Top Avana

By I. Hanson. Long Island University. 2019.

Outcome rates (per 10000 person-weeks) for each of 3 influenza outcomes top avana 80mg, by influenza season and during periods of high top avana 80 mg, medium 80 mg top avana, and low influenza activity 80mg top avana. Published by Oxford University Press for the Infectious Diseases Society of America 2017 . Effectiveness of adjuvanted influenza vaccination in elderly subjects in northern Italy . Influenza Vaccine during Pregnancy Protects Infants < 6 Months of Age from Laboratory-Proven Influenza Zaman et al . Excluded from this definition are in vitro studies that utilize human tissues that cannot be linked to a living individual . Patient-oriented research includes: (a) mechanisms of human disease , (b) therapeutic interventions , (c) clinical trials, and (d) development of new technologies). Additionally, up to 3 publications may be included that are not publically available. Format for Attachments Designed to maximize system-conducted validations, multiple separate attachments are required for a complete application. When the application is received by the agency, all submitted forms and all separate attachments are combined into a single document that is used by peer reviewers and agency staff. Applicants are encouraged to submit in advance of the deadline to ensure they have time to make any application corrections that might be necessary for successful submission. They must make required changes to the local copy of their application and submit again through Grants. Once you can see your application in the Commons, be sure to review it carefully as this is what the reviewer will see. This process and email notifications of receipt, validation or rejection may take two (2) business days. Applicants are strongly encouraged to allocate additional time prior to the submission deadline to submit their applications and to correct errors identified in the validation process. Applicants are encouraged also to check the status of their application submission to determine if the application packages are complete and error-free. Applicants who encounter system errors when submitting their applications must attempt to resolve them by contacting the Grants. After submission of your application package, applicants will receive a “submission receipt” email generated by Grants. A third and final e-mail message is generated once the applicant’s application package has passed validation and the grantor has confirmed receipt of the application. Unsuccessful Submissions: If an application submission was unsuccessful, the applicant must: 1. Track his/her submission and verify the submission status (tracking should be done initially regardless of rejection or success). If there is time before the deadline, he/she should correct the problem(s) and resubmit as soon as possible. Due Date for Applications: 02/22/2017 Electronically submitted applications must be submitted no later than 5:00 p. For more information on expanded authority and pre-award costs, go to: http://www. The cost of sharing or archiving public health data may also be included as part of the total budget requested for first-time or continuation awards. Applicants must complete all required registrations before the application due date. For assistance with your electronic application or for more information on the electronic submission process, visit Applying Electronically (http://grants. See more resources to avoid common errors and submitting, tracking, and viewing applications: http:// grants. Criteria Only the review criteria described below will be considered in the review process. Scored Review Criteria Reviewers will consider each of the review criteria below in the determination of scientific merit, and give a separate score for each. An application does not need to be strong in all categories to be judged likely to have major scientific impact. For example, a project that by its nature is not innovative may be essential to advance a field. Significance Does the project address an important problem or a critical barrier to progress in the field? If the aims of the project are achieved, how will scientific knowledge, technical capability, and/or clinical practice be improved? How will successful completion of the aims change the concepts, methods, technologies, treatments, services, or preventative interventions that drive this field? Does the work address a scientific problem of great importance to public health research and/or practice? Will the work be influential in that it will lead others to investigate the problem, open new areas of research, or change the scientific approach or public health practice, and how will this improve and be of value to public health? If successful, do the research results have the potential to be scalable and reach a large portion of the population at risk? Have they demonstrated an ongoing record of accomplishments that have advanced their field(s)? Have previous research results provided high quality outputs and contributed to improvements in public health practice and population health? Innovation Does the application challenge and seek to shift current research or clinical practice paradigms by utilizing novel theoretical concepts, approaches or methodologies, instrumentation, or interventions? Are the concepts, approaches or methodologies, instrumentation, or interventions novel to one field of research or novel in a broad sense? Is a refinement, improvement, or new application of theoretical concepts, approaches or methodologies, instrumentation, or interventions proposed? Does the application challenge and seek to shift current public health practice paradigms or 15 of 57 Does the application challenge and seek to shift current public health practice paradigms or approaches? Does the project have the potential to increase efficiency or lead to cost savings? Approach Are the overall strategy, methodology, and analyses well-reasoned and appropriate to accomplish the specific aims of the project? Are potential problems, alternative strategies, and benchmarks for success presented? If the project is in the early stages of development, will the strategy establish feasibility and will particularly risky aspects be managed? If the project involves clinical research, are there plans for 1) protection of human subjects from research risks, and 2) inclusion of minorities and members of both sexes/genders, as well as the inclusion of children, justified in terms of the scientific goals and research strategy proposed? Does the application propose to use evidence-based interventions or strategies in the research plan? If the project is in the latter stages of development, will the strategy establish scalability? Environment Will the scientific environment in which the work will be done contribute to the probability of success? Are the institutional support, equipment and other physical resources available to the investigators adequate for the project proposed? Will the project benefit from unique features of the scientific environment, subject populations, or collaborative arrangements? Does the project support key stakeholder involvement throughout the research process? Additional Review Criteria As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items. If your proposed research involves the use of human data and/or biological specimens, you must provide a justification for your claim that no human subjects are involved in the Protection of Human Subjects section of the Research Plan. Inclusion of Women, Minorities, and Children When the proposed project involves clinical research, the committee will evaluate the proposed plans for inclusion of minorities and members of both genders, as well as the inclusion of children. For additional