Edward Buckley, M.D.

• Department of Neurology
• Duke University Medical Center
• Durham, NC

Patients with acute respiratory illness may be at risk of serious acute exacerbation of their respiratory compromise due to hypersensitivity reactions allergy forecast orange county ca discount 10mg prednisone overnight delivery. Pre-medication and reduction of infusion rate may alleviate those reactions associated with the infusion [see Warnings and Precautions (5 allergy kit discount prednisone 5mg with amex. Morquio A Registry Inform patients of the Morquio A Registry established in order to better understand the variability and progression of the disease in the population as a whole allergy lotion order prednisone 20 mg otc, and to monitor and evaluate long-term treatment effects of Vimizim allergy medicine mixed with alcohol discount prednisone 10 mg otc. The Morquio A Registry will also monitor the effect of Vimizim on pregnant women allergy forecast pittsburgh cheap prednisone 40mg amex, nursing mothers and their offspring allergy medicine nasacort cheap 40mg prednisone with mastercard, and determine if Vimizim is excreted in breast milk. Patients should be encouraged to participate and advised that their participation is voluntary and may involve long-term follow-up. This indication is approved under accelerated approval based on tumor response rate and progressionfree survival. Urothelial Carcinoma · for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin-containing chemotherapy. This indication is approved under accelerated approval based on tumor response rate and duration of response. We acknowledge receipt of your major amendment dated March 9, 2017, which extended the goal date by three months. It is approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling text. We remind you of your postmarketing requirement specified in your submission dated May 17, 2017. For administrative purposes, all submissions relating to this postmarketing requirement must be clearly designated "Subpart E Postmarketing Requirement(s). This product is appropriately labeled for use in all relevant pediatric populations. Finally, we have determined that only a clinical trial (rather than a nonclinical or observational study) will be sufficient to assess a signal of cerebral edema in children with microsatellite high or mismatch repair deficient central nervous system tumors who are exposed to Keytruda. Prominently identify the submission with the following wording in bold capital letters at the top of the first page of the submission, as appropriate: "Required Postmarketing Final Report Under 505(o)", "Required Postmarketing Correspondence Under 505(o)". We remind you that to comply with 505(o), your annual report must also include a report on the status of any study or clinical trial otherwise undertaken to investigate a safety issue. The status summary should include expected summary completion and final report submission dates, any changes in plans since the last annual report, and, for clinical studies/trials, number of patients entered into each study/trial. All submissions, including supplements, relating to these postmarketing commitments should be prominently labeled "Postmarketing Commitment Protocol," "Postmarketing Commitment Final Report," or "Postmarketing Commitment Correspondence. Please ask to speak to a regulatory project manager or the appropriate reviewer to discuss this issue. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. Withhold or permanently discontinue for severe or lifethreatening hyperthyroidism. Withhold for moderate, and permanently discontinue for severe or life-threatening nephritis. This indication is approved under accelerated approval based on tumor response rate and progression-free survival. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Preparation for Intravenous Infusion Visually inspect the solution for particulate matter and discoloration prior to administration. The final concentration of the diluted solution should be between 1 mg/mL to 10 mg/mL. Storage of Reconstituted and Diluted Solutions the product does not contain a preservative. Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of reconstitution. If refrigerated, allow the diluted solution to come to room temperature prior to administration. Under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 24 hours from the time of dilution. Administration Administer infusion solution intravenously over 30 minutes through an intravenous line containing a sterile, non-pyrogenic, low-protein binding 0. Evaluate patients with suspected pneumonitis with radiographic imaging and administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater pneumonitis. Sixty-three (67%) of the 94 patients received systemic corticosteroids, with 50 of the 63 receiving high-dose corticosteroids for a median duration of 8 days (range: 1 day to 10. Pneumonitis occurred more frequently in patients with a history of prior thoracic radiation (6. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater colitis. Thirty-three (69%) of the 48 patients received systemic corticosteroids, with 27 of the 33 requiring high-dose corticosteroids for a median duration of 7 days (range: 1 day to 5. Thirteen (68%) of the 19 patients received systemic corticosteroids, with 12 of the 13 receiving high-dose corticosteroids for a median duration of 5 days (range: 1 to 26 days) followed by a corticosteroid taper. Monitor for signs and symptoms of hypophysitis (including hypopituitarism and adrenal insufficiency). Sixteen (94%) of the 17 patients received systemic corticosteroids, with 6 of the 16 receiving high-dose corticosteroids. Monitor patients for changes in thyroid function (at the start of treatment, periodically during treatment, and as indicated based on clinical evaluation) and for clinical signs and symptoms of thyroid disorders. Administer replacement hormones for hypothyroidism and manage hyperthyroidism with thionamides and beta-blockers as appropriate. Administer corticosteroids (initial dose of 1 to 2 mg/kg/day prednisone or equivalent followed by a taper) for Grade 2 or greater nephritis. For suspected immune-mediated adverse reactions, ensure adequate evaluation to confirm etiology or exclude other causes. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Based on limited data from clinical studies in patients whose immune-related adverse reactions could not be controlled with corticosteroid use, administration of other systemic immunosuppressants can be considered. Monitor patients for signs and symptoms of infusion-related reactions including rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Among the 2799 patients, 41% were exposed for 6 months or more and 21% were exposed for 12 months or more. The most common adverse reactions (reported in at least 20% of patients) were fatigue and diarrhea. Patients with autoimmune disease, medical conditions that required systemic corticosteroids or other immunosuppressive medication, or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. The study population characteristics were: median age of 63 years (range: 20 to 88), 42% age 65 years or older, 61% male, 72% white and 21% Asian, 8% with advanced localized disease, 91% with metastatic disease, and 15% with history of brain metastases. Twenty-nine percent received two or more prior systemic treatments for advanced or metastatic disease. