinity of the enzyme for substrate because a low conc of substrate is needed to half saturate the enzyme- that is reach a velocity of ½ Vmax. High Km - A numerically large (high) Km reflects a low affinity of enzyme for substrate b/c a high conc of substrate is needed to half saturate the enzyme. Relationship of Velocity to Enzyme Concentration The rate of the reaction is directly proportional to enzyme concentration at all substrate concentration. For example, if the enzyme concentration halved, the initial rate of the reaction (Vo) is reduced to one half that of the original. Effect of Enzyme concentration on enzymatic reaction Order of Reaction When [S] is much less than Km, the velocity of the reaction is roughly proportional to the substrate concentration. The rate of reaction is then said to be first order configuration with respect to substrate. The rate of reaction is then independent of substrate concentration and said to be zero order with respect to substrate concentration. Enzyme Inhibition Any substance that can diminish the velocity of an enzyme-catalyzed reaction is called an inhibitor and the process is known as inhibition. Example: Inhibition of triose phosphate dehydrogenate by iodo acetate which block the activity of the enzyme. In competitive inhibition the inhibitor and substrate compete for the same active site on the enzyme as a result of similarity in structure. A classical example is Malonate that competes with succinate and inhibits the action of succinate dehydrogenase to produce fumarate in the Krebs cycle. The enzyme can be also inhibited by oxalate and glutarate because of the similarity of this substance with succinate Eg. This competition blocks the conversion of these precursors, and of hypoxanthine and xanthine, to uric acid and result in lower serum urate levels. A Lineweaver-Burk Plot An alternative linear transformation of the Michaelis-Menten equation is the Eadie-Hofstee transformation: v/[S] = -v [1/Km] + [Vmax/Km] and when v/[S] is plotted on the y-axis versus v on the x-axis, the result is a linear plot with a slope of -1/Km and the value Vmax/Km as the intercept on the y- axis and Vmax as the intercept on the x-axis. Both the Lineweaver-Burk and Eadie-Hofstee transformation of the Michaelis-Menton equation are useful in the analysis of enzyme inhibition. Since most clinical drug therapy is based on inhibiting the activity of enzymes, analysis of enzyme reactions using the tools described above has been fundamental to the modern design of pharmaceuticals 15 Effect of Competitive inhibitors 1. Effect on Vmax: The effect of a competitive inhibitor is reversed by increasing [s]. Effect on Km: A competitive inhibitor increases the apparent Km for a given substrate. This means that in the presence of a competitive inhibitor more substrate is needed to achieve ½ Vmax. Figure: Competitive inhibition Non-Competitive Inhibition In non-competitive inhibition the inhibitor binds at different site rather than the substrate-binding site.

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