information on review of the Inclusion section, please refer to the policy on the Inclusion of Women and Racial and Ethnic Minorities in Research (http:// www. For additional information on review of the Vertebrate Animals section, please refer to the Worksheet for Review of the Vertebrate Animal Section (http://grants. Biohazards Reviewers will assess whether materials or procedures proposed are potentially hazardous to research personnel and/or the environment, and if needed, determine whether adequate protection is proposed. For more information about this Policy and other policies regarding dual use research of concern, visit the U. Additional Review Considerations As applicable for the project proposed, reviewers will consider each of the following items, but will not give scores for these items, and should not consider them in providing an overall impact/priority score. Does the applicant adequately address the additional review criteria detailed in the Special Interest Project they are applying for? As applicable for the project proposed, reviewers will evaluate the following additional items while determining scientific and technical merit, and in providing an overall impact/priority score, but will not give 17 of 57 determining scientific and technical merit, and in providing an overall impact/priority score, but will not give separate scores for these items. Budget and Period of Support Reviewers will consider whether the budget and the requested period of support are fully justified and reasonable in relation to the proposed research. As part of the scientific peer review, all applications: Will undergo a selection process in which all responsive applications will be discussed and assigned an overall impact/priority score. Following initial peer review, recommended applications will receive a second level of review. The following will be considered in making funding decisions: Scientific and technical merit of the proposed project as determined by scientific peer review. Following initial peer review, recommended applications will receive a second level of review. At a minimum, the information in the system for a prior Federal award recipient must demonstrate a satisfactory record of executing programs or activities under Federal grants, cooperative agreements, or procurement awards; and integrity and business ethics. If it is determined that a Federal award will be made, special conditions that correspond to the degree of risk assessed may be applied to the Federal award. These provisions restrict Federal awards, subawards and contracts with certain parties that are debarred, suspended or otherwise excluded from or ineligible for participation in Federal programs or activities. A formal notification in the form of a Notice of Award (NoA) will be provided to the applicant organization for successful applications. The NoA signed by the Grants Management Officer is the authorizing document and will be sent via email to the grantee’s business official. Selection of an application for award is not an authorization to begin performance. This section should address access to identifiable and de-identified data (see below for additional information about access); • Statement of the use of data standards that ensure all released data have appropriate documentation that describes the method of collection, what the data represent, and potential limitations for use; and • Plans for archiving and long-term preservation of the data, or explaining why long-term preservation and access are not justified. This section should address archiving and preservation of identifiable and de-identified data (see below for additional information regarding archiving). The final version of a collected and/or generated data set intended for release or sharing should be made available within thirty (30) months after the end of the data collection or generation, except surveillance data which should be made accessible within a year of the end of a collection cycle. In addition, awardees should ensure the quality of data they make accessible and seek to provide the data in a nonproprietary format. Awardees who fail to release public health data in a timely fashion may be subject to procedures normally used to address lack of compliance consistent with applicable authorities, regulations, policies or terms of their award. For public use de-identified (removal of sensitive identifiable or potentially identifiable information) datasets, an accompanying data dictionary, and other documentation relevant to use of the data set should be deposited in a sustainable repository to provide access to the data. Data that cannot be de-identified can be provided on request under a data-use agreement. For data underlying scientific publication, awardee should make the data available coincident with publication of the paper, unless the data set is already available via a release or sharing mechanism. At a minimum, release of the data set should consist of a machine-readable version of the data tables shown in the paper. Requirements set forth in this policy are not intended to conflict with or supersede applicable grants regulations related to agency access to awardee data and records. For more information on the Code of Federal Regulations, visit the National Archives and Records Administration at: http​://www​. For the full text of the requirements, please review the following website: https://www. Plain Writing Act The Plain Writing Act of 2010, Public Law 111-274 was signed into law on October 13, 2010. The law requires that federal agencies use "clear Government communication that the public can understand and use" and requires the federal government to write all new publications, forms, and publicly distributed documents in a "clear, concise, well-organized" manner. These policies build on the current federal commitment to reduce exposure to secondhand smoke, which includes The Pro-Children Act, 20 U. Tobacco: 23 of 57 Tobacco: Tobacco-free indoors – no use of any tobacco products (including smokeless tobacco) or electronic cigarettes in any indoor facilities under the control of the applicant. Tobacco-free indoors and in adjacent outdoor areas – no use of any tobacco products or electronic cigarettes in any indoor facilities, within 50 feet of doorways and air intake ducts, and in courtyards under the control of the applicant. Tobacco-free campus – no use of any tobacco products or electronic cigarettes in any indoor facilities and anywhere on grounds or in outdoor space under the control of the applicant. Nutrition: Healthy food service guidelines that at a minimum align with Health and Human Services and General Services Administration Health and Sustainability Guidelines for Federal Concessions and Vending Operations for cafeterias, snack bars, and vending machines in any facility under the control of the recipient organization and in accordance with contractual obligations for these services. The following are resources for healthy eating and tobacco free workplaces: - http://www. However, no applicants will be evaluated or scored on whether they choose to participate in implementing these optional policies. This includes ensuring your programs are accessible to persons with limited English proficiency. Recipients of federal financial assistance must take the reasonable steps to provide meaningful access to their programs by persons with limited English proficiency. For purposes of this announcement, “public health data” means digitally recorded factual material commonly accepted in the scientific community as a basis for public health findings, conclusions, and implementation. Cooperative Agreement Therms and Conditions The following special terms of award are in addition to, and not in lieu of, otherwise applicable U.