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible [see Clinical Studies (14. The study population characteristics were: median age of 64 years (range: 37 to 80), 48% age 65 years or older, 39% male, 87% White and 8% Asian, 97% with metastatic disease, and 12% with brain metastases. The median age of patients was 60 years (range: 20 to 84), 35% were age 65 years or older, 83% were male, 77% were White, 15% were Asian, and 5% were Black. Sixty-one percent of patients had two or more lines of therapy in the recurrent or metastatic setting, and 95% had prior radiation therapy. The most frequent serious adverse reactions reported in at least 2% of patients were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. The incidence of adverse reactions, including serious adverse reactions, was similar between dosage regimens (10 mg/kg every 2 weeks or 200 mg every 3 weeks); these data were pooled. The most common adverse reactions (occurring in 20% of patients) were fatigue, decreased appetite, and dyspnea. Fifteen percent (15%) of patients had an adverse reaction requiring systemic corticosteroid therapy. The most frequent serious adverse reactions (1%) included pneumonia, pneumonitis, pyrexia, dyspnea, graft versus host disease and herpes zoster. Patients with autoimmune disease or medical conditions that required systemic corticosteroids or other immunosuppressive medications were ineligible. The most common adverse reactions (reported in at least 20% of patients) were fatigue, musculoskeletal pain, decreased appetite, constipation, rash and diarrhea. The most frequent serious adverse reactions (2%) were urinary tract infection, hematuria, acute kidney injury, pneumonia, and urosepsis. Immune-related adverse reactions that required systemic glucocorticoids occurred in 8% of patients, use of hormonal supplementation due to an immune-related adverse reaction occurred in 8% of patients, and 5% of patients required at least one steroid dose 40 mg oral prednisone equivalent. Patients with autoimmune disease or a medical condition that required systemic corticosteroids or other immunosuppressive medications were ineligible. In clinical studies in patients treated with pembrolizumab at a dose of 2 mg/kg every 3 weeks, 200 mg every 3 weeks, or 10 mg/kg every 2 or 3 weeks, 26 (2. Among the 26 patients who tested positive for treatment emergent anti-pembrolizumab antibodies, only 4 patients were tested for neutralizing antibodies and one was positive. There was no evidence of an altered pharmacokinetic profile or increased infusion reactions with anti-pembrolizumab binding antibody development. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. Human IgG4 (immunoglobulins) are known to cross the placenta; therefore, pembrolizumab has the potential to be transmitted from the mother to the developing fetus. Based on its mechanism of action, fetal exposure to pembrolizumab may increase the risk of developing immunemediated disorders or of altering the normal immune response. The concentrations of pembrolizumab in pediatric patients were comparable to those observed in adult patients at the same dose regimen of 2 mg/kg every 3 weeks. The safety profile in these pediatric patients was similar to that seen in adults treated with pembrolizumab; toxicities that occurred at a higher rate (15% difference) in pediatric patients when compared to adults under 65 years of age were fatigue (45%), vomiting (38%), abdominal pain (28%), hypertransaminasemia (28%) and hyponatremia (18%). No overall differences in safety or effectiveness were observed between elderly patients and younger patients. Pembrolizumab is an IgG4 kappa immunoglobulin with an approximate molecular weight of 149 kDa. Each 2 mL of reconstituted solution contains 50 mg of pembrolizumab and is formulated in L-histidine (3. Each 1 mL of solution contains 25 mg of pembrolizumab and is formulated in: L-histidine (1. Steady-state concentrations of pembrolizumab were reached by 16 weeks of repeated dosing with an every 3-week regimen and the systemic accumulation was 2. Pembrolizumab concentrations with weight-based dosing at 2 mg/kg every 3 weeks in pediatric patients (2 to 17 years) are comparable to those of adults at the same dose. In 1-month and 6-month repeat-dose toxicology studies in monkeys, there were no notable effects in the male and female reproductive organs; however, most animals in these studies were not sexually mature. Patients with disease progression could receive additional doses of treatment unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, occurred with a decline in performance status, or was confirmed at 4 to 6 weeks with repeat imaging. Key eligibility criteria were unresectable or metastatic melanoma; no prior ipilimumab; and no more than one prior systemic treatment for metastatic melanoma. Assessment of tumor status was performed at 12 weeks, then every 6 weeks through Week 48, followed by every 12 weeks thereafter. Assessment of tumor status w as performed at 12 weeks after randomization, then every 6 w eeks through week 48, followed by every 12 weeks thereafter. Patients with autoimmune disease that required systemic therapy within 2 years of treatment; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. Assessment of tumor status was performed every 6 weeks through Week 18 and every 9 weeks thereafter. Patients with autoimmune disease; a medical condition that required immunosuppression; or who had received more than 30 Gy of thoracic radiation within the prior 26 weeks were ineligible. All patients had received prior therapy with a platinum-doublet regimen, 29% received two or more prior therapies for their metastatic disease. Among the 28 responding patients, the median duration of response had not been reached (range 2. Fifty-eight percent were refractory to the last prior therapy, including 35% with primary refractory disease and 14% whose disease was chemo-refractory to all prior regimens. Tumor response assessments were performed at 9 weeks after the first dose, then every 6 weeks for the first year, and then every 12 weeks thereafter. Eighty-one percent had a primary tumor in the lower tract, and 19% of patients had a primary tumor in the upper tract. Eighty-five percent of patients had visceral metastases, including 21% with liver metastases. Ninety percent of patients were treatment naпve, and 10% received prior adjuvant or neoadjuvant platinum-based chemotherapy. The trial excluded patients with autoimmune disease or a medical condition that required immunosuppression. Patients with initial radiographic disease progression could receive additional doses of treatment during confirmation of progression unless disease progression was symptomatic, was rapidly progressive, required urgent intervention, or occurred with a decline in performance status. Assessment of tumor status was performed at 9 weeks after randomization, then every 6 weeks through the first year, followed by every 12 weeks thereafter.