top avana 80 mg

Dose recommendations range from one or two 150-mg tablets top avana 80 mg, standardized to contain at least 0 80 mg top avana. Commercial preparations of feverfew leaves are known to vary widely in parthenolide content top avana 80mg. Plants from commercial sources and dark-leafed vari- eties have lower mean parthenolide levels than plants from wild-collected seeds and light green– or yellow–leafed varieties 80mg top avana. Although reviews of randomized , placebo-controlled , double-blind trials suggest that feverfew prevents migraine more effectively than placebo ,3 ,4 a large , methodologi- cally rigorous trial failed to demonstrate a significant difference between the clinical efficacy of feverfew and placebo . However, the dose and circumstances of parthenolide use are likely to be critical. Allergic contact dermatitis, mouth ulcers, and a swollen, tender tongue or lips may result from chewing fresh leaves. Feverfew—like fish oils, garlic, Gingko biloba, and willow bark—increases the potential for bleed- ing in patients who are taking aspirin. Chapter 63 / Feverfew (Tanacetum parthenium) 515 ● Treatment may be required for more than 4 months before clinical benefits are achieved. Involvement of sesquiterpene lactones and other components, Biochem Pharmacol 43:2313-20, 1992. Fish is the major dietary source of long-chain omega-3 (ω-3) polyunsaturated fatty acids. Linolenic acid and linoleic acid, an 18 carbon ω-6 polyun- saturated fatty acid, are both essential fatty acids. The long- chain ω-3 polyunsaturated fatty acids dampen inflammation and modulate immunity. Patients with immune disorders are often found have deficiencies of ω-3 fatty acids. Animal studies have shown that fish oil has an anti-inflamma- tory and immunomodulatory effect. This can cause subtle changes in receptor function, alterations in cell signaling mechanisms, and mem- brane-bound enzyme activity. Through their ability to modulate the activ- ity of protein kinase C and T-cell and B-cell responses, lymphokine secre- tion, cell proliferation, free radical generation, and lipid peroxidation, these polyunsaturated fatty acids have antimutagenic and antimicrobial (includ- ing antiviral) properties. Thromboxane A3 is a weak platelet aggregator and vasoconstrictor, and prostacyclin is a vasodilator and inhibitor of platelet aggregation. Fish oil affects lipid metabolism by decreas- ing both very low density lipoproteins and triglycerides as a result of inhi- bition of hepatic triglyceride synthesis. Flaxseed, also called linseed, is a potent source α-linolenic acid and contains ω-6 fatty acids and lignans. Department of Agriculture has not established a recommended daily intake for ω-3 fatty acids, but Canada recommends that 0. Fish is the best source of long-chain ω-3 fatty acids, and at least one meal that includes fish per week is recommended. People who do not eat fish should consider obtaining at least 200 mg of very-long-chain ω-3 fatty acids daily from other sources. The risk of vascular occlusion is reduced by changes in the eicosanoid profile and nitric oxide, which decrease the risk of vasospasm and thrombosis. Research suggests that relatively small intakes of ω-3 fatty acids are cardioprotective and may operate by stabilizing the myocardium itself. Fish oil significantly lowers serum triglyceride levels in patients with hyperlipidemia but is only marginally effective in individuals with normal lipid levels. Several dou- ble-blind, placebo-controlled trials of γ-linolenic acid and fish oil have demonstrated significant improvements in various clinical parameters; it has been suggested that these polyunsaturated fatty acids should be included as part of the normal therapeutic approach to rheumatoid arthritis. Analysis of randomized, controlled trials, in which marine ω-3 fatty acid supplementation was compared with placebo in patients with asthma, showed no consistent effect on forced expiratory vol- ume in 1 second, peak flow rate, asthma symptoms, asthma medication use, or bronchial hyperreactivity after 4 or more weeks. Daily treatment with ω-3 fatty 522 Part Three / Dietary Supplements acids may reduce hypercalciuria in patients who have kidney stones and may benefit those receiving maintenance hemodialysis by helping to control immunoglobulin A nephropathy. Ajiro K, Sawamura M, Ikeda K, et al: Beneficial effects of fish oil on glucose metabolism in spontaneously hypertensive rats, Clin Exp Pharmacol Physiol 27:412-5, 2000. Tidow-Kebritchi S, Mobarhan S: Effects of diets containing fish oil and vitamin E on rheumatoid arthritis, Nutr Rev 59:335-8, 2001. Mischoulon D, Fava M: Docosahexanoic acid and omega-3 fatty acids in depression, Psychiatr Clin North Am 23:785-94, 2000. Kontogiannea M, Gupta A, Ntanios F, et al: Omega-3 fatty acids decrease endothelial adhesion of human colorectal carcinoma cells, J Surg Res 92:201-5, 2000. Bougnoux P: N-3 polyunsaturated fatty acids and cancer, Curr Opin Clin Nutr Metab Care 2:121-6, 1999. Calviello G, Palozza P, Piccioni E, et al: Dietary supplementation with eicosapentaenoic and docosahexaenoic acid inhibits growth of Morris hepatocarcinoma 3924A in rats: effects on proliferation and apoptosis, Int J Cancer 75:699-705, 1998. Danno K, Sugie N: Combination therapy with low-dose etretinate and eicosapentaenoic acid for psoriasis vulgaris, J Dermatol 25:703-5, 1998. Polyphenols are a large and diverse class of compounds, many of which occur naturally in a wide range of plant foods. The more clinically important flavonoids are categorized as flavonols, flavones, catechins, flavanones, antho- cyanidins, and isoflavonoids. Many plant polyphenols are either being actively developed or currently sold as dietary supplements and/or herbal remedies. Flavonoids and carotenes are largely responsible for the color in fruit and vegetables. In plants, flavonoids act as antioxidants, antimicrobials, photoreceptors, and visual attractors; they also repel feeding insects. Animal and human studies suggest that flavonoids have potential as antiallergenic, antiviral, anti-inflammatory, vasodilating, and antioxidant agents. An oxy group at position 4, a dou- ble bond between carbon atoms 2 and 3, or a hydroxyl group in position 3 of the C (middle) ring enhances potency, especially antioxidant and antiprolif- erative activity. Such cells include mast cells, basophils, neutrophils, eosinophils, T and B lymphocytes, macrophages, platelets, smooth muscle cells, and hepatocytes. Although flavonoids are widely distributed, certain fruits and vegetables are better sources of particular flavonoids. Bilberry is the preferred source of anthocyanosides, soy products are a good source of genistein, and epigallocatechin gallate is found in green tea. Of the flavanols, proanthocyanidins are widely available naturally occurring plant metabolites found in wine, cranberries, and the leaves of bilberry, birch, ginkgo, and hawthorn. Among the medicinal botanicals rich in flavonoids are Ginkgo biloba, Hypericum perforatum (St. Eating the white pulp of cit- rus fruits and the peel of apples can enhance dietary intake. However, processing ensures that small volumes of wine provide a more potent concentration of flavonoids. Although flavonoids are present in both black and green tea, green tea appears to be a stronger antioxidant than black tea. The maximum effect of flavonoids in green tea peaks earlier, around 30 minutes after consumption. In fact, despite a considerable amount of in vitro data, some animal and epidemiologic stud- ies, plus a few well-controlled human trials, it is premature to recommend specific polyphenolic supplements at specific doses in the human popula- tion. Flavonoids present in foods used to be con- sidered nonabsorbable because they are bound to sugars as β-glycosides. More recently, however, it was found that human absorption of the quercetin glycosides from onions (52% absorption) is better than that from the pure aglycone (24%). They have demonstrated preferential binding to areas characterized by a high content of glycosaminoglycans, such as epidermis, capillary wall, and mucosa. Their antioxidant, antibacterial, antiviral, anti- carcinogenic, anti-inflammatory, antiallergic, and vasodilatory actions make them clinically versatile. They are regarded as particularly useful for enhanc- ing perfusion and increasing vascular integrity. Experimental studies suggest that flavonols and flavones are effective free radical scavengers, metal chelators, and antithrombotic agents. Some epidemiologic studies suggest an inverse association between intake of flavonols and flavones and the risk of cardiovascular disease. In a ran- domized, double-blind, placebo-controlled trial, in which subjects had daily supplementation of α-tocopherol (50 mg/day) and/or beta-carotene (20 mg/day), dietary analysis showed that, compared with men consuming 4 mg/day, those ingesting 18 mg of flavonols and flavones per day had a decreased risk of nonfatal myocardial infarction. The citrus flavonoids show little effect on normal, healthy cells and thus typically exhibit remark- ably few toxic effects in animals. On the other hand, at higher doses, certain flavonoids may act as mutagens, prooxidants that generate free radicals, and as inhibitors of key enzymes involved in hormone metabolism. Chapter 65 / Flavonoids 529 ● In addition to a high-fiber diet and drinking lots of fluids, consumption of berries, which are rich in proanthocyanidins, may prevent bleeding hemorrhoids. Diefendorf D, Healey J, Kalyn W, editors: The healing power of vitamins, minerals and herbs, Surry Hills, Australia, 2000, Readers Digest. Middleton E Jr: Effect of plant flavonoids on immune and inflammatory cell function, Adv Exp Med Biol 439:175-82, 1998. Mills S, Bone K: Principles and practice of phytotherapy, Edinburgh, 2000, Churchill Livingstone. Brighthope I: Nutritional medicine tables, J Aust Coll Nutr Env Med 17:20-5, 1998. Hirvonen T, Pietinen P, Virtanen M, et al: Intake of flavonols and flavones and risk of coronary heart disease in male smokers, Epidemiology 12:62-7, 2001. Kobayashi T, Nakata T, Kuzumaki T: Effect of flavonoids on cell cycle progression in prostate cancer cells, Cancer Lett 176:17-23, 2002. Fluoride is of potential value in the prevention of dental caries and the treatment of postmenopausal osteoporosis. More than 90% of retained fluoride is deposited in the skeleton; the remainder is excreted in the urine. The margin of safety for fluoride is about 100:1 between the dosage effective for reversal of osteoporotic lesions in the elderly and a toxic level for adults not forming teeth. Dietary sources of fluoride are tea and seafood; fluoride-enriched toothpaste is also readily available. Supplementation in the form of sodium fluoride at levels around 60 mg should always be accompanied by an adequate calcium intake. Potentially toxic adult levels are reached when 10 mg is taken for a prolonged period. In fact, optimal (1 ppm) water fluor- idation is seen as the most socially equitable way to prevent dental caries. Studies strongly suggest that fluoride at concentrations of up to 1 ppm has no adverse effect on bone strength, bone mineral density, or fracture inci- dence. Its effect on bone mineral content has consequences for bone structure and function and for the treatment of osteoporosis. At higher con- centrations with greater skeletal uptake, fluoride may cause the formation of abnormally mineralized bone of impaired quality. Concern has been expressed that fluoride may increase bone density without increasing bone strength. A meta-analysis to determine the efficacy of fluoride therapy in preventing bone loss and vertebral and nonvertebral fractures in post- menopausal women indicated that although fluoride has the ability to increase bone mineral density at the lumbar spine, it does not result in a reduction in vertebral fractures. On the other hand, a combination of sustained-release sodium fluoride, calcium citrate, and cholecalciferol significantly decreased the risk for vertebral fractures and increased spinal bone mass without reducing bone mass at either the femoral neck or total hip. Osteosclerosis Chapter 66 / Fluoride 533 is most marked in the vertebrae and pelvis. It must be emphasized that a bone with increased radiologic density caused by fluoride incorporation is not necessarily stronger or harder. With fluoride accumulation from a diet with a fluoride concentration of greater than 5000 ppm, bone changes include the following: ● Patchy osteoporosis ● Patchy osteosclerosis/hypermineralization ● Bands of uncalcified osteoid tissue, as seen in osteomalacia ● Severe chronic osteofluorosis (On microscopic examination, this manifests as a mixture of normal bone and dense, rarefied, disorganized bone. Calcification of ligaments and tendons can present clinically as a poker spine or hunch back. After 3 years of fluoride treatment, patients with osteoporosis supplemented with calcium and 30 to 60 mg fluoride each day had a reduced fracture rate compared with those not receiving fluoride. Fluoride, although not without risk, is worthy of consideration in osteoporosis treatment. Early signs of possible chronic fluoride overdose are bone pain, skin rashes, and tooth discoloration. A two-year caries clinical trial on children in New Jersey and Puerto Rico, Am J Dent 13: 221-6, 2000. Newbrun E: Topical fluorides in caries prevention and management: a North American perspective, J Dent Educ 65:1078-83, 2001. Haguenauer D, Welch V, Shea B, et al: Fluoride for the treatment of postmenopausal osteoporotic fractures: a meta-analysis, Osteoporos Int 11:727-38, 2000. Folate coenzymes are involved in the synthesis of nucleic acids, interconversion of amino acids, and single-carbon metabolism (e. Folate is involved in the formation of glutamic acid, norepinephrine, and serotonin. It is critical to the formation of nucleic acid and has an impor- tant role in cell maturation. Folate deficiency has a particularly adverse effect on the neural tube, erythrocytes, and epithelial cells of the gastrointestinal tract. The low cost and safety profile of folic acid favor its empiric supplementation in recom- mended doses. Folate defi- ciency leads to impaired cell division, a problem that becomes apparent first in rapidly regenerating tissue (e. Folate is involved in amino acid metabolism, including the synthesis of serine from glycine and the methylation of homocysteine to methionine. Methionine is activated by adenosine triphosphate to produce S-adenosyl- methionine, the primary intracellular methyl donor. It is best to eat fresh fruits and vegetables when- ever possible, since they contain the most vitamins. Dietary folates are a complex and vari- able mixture of compounds that are readily destroyed.