Among other problems allergy quick relief purchase prednisone 40mg with mastercard, migration of the population to the cities sets the new challenges to the Health Care and Public health systems allergy haven cheap 20 mg prednisone. Studies show that drug abuse allergy shots unitedhealthcare prednisone 20 mg visa, psychiatric and psychological disorders allergy medicine zyrtec dosage discount prednisone 5 mg amex, unemployment rates are higher in this group than in overall population allergy testing reno prednisone 5 mg on line. Unlike neighbor countries (Turkey allergy quick dissolve strips purchase 40mg prednisone overnight delivery, Azerbaijan) where the number of natural children makes up 25-60% of the total number of newborns due to the Georgian traditions, the share of natural children in our country is 6-10% (by different regions nationalities). Although the number of registered divorces increased five times in the last 10 years, different studies confirm the number of unregistered divorces to be even higher. The above-mentioned demographic trends affected the age-sex structure of population and stimulated the process of the population aging which, from our viewpoint, will have negative influence on the economy of the country (Figure 3). The quantity of Georgian population according to the sex and age 500000 450000 400000 350000 300000 250000 200000 150000 100000 50000 0 0 5 10 15 20 25 30 7 35 40 45 50 55 60 65 70 75 80 85 90+ Total population Males Females the number of population over 60 is 900 000 in Georgia. This rising number of economically less active population is a growing burden for the State. In this aspect, the new and rapidly changing demographic trends, such as deterioration of traditional multigenerational structure of Georgian families and increase of the portion of the so-called nuclear families, are increasing this burden. On one hand, the state is compelled to deliver old people social and medical care, which was mainly provided by the member of multigenerational families (care, feeding, primary medical care, etc. On the other hand, the young generation of nuclear families may become an issue for the society and state, being left unattended, not forming the social and traditional bonds with older generation, and experiencing considerable lack of control and supervision. Mortality dynamics of the population is significantly different in urban and rural regions. For example, contingent mortality level is much lower among children under one year and adult population. The existing trends of the population morbidity and mortality indicators are gradually approaching those of the developed countries, although some of the indicators typical for developing countries will be preserved. This is supported by the fact that referral of patients with some chronic diseases to health facilities significantly reduced. The registered reason for their death is not the disease which really caused the death, but some diagnosis of previous years or a disease adjusted to the age. This explains the extremely high rates of mortality from some pathologies which do not correspond with the real situation. The existing situation requires immediate intervention and appropriate measures due to its negative effects on various aspects of the Health Care system. Influence of the population life conditions on the medico-demographic indicators According to the data obtained from the State Department of Statistics, the average number of adult population over 15 was 713,9 per 1000. Despite the high level of unemployment, many of them are not officially registered. In addition, incomes from farming in rural regions were 30-40% less than in urban regions. It must be stressed that population spends only 2,5% of the total expenses on health (including purchasing of medications, covering ambulatory and hospital expenses through co-payment, etc. This takes into consideration that this category is mainly represented by elderly population; the state has to make big contributions in their medical care and social security. The carried out studies revealed that in the structure of the expenses of the poorest population, expenses on food had the leading position, while the least amount of money was spent on education and cultural activities - 1,6%, and on transport- 2,3%. Population expenses on transport increased to 7,2%, on rest - 3,9% and purchasing utensils and other goods - 10%. In 2016, the number of families with middle income increased to 7,4% in comparison with the last year indicator 6,9% compared to 1. Difference in basic health indicators became obvious as well, especially between the low- and middle-income populations. According to studies, middle-income population group spends 20-30% less on treatment and purchasing of medications. It is quite understandable as poverty is always accompanied by high level of morbidity and correspondingly, with the increase of medical expenses. A special study, aiming to compare the health state of two groups of Tbilisi population of lower and high income, was held (Figure 4). Index of medical activities of the Georgian population with high and low incomes the study shows that health indicators of the low-income group were much worse than expected. It would be reasonable to assume that the referral of this group to the Health Care facilities should be very high; on the contrary, the study findings show that the referral to medical services is extremely low. It is important to underline that many of those who belong to socially vulnerable group are not an invariable part of population as some of them are at least partially employed. Income is closely connected with socio-economic situation existing in the country. Variation of their incomes is connected with timely and full paying of salaries, pensions and premiums from the state budget. The dynamics of food products consumption significantly changed in the recent years and greatly depends on the above mentioned factors. According to the available data, everyday diet of the most part of the population includes mainly bread and bread products (65-85% according to the different social groups), vegetables (including potato) - 8-14%, fruit (by seasons) - 2-12%. Besides, consumption of milk and dairy products (2-8% according to the different groups), meat and meat products (5-12%), sugar and confectionery (2-6%) significantly reduced. Besides, caloricity of diet in South-Caucasus countries is lower than the established physiologic standard (according to some authors, it makes up 3200-2800 calories). Making up for the deficiency of meat and dairy products ingredients amino acids, proteins and vitamins, the traditional Georgian diet includes beans, different cereals, vegetables and fruit. However, impoverishment of the diet conditioned by lack of meat and dairy products significantly affects the health of the population. Special study proved that low income, bad living conditions, malnutrition and unemployment cause social isolation of a person and increase of frequency of respective somatic and psychic disorders. The respective study shows the significant statistical increase of morbidity and mortality indicators in this group. It is important to mention that this population group is provided with adequate and free medical care; however, the referral to the medical institutions is extremely low. The structure of the referral shows that the main reason for referring to the health care professionals is not the onset of the disease, but the occurring disability resulting in the risk of unemployment. Heavy dependency on the social welfare and high rates of unemployment are thus the main determinants of the economic wellbeing of this population group, predominantly those living below the poverty line. Difficult social and economic conditions are among leading contributing factors in the high spread of tobacco, alcohol and drug abuse. Poorly regulated markets of developing countries, such as Georgia have become prime targets for tobacco and alcohol producing companies in last several decades. The imperfect legislation, taxation and quality control attract international tobacco companies and create the favorable situation for the increase of smokers and alcohol users. Unlike most of the European countries, Georgia allows the advertisement of tobacco in the streets; it is not restricted to sell tobacco and alcoholic beverages near schools. Smoking and tobacco sale restriction law enforcement is mostly uncontrolled, the price range is still very affordable, and there is no major anti-tobacco campaigns conducted. The number of tobacco abusers, especially among the young population, rapidly increases. Several studies revealed that the average age of stable tobacco consumers decreases. The data number of smokers among adult males in Georgia is nearly 60%, which is much higher than the same indicator of the European countries where demand for tobacco products steadily reduces. Ancient tradition of moderate consumption of wine and other alcohol drinks conditioned low level of alcoholism until the 90s. However, these numbers are underestimating the importance and spread of the so-called "social" alcoholism what is mostly typical for the Georgian society. Certainly, it negatively affects the health indicators, increasing the morbidity of the population (cardiovascular, endocrine, digestive and other systems). One of the serious problems is the tradition of alcohol consumption and therefore acceptance of young drinking age by the society. These factors significantly promoted the increase of alcohol consumption among young population and women. The study revealed that 90% of females respondents under 18 consider that alcohol consumption is a bad habit, 50% of them consumed alcohol irregularly, 80% from 300 female respondents above 18 consumed alcohol (70% periodically, and 10% systematically), 70% of them also considered that it was a bad habit. Conclusion Demographic changes in the Georgian society occurring in the last decades were heavily dependent on the social-economic environment of the country. Despite the fact that the changes are stabilizing in the last few years, we believe that the changes in the reproductive behavior continue to develop in the negative direction. As compared to the previous years, the number of desired children has been decreasing and only 8% of Georgian women desire to have three or more children. In addition to this tendency, the number of marriages decreases year on year and the number of divorces has increased dramatically over the last ten years. All of the above changes are contributing factors to the demographic changes and are expected to have a serious longterm negative effect on the population structure of the country. It should be stressed also that the tendency of multichildren families is maintained in several regions of the country (Zemo Adjara, Kvemo Kartli), but it has no significant influence on the general indicators. It means that in case of maintaining the existing tendency, the family is unable to provide enlarged reproduction. According to the data of the general census of population carried out in 1979, 150 women per thousand had one child, 240 - 2 children, 329 - three and more children. The census of the population carried out in 1989 revealed the trend of reducing the number of women with three or more children (300 per 1000 married women). The differences are not only in economic, but also in sociocultural characteristics of this layer. This situation causes serious problems in the social and medical financing of the growing poor population. It should be noted that the cause for delay of medical interference for them is not just a financial problem, but an issue of a low literacy level, peculiarities in the flow of disease, transportation problems, etc. Difference in basic health indicators became obvious as well, especially between the low and middle-income groups of population. Poverty is always accompanied by high level of morbidity and correspondingly with the increase of medical expenses. In most cases, poor patients receive practically no conservative treatment but need urgent surgical operations. Complex study of the problem on accessibility to high quality medical care in the population of Georgia. Management problems of improving the quality and efficiency of primary health care system of Georgia. Determining Priority Retention Packages to Attract and Retain Health Workers in Rural and Remote Areas in Uganda. However, the major exporting partners were Germany, Netherland, the Czech Republic, France, Poland, Latvia, Lithuania, etc. Keywords: Agricultural, Foreign, Products Introduction the Government of Georgia implemented reforms in tariff policy as well as in technical regulations sphere. As a result, nowadays, Georgia has one of the most liberal foreign trade policies in the world which implies the facilitated foreign trade regimes and customs procedures, low import tariffs, and minimal non-tariff regulations. The Export of Basic Agricultural Products the export increased by the following products: · Canned fruit and vegetables ­ export was up by 14% with a total of 8. The product was exported in France 46%, Netherlands 29%, and the United Kingdom 14%; · Wine ­ export increased by 14% with a total of 14. The product was exported in Poland 35%, Latvia 20%, Estonia 11%, and Lithuania 11%; · Mineral waters ­ increased by 14% with a total of 12. The export reduced by the following products: · the Hazelnut went down to 3% and totally reached 145. The basic exporting countries were Italy 33%, Germany 33%, France 6%, Spain 6%, Czech 6%, and Slovakia 4%; · Fruit and Vegetable Juices went down to 38% and amounted to 2. The Import of Basic Agricultural Products the import increased by the following products: · Diary butter ­ import increased up to 60% and made up 6. The product was imported from Spain 38%, Germany 14%, Hungary 8%, Netherland 8%, and France 7%; · Pigs ­ made up 1. Product was imported from Bulgaria 40%, Hungary 30%, Romania 20%, and Denmark 10%; · Cotton-cake ­ reduced to 72% and made up 1. In the bilateral format with those countries, Georgia has signed the bilateral agreements also. Bilateral International Agreements on Free Trade Georgia has signed Free Trade Agreements with the following countries: the Russian Federation, Azerbaijan, Armenia, Ukraine, Moldova, Kazakhstan, Uzbekistan, Turkmenistan, and Turkey. Modern technologies are accessible for the majority of the world tourists, but only a small number of potential tourist resources are utilized. Partially this is because tourism is not developed equally or accidentally in space - so pressure is concentrated in seasonal and unique locations. This requires effective planning of tourism resources, and agro-tourism is remarkable with its working period throughout the year. In the development of agro-tourism, the practical and effective coordination between all stakeholders, including government, private enterprises and local authorities is of utmost importance. It is necessary to create appropriate legal and organizational mechanisms for the support and effectiveness of local residents. Professionalism in Georgia is an important condition for the development of tourist activities and mainly agro-tourism. Depending on the current economic situation of Georgia, the amount of investments which are invested in tourism sector is quite solid. The accelerated rhythm of modern life has a great influence on the spiritual or physical condition of a person. That is why we often wish to relax in the quiet environment of the city and be restricted to agro-tourism. However, in terms of increased demand on tourism, which is focused on a small resource base, tourist destinations are under pressure. This requires effective planning of tourism resources, and agro tourism is remarkable with its working period throughout the year.