A prodrome must allow time for a driver to fnd a safe place to stop before losing consciousness 80 mg top avana. A prodrome is reliable if the signs are clear 80mg top avana, consistent across all events and provide suffcient duration to fnd a safe stop top avana 80mg, or unreliable if these are absent top avana 80 mg. Must not drive until annual risk of Must not drive until annual risk of recurrence is assessed as below 20% . Otherwise must not drive until annual risk of recurrence is assessed as below 20% . Driving may resume after 4 weeks Driving may resume after 3 months only if the cause has been identifed only if the cause has been identifed and treated . Group 1 Group 2 car and motorcycle bus and lorry Unexplained syncope , including syncope without reliable prodrome This diagnosis may apply only after appropriate neurological and/or cardiological opinion and investigations have detected no abnormality . If no cause has been identifed , the If no cause has been identifed, the licence will be refused or revoked for licence will be refused or revoked for 12 months. If there are factors that would lead to Driving may resume after 3 months an increased risk of recurrence, then 1 only if the cause has been identifed year off driving would be required. If no cause has been identifed, the licence will be refused or revoked for 2 years. Blackout with seizure markers This category is for those where on the balance of probability there is clinical suspicion of a seizure but no defnite evidence. Depending on previous medical Depending on previous medical history, the standards for isolated history, the standards for isolated seizure or epilepsy will apply. Must not drive for 6 months following Must not drive for 12 months following a single episode and for 12 months a single episode and 5 years following following multiple episodes over multiple episodes over 5 years. If more than one episode of cough If more than one episode of cough syncope occurs within a 24 hour syncope occurs within a 24 hour period, this will be counted as a single period, this will be counted as a single event. However if the episodes of cough syncope are more than 24 hours cough syncope are more than 24 hours apart, these are considered as multiple apart, these are considered as multiple episodes. Primary/central hypersomnias – including narcolepsy and the narcolepsy/cataplexy syndrome For other causes of excessive sleepiness, see Chapter 8 (miscellaneous conditions). A licence may be reissued only when Relicensing may be considered subject there has been satisfactory symptom to specialised assessment and a control for at least 3 months before satisfactory objective assessment of being considered for re-licensing. For information on in-car driving assessments for those with a disability, see Appendix G (page 133). May drive as long as safe vehicle May drive as long as safe vehicle control is maintained at all times. If driving is not impaired and the The licence may specify a restriction to underlying condition is stable, licensing cars with certain controls. May drive as long as safe vehicle May drive as long as safe vehicle control is maintained at all times. If the individual’s condition is disabling If the individual’s condition is disabling and/or there is clinically signifcant and/or there is clinically signifcant variability in motor function, the licence variability in motor function, the licence will be refused or revoked. If driving is not impaired, licensing will If driving is not impaired, licensing will be considered subject to satisfactory be considered subject to satisfactory medical reports. Dizziness – liability to sudden and unprovoked or unprecipitated episodes of disabling dizziness Sudden is defned as ‘without suffcient warning to allow safe evasive action when driving’ and disabling is defned as ‘unable to continue safely with the activity being performed’. When satisfactory control of symptoms If there are sudden and disabling has been achieved, relicensing may be symptoms, the licence will be refused considered for restoration of the ’til 70 or revoked. If an underlying diagnosis is likely to cause recurrence, the patient must be asymptomatic and completely controlled for 1 year from an episode before reapplying for their licence. With adaptations, is no previous history of cardiovascular severe physical impairment may not be disease, a licence may be issued an obstacle to driving. If the level of stenosis is severe enough to warrant surgical or radiological intervention, the requirements for exercise or other functional test must be met – see Appendix C, page 121. May drive unless prophylactic treatment medication for seizures is prescribed, in which case an individual assessment will be required. Driving may resume after 6 months Driving will remain prohibited for provided there is no visual feld defect. If the tumour is associated with seizure, relicensing will not be considered until 10 years after surgery, provided these years are then free from seizures without epilepsy medication. Relicensing may be considered after 2 scans performed 12 months apart show no growth. Individual assessment will be considered if such lack of growth cannot be demonstrated. Driving may resume after 12 months provided there is no debarring residual impairment likely to affect safe driving. Driving may resume on recovery from Driving may resume on recovery from treatment. Malignant brain tumours – including metastatic deposits and pineal tumours The standards will apply to frst occurrence, recurrence and progression. Driving may resume 1 year after The licence will be refused or revoked completion of primary treatment. If these criteria cannot be met, a further 1 year off driving will be required following completion of primary treatment or following seizure. Driving may resume 2 years after the The licence will be refused or revoked completion of primary treatment. For those receiving immunotherapy and other molecular target treatments licensing will be considered by individual assessment. Relicensing may be considered 1 year The licence will be refused or revoked after completion of the primary treatment permanently. If these criteria cannot be met then driving must cease for 2 years following completion of primary treatment. For those receiving immunotherapy and other molecular target treatments licensing will be considered by individual assessment. Relicensing may be considered 1 year Relicensing may be considered after completion of the primary treatment 5 years after completion of the if the patient is otherwise well. If there has been a small subarachnoid haemorrhage but the bullet points above can otherwise be satisfed, and there is documented evidence of a full clinical recovery, driving may resume after 6 months. Subdural haematoma With any procedure, if another one is also undertaken (for example, a ventriculoperitoneal shunt and a craniotomy for a haematoma), the standards for that procedure also apply, and may take precedence. Resume driving on recovery if no At least 6 months off driving and will underlying lesion. Refusal or revocation: May be able to return to driving when risk of seizure has fallen to no greater than 2% per annum. Will need clinical confrmation of Relicensing may be considered after recovery and a documented normal 6 months provided comprehensive cerebral angiogram. Relicensing will not be considered until after at least 2 years and a specialist assessment. Annual seizure risk should be no greater than 2% and there should be no residual impairment likely to affect driving. Relicensing will not be considered until after at least 2 years and a specialist assessment. Annual seizure