Besides allergy pro discount prednisone 5 mg with amex, development of their socio-economic integration approaches in close cooperation with the Government and Civil Society allergy testing information discount prednisone 40mg on line. The consortium carried out works in target regions in accordance with the pre-designed plan allergy shots medicaid discount 5 mg prednisone visa. Among the activities carried out in terms of support of business grants allergy medicine and grapefruit juice purchase prednisone 40mg without a prescription, a wide range of activities were executed within the project allergy shots location 20mg prednisone with mastercard. The research results and findings created a solid basis for proper planning and implementation of business grants support activities allergy medicine 732 purchase 10 mg prednisone with mastercard. The research covered many aspects of the social-economic conditions of the target groups. It can be said that the results of the research have fully reflected business development situation in the target regions, especially if we will take into account the official statistics of business sector in Georgian regions. Besides, it has to be noted that not only in targeted regions, but also in the whole country, small and medium enterprises are not still playing a significant role in economy. This is based on what is confirmed by the low share of small and medium enterprises in the gross domestic product (2014 - 18 %). There can be many reasons that is hindering the development of small and medium businesses. According to the opinions of the research respondents, the projects of small and medium business facilitation are not executed in the target areas. Local population did not have the proper motivation and knowledge, and the existing business units were not interested in the development of entrepreneurial activities within the region. In the opinion of local non-governmental organizations, in the target regions, a number of small businesses is very small and they do not have the motivation for expansion and development direction, which is an important factor that is hindering the economy development. The reason for the mentioned issue may be the lack of availability of cheap credits for the owners of small businesses. In Shida Kartli, climate and inadequate irrigation system with limited access on a land resourses are considered as a main barrier of agribusiness development. Whatever is the reason that is hindering the development of small business, it is clear that in the target regions, small business cannot equip the enterprise with modern technology in order to independently increase the market competitiveness. We have to assume, that not only the internally displaced persons, but also any other category of population recipients of Government allowance, similarly consider business grants and other entrepreneurship support programs as a danger. Therefore, people lose the stimulus to improve their social conditions with legal business or with additional revenue reception activities". The target groups did not know what the labor market requested from them and what the requirements could be in the future. In the target regions, half of internally displaced persons considered themselves as unemployed, but did not think that the lack of their knowledge and skills was one of the causes of unemployment. However, in the target regions from the research of potential employers, quite an opposite result has been received, in particular - the employers have had problems with finding the work force, with proper qualification and skills. Potential sources of funding may be: Bank loans; Loans, received from Micro Financial Organizations; Programs of central and local government; Grants. In accordance to the fundamental market principles of business development, the most effective way for a businessman and a financial institution will be to independently find ways of mutually beneficial cooperation. However, the "current market rate of financial resources (money value) will not affect the individual and social benefits received for the vulnerable groups by means of business activity. In particular, financial institutions are not obliged to take into account the long-term social consequences of the specific business activities. Internationally recognized methods of external stimulus are presented by governmental programs and grants. On the basis of the successful examples of social policies worldwide, it can be said that by means of stimulating business activities in regard of vulnerable groups for the improvement of livelihood sources, desired results are achieved only in case if these activities are accompanied with the well developed mechanisms of business grants support. Many programs and activities for entrepreneurial activities support are implemented in Georgia. Also, special agencies and structures are created which have specific goals for the business support across the country. For example, Enterprise Development Agency (implementing the state program "Produce in Georgia"); Innovation and Technology Agency; the project "Business Incubator" (FabLab); "Cheap credit" program, etc. To achieve the project results, it uses specific schemes of business grants support. Small Scale Grants Small grants were intended for those who want to start a business or individual entrepreneurs, who are at the initial stage of business development. Within the project, small business grant applicant beneficiaries filled out 273 business plans in total; among them, 148 in Shida Kartli region and 225 in Samegrelo region. In both regions, 188 small grants have been issued164: 59 in Shida Kartli and 129 in Samegrelo region. Medium Scale Grants the medium size grants were for those reprsentatives of the mediumsized businesses, who wanted to expand their business. The maximum amount of the grant for the expansion of the existing business was 7800 Euros. However, the condition of co-financing was the provision of 50% of the total budget. Applicants, wishing to expand their business, initially had to fill in and present the business idea form. At the present stage of selection, one person had a right to become a business partner only within one business idea. Selection on the basis of business ideas was executed by the same criteria used at the selection of small business ideas. After the business ideas competition, beneficiaries went through 3 days intensive training course on business and entrepreneurial issues. The legal issues of business and entrepreneurship were considered as a single module of the training course. Provision of Basic Tool Kits to Start Small Businesses There is a wide spread practice in Georgia, when the significant/important part of economically active population is involved in some kind of economic/business activity as self-employed166. This category of self-employed people does not hire a work force and independently runs its economic activity. Since this category accumulates some experience, they know well the segment of the narrow market that is relevant to their activity, they develop the skills of communication with their clients etc. We have to consider the activities of these people as a good basis for starting a small business in the future. For the implementation of this direction of the project, criteria for the selection of tool kits applicants have been determined. In accordance to these criteria, the preference was given to part of the population which receives social allowance. In order to ensure purposefulness of the resources allocated for the grant, the group of people receiving social allowance was narrowed into the separate groups. Finally, developed business ideas and the interested part filled out the special application forms created for tool kits applicants. In both regions, 129167 beneficiaries (Shida kartli ­ 79, Samegrelo ­ 65) expressed the desire to receive tool kits and accordingly filled out application forms in complete. Finally, on the basis of information received from the revision of applications and field monitoring, selection commission, 166 this does not includes the category of self-employed, which by the National Statistics Service are refered to the "entrepreneur, tenant employer" category. During the project, constant communication with tool kits recipients was retained. They have been receiving consulting services and were running their business in accordance to the conditions determined by the grant agreements. Such activities did not consider direct monetary or material support of starting the business or expanding the existing businesses, but supported establishment of a solid basis for the business development in the region. One of such activities was the activity carried out with the purpose of the establishment of mutually beneficial ties between business grants applicants and representatives of financial institutions. An attempt of consortium members to connect financial institutions and grant applicants brought certain positive results. Few participants of grant competitions addressed financial institutions in order to receive co-financing funds and received loans (for example, 6 applicants from Shida Kartli, generally beneficiaries of medium grants). Start of such relations will have a bigger impact on the development of entrepreneurial activity in the region. In the target regions, as well as in the whole country, one of the factors hindering the business is the lack of skilled work force. Numerous activities (meetings with representatives of local and central government, conferences, forums, presentations, workshops) along with solving the other problems served the improvement of business environment and the establishment of systematic approaches for business support. Conclusions and Recommendations the experience, gained from the project and the received results, gives an opportunity to make conclusions and develop recommendations and consideration of which will bring benefits to the future projects and programs of the business grants support. Namely: the project has basically helped those target groups who were in need of support by all the criteria. In addition, used scheme of business grants suppot is in full compliance with the strategy of support of entrepreneurship in the country and European Small Business Act Think Small First171 principles; Long time unemployment and vulnerability forces people to get out of work force and become economically inactive. They are skeptical in regard of any initiative which may somehow improve their condition. Therefore, the basis of the business grant support project must be stimulating this kind of people to get actively involved and use new opportunities to improve their financial and social conditions; In order to implement business support scheme on the practice with the purpose of pre-designing the project, it is necessary to prepare the following documents: needs analysis methods; business and entrepreneurial skills training plan; business plans application forms with the consideration of grants directions; business grants assessment forms with the criteria of detailed selection; project monitoring forms; procurement procedures and regulating documents for the grant; forms of individual grants agreements, etc. The reasons may be: first, avoidance of risks related to business activities; second, the lack 171 "Small Business Act for Europe"2008. Inactivity of beneficiaries caused by the fear of loosing the monthly social allowance is a more complex problem for the country compared to certain challenge of a specific project. Therefore, it is necessary for the social support system and social policy in general not to mute individual incentives. Otherwise, a large number of people will have to live in poverty for a very long time; the indicators of the effectiveness of business grant support (upon their implementation) are the new or expanded business objects which successfully conduct business activities. Employed people have more knowledge and experience after the participation in the project. The income of these people is higher than what they had, before the participation in the project; Within the grants support, a part of beneficiaries received the tool kits they have requested in a personal possession. With this activity, the program gave the beneficiaries an opportunity with the status of a self-employed to become actually employed. In addition, we have to consider their activity as a good basis for starting a small business in the future; Business grant support has improved business activities in the target regions. In addition, within the project, other activities have been carried out which has indirectly promoted the development of entrepreneurship. For example, personal and professional development trainings; internships of beneficiaries; employment program - "Employment Shuttle"; consulting beneficiaries on legal issues of employment opportunities; organizing meetings with representatives of financial institutions, etc. The knowledge beneficiaries gained during the business trainings was important as well, since they will be able to use it in a real practice, or in any other project and program. The fact that some of the beneficiaries received funding from the other programs perfectly demonstrates the above mentioned. In many cases, people start their business activities, but due to financial and other reasons, they fail to develop. The paper will identify the common challenges that young and motivated generation faces nowadays. The work will display the foundations where these challenges are derived from and how they could be addressed. Information provided in the paper is based on the materials of different organizations, government structures, and agencies. I have explored relevant reports of the World Bank, considered researches of Colliers International, and some research papers. The statistical data is mainly based on the source of National Statistics Office of Georgia. In the last fifteen years, there have been important changes in the country that affected the masses of population. The changes were related to structural reforms, but meanwhile included significant amendments in the legislation. Government initiated a cycle of reforms to change the entire system of business registration, collecting revenues, custom procedures172. Important supporting mechanisms have been carried out to facilitate doing business process; bureaucracy has significantly reduced and excessive administrative burden has been removed from investors. A huge relief was felt through the abolishment of numerous licenses that took even months to obtain. Overall, 70% of business-related licenses and 90% of business permits were abolished during a certain time period174. Another dynamic effect that influenced business environment is related to taxation. The facilitation resulted in: No payroll tax or social insurance Tax No capital gains tax No wealth tax and inheritance tax Personal income tax for interest, dividend ­ 5% 172 Colliers International. Four electronic service has been proposed for businesses to facilitate their relations and acquiring necessary information in the shortest time possible: Businesses gained the possibility to receive the permit for construction online procedures Online auction for municipal property purchase has been introduced the city announced tenders electronically for executing government procurements Interactive Map has been published that enables businesses to view any private or municipal land of Tbilisi online As a result of the reforms, the progress has been fully translated into increased amount of foreign direct investments, expanded export activities that are, in general, directed to sustainable economic growth. As for enterprises, it can be said that for the period of June, 2017 according to Geostat data, there are over 600,000 Economic entities in Georgia, out of which 167,554 are active178. It is worth mentioning that from the active economic entities, just 4% is fully owned by foreign person. If we look from the regional perspective, it is not surprising that the majority of the companies are registered in the Capital. Herewith, it should be also mentioned that the capital tends to be an ideal place for small businesses; the statistics show that over 80% of operating business entities are small enterprises, while medium enterprises amount just 10%. Another interesting statistics that clarifies the attractiveness of the capital in comparison with other cities of Georgia is provided by Tbilisi City Hall based on the data of the National Statistics Office of Georgia. It is interesting to draw our attention that more than 77% of the Total Foreign Direct Investments is connected to Tbilisi. However, recent progresses have not fully translated into benefits for the whole Georgian population what is absolutely natural: with unemployment remaining at high levels, the problems associated with start-ups and the lack of supporting tools still remained tangible.