risk should be no greater than 2% and there should be no residual impairment likely to affect driving. Driving may resume following clinical Relicensing may be considered after recovery. Driving may resume following clinical Driving may resume following clinical recovery. Driving may resume after 1 month The licence will be refused or revoked provided there is no debarring residual permanently. There must be no debarring residual The licence will be refused or revoked impairment likely to affect safe driving. Relicensing may be considered without the need for review on confrmation of complete obliteration provided there is no debarring residual impairment likely to affect safe driving. Relicensing may be considered on an Relicensing may be considered on an individual assessment. Cavernous malformation Cavernomas are also known as cavernous malformations, cavernous angiomas, or cavernous haemangiomas. The risk of events that might affect driving differs according to cavernoma location (brainstem versus other locations) and symptoms attributable to the cavernoma (stroke versus epileptic seizure versus no symptoms). A person’s age, the number of cavernomas, and the size of the cavernoma do not seem to affect these risks. With multiple cavernomas, licensing restrictions differ according to cavernoma location, symptoms, or treatment. The epilepsy regulations (see Appendix B, The epilepsy regulations (see Appendix B, page 116) apply if there is a history of page 116) apply if there is a history of seizure. Driving will depend on the following: There must be no debarring residual there must be no debarring residual impairment likely to affect safe driving. Given that there is a very high prospective risk of seizure, it will be 10 years before relicensing may be considered and there must have been no seizures and no treatment for seizures in that time. Driving may resume on recovery Relicensing may be considered after providing there are no complications. If the hydrocephalus is asymptomatic, Driving will be allowed to continue if driving may continue under the ’til 70 the hydrocephalus is asymptomatic licence. May be relicensed after 6 months May be relicensed/licensed after a if there is no debarring residual minimum of 6 months depending impairment likely to affect safe driving. The prospective risk from the The prospective risk from the underlying condition must be underlying condition must be considered. Implanted electrodes Group 1 Group 2 car and motorcycle bus and lorry Deep brain stimulation for movement disorder or pain Must not drive until clinical Must not drive and must notify confrmation of recovery. May drive if: Fitness to drive may be assessed for there are no complications from relicensing if: surgery there are no complications from the patient is seizure-free surgery there is no debarring residual the patient is seizure-free with impairment likely to affect safe an underlying condition that is driving. If the aetiology is cerebral – stroke, for example – may be relicensed/licensed after 12 months provided there is no debarring residual impairment likely to affect safe driving. May be relicensed/licensed (provided Driving may resume after satisfactory there is no other disqualifying symptom control. If not treated by successful coronary intervention or any of the above are not met, driving may resume only after 4 weeks from the acute event, provided there is no other disqualifying condition. Driving may resume after 1 week Driving may resume after 6 weeks provided there is no other disqualifying provided there is no other disqualifying condition. Licence will be refused or revoked until Licence will be refused or revoked pacemaker implanted. Driving may resume after 6 months Licence will be refused or revoked following implantation – except that permanently. Licence will be refused or revoked (whether incapacity Exceptions to this 2 year requirement permanently. If therapy delivery was due to an inappropriate cause such as atrial fbrillation or programming issues: driving may resume 1 month after complete control of any cause to the satisfaction of the cardiologist. If therapy delivery was appropriate due to sustained ventricular tachycardia or ventricular fbrillation, driving may resume 6 months after event: provided preventive steps against recurrence have been taken with anti-arrhythmic drugs or ablation procedure, for example and there is an absence of further symptomatic therapy. Driving may resume 1 week after Licence will be refused or revoked box change provided there is no other permanently. Note: for Group 2 cases, the exercise or other functional test requirements will need to be met in all cases of abdominal aortic aneurysm irrespective of the diameter. Note: the exercise or other functional test requirements will need to be met in all cases of abdominal aortic aneurysm irrespective of the diameter. May be relicenced/licensed after successful surgical treatment without evidence of futher enlargement and no other disqualifying condition. Note: the exercise or other functional test requirements will need to be met in all cases of abdominal aortic aneurysm irrespective of the diameter. May be relicenced/licensed after successful surgical treatment without evidence of further enlargement and no other disqualifying condition. In cases of bicuspid aortopathy, In cases of bicuspid aortopathy, maximum aortic diameter should be maximum aortic diameter should be less than 6. If any of the above apply, the maximum aortic diameter allowed would be less than 5cm. Note: the exercise or other functional test requirements will need to be met in all cases of abdominal aortic aneurysm irrespective of the diameter. Driving may resume only after May be relicensed/licensed only after satisfactory surgical intervention and/or: satisfactory surgical intervention and/ satisfactory medical therapy (blood or all the following are met: pressure well controlled) satisfactory medical therapy (blood medical follow-up pressure well controlled) no other disqualifying condition. Relicensing will be considered only if: maximum aortic diameter is less than 5cm no family history of aortic dissection no severe aortic regurgitation is under annual cardiac review to include aortic root measurement. If there is a family history of dissection, relicensing will only be allowed if aortic diameter is less than 4. Elective aortic root surgery – individual assessment (see Appendix C, page 121 for full details). For aortic root replacement, driving may be relicensed after an individual assessment (see Appendix C, page 121). There must be no other disqualifying May be relicenced/licensed only if: condition. Also refer to the following sections in this document: arrhythmias (page 53) pacemaker implant (page 54) implantable cardioverter defbrillator (page 55). There must be no other disqualifying Must not drive if in the High Risk group condition. If in the Low Risk or Intermediate Risk group licensing will be permitted if the exercise tolerance test requirements are met with at least a 25mm Hg increase in systolic blood pressure during exercise testing (testing to be repeated every 3 years) (see Appendix C for details). If there is a history of associated syncope the standards for syncope need to be met in addition. May be relicensed/licensed following specialist electrophysiological assessment, provided there is no other disqualifying condition. Relicensing may be permitted if: May be relicensed/licensed once the applicant is on treatment arrhythmia is controlled, provided there is no other disqualifying condition. A 1–3 year licence may be considered if the specialist electrophysiological review is satisfactory.