Fetal platelet destruction results from transplacental passage of these antibodies allergy forecast for philadelphia proven 40mg prednisone, and severe bleeding allergy medicine 19 month old buy 20mg prednisone mastercard, including intracranial haemorrhage allergy symptoms face numbness discount 5mg prednisone with amex, can occur in utero or within the first few weeks of life allergy treatment sublingual immunotherapy generic prednisone 5 mg amex. Firstborns are frequently affected allergy forecast las vegas generic 20mg prednisone, and successive pregnancies are equally or more affected allergy kansas city prednisone 20 mg cheap. Heparininduced thrombocytopenia Heparininduced thrombocytopenia occurs during unfractionated heparin therapy in up to 5% of patients, but is less frequently associated with low molecular weight heparins. It may become manifest when arterial or venous thrombosis occurs during a fall in the platelet count and is thought to be due to the formation of antibodies to Figure 7. Platelet Disorders 45 heparin that are bound to platelet factor 4, a platelet granule protein. The immune complexes activate platelets and endothelial cells, resulting in thrombocytopenia. Heparininduced thrombocytopenia carries an appreciable morbidity and mortality, especially from resulting thrombosis, if the diagnosis is delayed. The condition is suspected clinically by thrombocytopenia, red cell fragmentation on the blood film and a reticulocytosis. The demonstration of an abnormal pattern of von Willebrand multimers makes the diagnosis highly likely, and the complete absence of the cleaving protease caused by an inhibitory antibody can be proven in some specialised laboratories (Figure 7. The blood films may be similar in all these disorders, with thrombocytopenia, anaemia and fragmented red blood cells. Massive blood transfusion In patients with lifethreatening bleeding, transfusion of 8­10 units of red blood cells without replacing clotting factors or platelets may result in prolonged clotting screen and thrombocytopenia. Massive splenomegaly the spleen normally pools about a third of the platelet mass, but in massive splenomegaly this can increase up to 90%, resulting in apparent thrombocytopenia. Aspirin acts by irreversibly inhibiting cyclooxygenase activity in the platelet, resulting in impairment of the granule release reaction and defective aggregation. The effects of a single dose of aspirin last for the lifetime of the platelet (7­10 days). Recently, clopidogrel, a thienopyridine derivative, has been introduced as an oral antiplatelet agent that inhibits adenosine diphosphate binding to the platelet membrane and is useful in patients who are intolerant or resistant to aspirin. It is becoming widely used as a prophylactic agent for myocardial ischaemia and related coronary syndromes. Bleeding in uraemic patients Bleeding most commonly results from defects in platelet adhesion or aggregation, although thrombocytopenia, severe anaemia with packed cell volume <20% or coagulation defects can also contribute. Essential (primary) thrombocytosis and reactive (secondary) thrombocytosis In these conditions, the platelet count is raised above the upper limit of normal. A wide range of disorders can cause a raised platelet count (>800 Ч 109/L), but patients are normally asymptomatic, except in essential thrombocytosis, when excessive spontaneous bleeding may develop when the count exceeds 1000 Ч 109/L. Antiplatelet drugs can be useful to prevent thrombosis in highrisk patients; for example, postoperatively. Some myelodysplastic syndromes may be complicated by an acquired storage pooltype platelet disorder (Box 7. History and examination of patients Abnormal bleeding associated with thrombocytopenia or abnormal platelet function is characterised by spontaneous skin purpura and ecchymoses, mucous membrane bleeding and protracted bleeding after trauma. Prolonged nosebleeds can occur, particularly in children, and menorrhagia or postpartum haemorrhage is common in women. In thrombocytopenic patients, severe spontaneous bleeding is unusual with a platelet count 20 Ч 109/L, unless there is associated platelet dysfunction. Investigations the investigations in a suspected platelet disorder will depend on the presentation and history in each patient. If the bleeding is severe, the patient may need urgent hospital referral for prompt evaluation, diagnosis and treatment, which may entail blood product support. All patients should have a full blood count, coagulation and biochemical screen, and then further investigations depending on the results of these. A thorough review of the blood film can help in the diagnosis or exclusion of many disorders associated with thrombocytopenia (Figure 7. Thrombocytopenia can be artefactual and due to platelet clumping or a blood clot in the sample, which should be excluded in all cases. The skin bleeding time, which is invasive, variable and not reliable in screening mild platelet disorders, has been replaced by devices that perform an in vitro bleeding time on small volumes of citrated blood and simulate platelet function in a high shear rate situation. The sensitivity of these devices for all platelet disorders is still under investigation. Management All serious bleeding due to a platelet disorder needs haematological assessment and treatment. Mild or trivial bleeding due to a transient postviral thrombocytopenia or aspirin ingestion needs no active treatment and can be managed on an outpatient basis (Box 7. Congenital disorders A neonate or small infant with bleeding must be referred for evaluation as the inherited bleeding disorders. Platelet Disorders 47 Severe bleeding episodes in all the congenital thrombocytopenias and platelet function disorders require filtered human leucocyte antigencompatible platelet transfusions to secure haemostasis, although, in minor episodes in the milder dysfunctional syndromes, desmopressin (1deamino8darginine vasopressin) given intravenously or intranasally with antifibrinolytics (tranexamic acid) may be sufficient. This avoids