Zinc-induced deterioration in Wilson’s disease accumulation in the liver of male patients with Wilson disease 80 mg top avana. Am J aborted by treatment with penicillamine 80mg top avana, dimercaprol top avana 80mg, and a novel zero Gastroenterol 2001;96:3147–3151 top avana 80 mg. Chelation treatment of neurological Wilson’s in vitro and in vivo interaction of D-penicillamine and triethylene- disease . N Engl J [134] von Herbay A , de Groot H , Hegi U , Stremmel W , Strohmeyer G , Sies H. Liver transplantation for Wilson’s comparison of tetrathiomolybdate and trientine in a double-blind study of disease: indications and outcome. Adverse reaction after tetrathiomolybdate treatment for Wilson’s disease: Liver transplantation in neurologic Wilson’s disease. Outcomes of living- deficiency induced by tetrathiomolybdate suppresses tumor growth and related liver transplantation for Wilson’s disease: a single-center experi- angiogenesis. Neurological presentation of term treatment in Wilson’s disease (hepatolenticular degeneration). Pregnancy in penicillamine-treated patients with [154] Rubinfeld Y, Maor Y, Simon D, Modai D. Wilson’s disease presenting with features of hepatic dysfunc- pregnancies and abortions in symptomatic and asymptomatic Wilson’s tion: a clinical analysis of eighty–seven patients. The Facility will work closely with all stakeholders in the field of antibiotic research and development (R&D) – including pharmaceutical and biotechnology companies, startups, other product development partnerships, academia, civil society, and health authorities – from countries of all income levels to develop new antibiotic treatments. In the short term, the Facility will start by identifying priorities for the development of new antibiotics and antibiotic regimes not addressed by other actors. Based on this analysis, it will launch short-term R&D projects to develop needed new therapeutic solutions, such as missing paediatric formulations, combinations, new formulations, or improved regimens of existing antibiotics. In the long term, the Facility will develop a broader portfolio of new antibiotic treatments and see them through to registration. Carefully aligned with existing initiatives that invest in new antibiotics, the Facility’s uniqueness lies in addressing global public health needs and placing emphasis on products or projects that industry does not invest in. A partnership model for product development based on the experience with neglected diseases is an important element of the overall strategy. Such a partnership can test alternative incentives that also contribute to conservation of and access to new antibiotics such as milestone prizes, buy-outs, and staggered end-stage prizes/payments. By doing so, a product development partnership will provide an important alternative to the traditional profit-oriented pharmaceutical approach. Research and product development: • develop improved formulations or combinations that may prolong the life of existing antibiotics through short-term product development projects; • work with partners on rapid and (near) point-of-care diagnostics; and • support innovative and paradigm-shifting approaches to the development of new antibiotics. Conservation: • directly build in conservation strategies in the R&D process; and • propose conservation strategies for antibiotic treatments, taking into account issues related to animal husbandry. Access: • implement and test new incentive models enabling the de-linkage of the cost of R&D from the price of the product; and • promote access for all in need, while minimizing unnecessary and non-rational use. Public investment into development of new antibiotics should come with appropriate obligations to governments, regulators, producers, and distributors with respect to the marketing and responsible use of these new products to avoid the rapid build-up of drug resistance. Ultimately, the team will include professionals with backgrounds in public health, biomedical research, infectious diseases, health economics, antimicrobial research and development, product formulations, business development, financing, drug markets, and drug regulation. Central to this is the concept that patient care can be improved through the development of new tools or by optimization of existing tools. For example, in the case of malaria, significant improvement in care and delay of emerging resistance has been achieved through drug combination use, new fixed-dose combinations including paediatric formulations, and rapid diagnostic tests. Thus, the management of many bacterial infections, often presenting as main syndrome fever, remains empirical. Restricting use alone is not the answer in low- and middle-income countries where still more children die from lack of access to treatment than from drug resistant bacteria. Determining whether a sick infant needs an antibiotic is complicated by a lack of simple diagnostic tests and appropriately adapted quality assured formulations. Currently, there is a growing risk of drug resistance in important pathogens causing (gram-negative) sepsis and diseases such as typhoid and gonorrhea. In low- and middle-income countries, neonates and children are particularly vulnerable sub-groups. The Facility will focus on these global health needs, address specific barriers to improving patient care, and promote responsible use of antibiotics. These three objectives can be broken down to short-, medium-, and long-term projects that will be further elaborated below. The Facility will ensure its work does not duplicate that of other initiatives and organizations. It will also ensure that relevant research ongoing in existing spheres can be appropriately transferred to meet low- and middle-income country needs and contexts. Active partnerships will play a key role in translating proposed interventions into concrete outcomes. These ideas are ‘placeholders’ to demonstrate the potential scope of the Facility, but have not yet undergone a thorough scientific review. More work needs to be done to develop a complete rationale for these and additional projects to be examined in the coming months. Projects will be developed according to disease priorities, but also according to gaps and opportunities, especially for already-existing antibiotics. Such examples could include a rapid diagnostic test that can differentiate bacterial and viral infections, a multiplex (fever) test to accurately diagnose important bacterial infections, and tests that can accurately identify resistance to specific antibiotics. Such potential tests already have analogies such as a rapid diagnostic test for malaria or the assay for the simultaneous detection of tuberculosis and rifampicin resistance directly from sputum. Potential diagnostic tests may also be important for identifying future epidemiological trends and hence needs, and accelerating the clinical testing of new antibiotics. In summary, the Facility, from a scientific perspective will add value by: • covering neglected areas, e. The fact that traditional market incentives will not guide the development strategies of the Facility will allow for a public health needs focus. It will also allow for taking conservation into account in the design of the R&D pipeline, so that conservation and access are built together into the product development. When bringing products to the market, the Facility, with its industry partners, will develop innovative approaches in packaging and labelling that support responsible use. It will also cover the resources required to raise further funding for new projects and the subsequent phases of the Facility. It compromises global human development, threatens the achievements of modern medicine, and undermines economic development and stability of social systems. The combined result of increased bacterial resistance against current antibiotics and the lack of research to identify new classes of antibiotics threatens human health at a global level. Industry mostly abandoned the field of antibiotic R&D because of its limited financial attractiveness, the scientific challenges inherent to antibiotic drug discovery, and the complex regulatory framework. This has partly contributed to the emergence of untreatable, multi-resistant strains of pathogens that are killing an increasing number of people worldwide. The need for new measures and incentives to overcome bottlenecks in the development of new antibiotics is widely recognized. A number of initiatives have been launched in the past years that aim to reinvigorate the antibiotic R&D pipeline. While this development is positive, even taken together, the initiatives still fall short of providing all the necessary tools to cope with the magnitude of the public health challenges faced today. In June 2015, the G7 therefore identified a need to: ‘engage in stimulating basic research, research on epidemiology, infection prevention and control, and the development of new antibiotics, alternative therapies, vaccines and 3 rapid point-of-care diagnostics’. It calls for new concepts for providing incentives to innovation and promoting cooperation between policy-makers, academia, and the pharmaceutical industry. The initial phase is aimed at defining, with the help of Member States, industry, academia, civil society, and other experts and stakeholders: the scope of the Facility; its governance model; the needs at a global level and specific gaps in developing countries; a set of short-term projects to be initiated, and the long-term priorities. The latter ensures that any new product has the necessary characteristics to respond to unmet needs worldwide and is not restricted to the health systems of some developed countries. In recent years, several important programmes have been set up to support antibiotic research in 5 various countries. It should be noted that these activities fall entirely under the responsibility of the pharmaceutical partners of the consortium. Facility complementarity: The Facility will focus on the short and medium term to address certain urgent needs (see ‘The Global Scientific Strategy’ section below) and on the specific needs of developing countries. Joint Programming is used in different areas to overcome the fragmentation of national research programmes in particular where challenges are global in nature. The latter is implemented through launching joint calls for proposals to facilitate cross-border research projects. The Review will assess the extent to which market failure is responsible for the lack of investment in R&D of new antimicrobials and short-, medium-, and long-term interventions, which could be undertaken by governments and 8 other funders to stimulate investment in new antimicrobials for human use. In 2015, the Review published initial proposals to kick-start antibiotic drug discovery efforts at a global level. The proposals include channeling new funds into early-stage research as well as creating a fund for product development to buy out new major breakthroughs. The latter would ensure a predictable and viable market for new antibiotics and, by doing so, provide an incentive for companies to 9 invest. Facility complementarity: The Facility fits very well into this new landscape and could become one of the implementers for R&D under the proposed R&D fund. Other treatments delivered include a set of treatments for visceral leishmaniasis in Asia, a combination therapy for visceral leishmaniasis in Africa, a paediatric dosage form of an existing drug for the treatment of Chagas disease, and a combination therapy for the treatment of human African trypanosomiasis. The R&D conducted has been made possible by the partnerships developed with 130 entities worldwide, including over 20 pharmaceutical companies and 9 biotechnology companies, and through the set up of three clinical research platforms, which build capacity while conducting clinical research in resource-limited settings. The basic diag- Guidelines on diagnosis and treatment of Wilson’s nostic approach includes serum ceruloplasmin and 24-hour urinary copper disease concerning mainly adults. What Is New Pharmacological treatment is life-long and aims at removal of copper excess by chelating agents as D-penicillamine, trientine, or inhibition of intestinal The most updated systematic review of literature copper absorption with zinc salts. Acute liver failure often requires liver related mainly to management of Wilson’s disease transplantation. Dzieci Polskich 20, 04-730 Warszawa, Poland Medical Center Utrecht, Utrecht, The Netherlands, the yyDepartment of (e-mail: w. Diagnosis Hepatology, Gastroenterology and Nutrition, King’s College Hospital, and treatment is at the discretion of physicians’’. Articles in languages other in progressive toxic accumulation of copper in the liver that begins than English and French, animal studies, and abstracts presented in infancy when copper-containing solids are introduced in the diet. Moderate (B): Further research is likely to have impact on our for adults may not be appropriate (3,4). Expert opinion supported tions, systematic reviews, prospective, and retrospective cohort or recommendations where the evidence was regarded as weak. Grade 1A (91%) 5 Copper estimation in the liver tissue could be helpful in children where the diagnosis is uncertain. Grade 1A (100%) 7 Given its safety profile, zinc salts, preferably zinc acetate, could be used in presymptomatic children identified through family screening, or as maintenance therapy after de-coppering with chelators as long as serum transaminase levels remain normal. Grade 2B (96%) 9 Dietary restriction of copper-rich foods is advised until remission of symptoms and normalization of liver enzymes in children treated with copper chelating agents. Grade 1A (100%) 11 Children with decompensated liver cirrhosis should be treated with a chelating agent or a combination of zinc salts and a chelating agent that may preclude the need for a liver transplantation. Grade 2B (96%) 12 Because liver transplantation corrects the enzymatic defect, chelating agents or zinc treatment is no longer required after transplantation. Grade 1A (96%) 13 All children should be closely followed-up during the first month following initiation of therapy, then every 1 to 3 months until remission, and every 3 to 6 months thereafter. Grade 1C (100%) 14 Monitoring includes physical examination, biochemical tests (ie, blood cell count, liver function tests, urea, creatinine, proteinuria), serum copper, and 24-hour urinary copper to assess efficacy, overdosage, or non-adherence to therapy and adverse events. Grade 1C (96%) 15 Evidence for non-adherence to zinc can be assessed by measuring serum zinc levels and/or urinary zinc/copper 24-hour excretion. Grade 2B (91%) 16 If increased transaminases remain or relapse despite treatment, poor compliance should be suspected. Grade 2B (96%) 17 The occurrence of penicillamine-related adverse events should prompt discontinuation and switching to trientine or zinc salts according to the severity of liver disease. Most Mild cognitive impairment such as working memory and language children present with liver disease (6) ranging from incidental difficulties, however, seems quite frequent (23). The prevalence of increased serum transaminases, was the most common presenting acute hemolysis was 6. But, an earlier onset at 3 years of age disease or nonalcoholic steatohepatitis (16), and autoimmune hep- has been reported (14). Low-titer autoantibodies have also been described in children, usually as case reports (mainly antinuclear antibodies) are commonly found in patients (Table 2). Urinary Copper Excretion Ceruloplasmin In asymptomatic children or children with mild liver disease, urinary copper values are often normal. The reported optimal basal Ceruloplasmin is a copper-carrying protein that is bound to urinary copper diagnostic cut-off value is 40 mg /24 hours (0. Importantly, plastic or acid- glycosylation disorders, Menkes disease, protein caloric malnutri- washed glass containers should be used for urine collection to avoid tion, nephrotic syndrome, protein-losing enteropathy, acquired cop- contamination with copper. Predominant mutations have been 40 clinically asymptomatic children with elevated serum transami- reported in specific populations, such as in Eastern Europe nases (44). In addition, misleadingly elevated serum outside the coding regions and in adjacent intron/exon junctions levels may be seen when using the immunological-nephelometric of the gene and deletions can still be missed using these assay which measures both ceruloplasmin and the biologically techniques. Second, their high-yield comes with the risk of inactive apoform (45,46), the reason why the enzymatic assay identifying variants of unknown significance which pose diag- measuring oxidase activity should be the preferred method (46). Lower concentrations are reported in up to 20% of patients diseases associated with impaired bile secretion (63). The Scoring System accuracy of liver copper measurement is improved with an adequately sized specimen (preferably >1 cm long, min. It has also been proposed that 2 liver biopsy passes be eters and molecular diagnostics.

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