exposure to blood products, but it is expensive and the response is variable. Bone marrow transplantation can potentially offer a cure in a number of these conditions. Acquired disorders In thrombocytopenia due to bone marrow failure or marrow infiltration. In childhood immune thrombocytopenia, spontaneous recovery is common, and treatment, such as corticosteroids or intravenous immunoglobulin, is given only if there are bleeding manifestations. In adults, the condition rarely remits without treatment and is more likely to become chronic. Initial treatment is either prednisolone 1 mg/kg daily (80% of cases remit), intravenous immunoglobulin (0. Other potential therapies include azathioprine, mycophenolate, highdose dexamethasone and thrombopoietinreceptor agonists. Patients in whom heparininduced thrombocytopenia is suspected are often inpatients with ongoing thrombosis and may have complex medical problems. It is essential to stop heparin and treat thrombosis with other anticoagulants; further use of heparins should be avoided. Platelet transfusions are contraindicated in heparininduced thrombocytopenia and in thrombotic thrombocytopenic purpura. If the latter is suspected clinically and on the basis of laboratory tests, largevolume plasma exchange should be started immediately and continued daily until substantial clinical improvement occurs and all the results of haematological tests have normalised. In patients requiring massive blood transfusion, replacement with fresh frozen plasma (15 mL/kg) and a pool of platelets should be given with every 8­10 units of red cells received. In pronounced bleeding or risk of bleeding due to the acquired disorders of platelet function, platelets usually have to be transfused to provide normally functioning platelets, although desmopressin and tranexamic acid can also be of value. Usually, treatment may only be necessary to cover surgical procedures or major haemorrhage. In Pediatric Hematology, 2nd edn (eds J Lilleyman, I Hann and V Blanchette), Churchill Livingstone, London, chapter 24. A review of its use in congenital or acquired haemophilia and other congenital bleeding disorders. In Pediatric Hematology, 2nd edn, (eds J Lilleyman, I Hann and V Blanchette), Churchill Livingstone, London, chapter 21. Genetic mutations the acquisition of further mutations favours selection of a dysplastic clone due to a proliferative advantage, usually via upregulation of multiple prosurvival and cell cycle pathways. Additionally, acquisition of certain mutations may cause impaired differentiation. Tcellmediated inhibition of haematopoiesis either via upregulation of cytotoxic T cells or reduction of Thelper cells coupled with natural killer cell Table 8. In brief, the main insult is believed to be due to an acquired genetic or epigenetic abnormality of the bone marrow haemopoietic stem cells inducing genomic instability, and predisposition to further mutations. Abnormal stem cell environment Increasing evidence suggests that the bone marrow microenvironment contributes to maintenance of the abnormal stem cell clones and disease progression. For example, mesenchymal stem and progenitor cells can induce altered haematopoietic­stromal interactions as can abnormal macrophages, monocytes and myeloid derived suppressor cells. As this is an invasive procedure it does not necessarily need to be performed in those who are asymptomatic and do not require intervention, as a watch and wait approach may be taken. The marrow examination shows increased numbers of dysplastic megakaryocytes, with relatively little dysplasia in the other cell lineages. Myeloid lineage Erythroid Blood film Macrocytosis Basophilic stippling Bone marrow Multinucleate forms and nuclear budding Cytoplasmic vacuolation Ring sideroblasts As peripheral blood findings Granulocytic Investigation A precise history and examination should be performed. A blood count and examination of a peripheral blood film can reveal characteristic features of dysplasia, but in order to make a definitive Megakaryocytic Nuclear hypolobulation (pseudo Pelger­Huлt) Hypersegmentation Large cytoplasmic granules (pseudo Chediak­Higashi) Hypogranularity Hypogranular platelets Micromegakaryocytes Monolobated nuclei Nuclear separation Myelodysplastic Syndromes 51 Figure 8. Severe systemic illness Drugs Toxins Management Owing to the variable nature of these syndromes, a stratified, individualised patient approach to management should be adopted, based on clinical and biological characteristics, disease subtype, patient choice and prognostic risk group. In cases of symptomatic anaemia, red cell transfusions may be given, with a haemoglobin threshold determined on an individual basis. The use of the exogenous growth factor erythropoietin, administered subcutaneously, can Myelodysplastic Syndromes 53 Table 8. Heavily transfused patients should be considered for iron chelation, in order to ameliorate the deleterious effects of iron loading in tissues such as the liver and heart. Febrile episodes in neutropenic patients are treated with broadspectrum antibiotics and antifungals where indicated. The use of granulocytic colony stimulating factor, to stimulate granulocytic development, is often used in patients with neutropenia. Platelet transfusions can be used where there are bleeding symptoms or during intensive chemotherapy but are otherwise not recommended in stable thrombocytopenia. The use of thrombopoietin mimetics, such as eltrombopag, is not currently recommended outside of clinical trials as these increase bone marrow blast counts. Eligibility for transplant should be based on prognostic risk category, performance status, comorbidities and patient preference. The use of reducedintensity conditioning transplants means that patients previously considered unsuitable for transplant due to age can be given this treatment option. Fully humanleukocyte antigenmatched siblings are the preferred source of stem cells, although unrelated matched donor transplants can have a similar outcome. Where no matched donor can be identified, alternative donor stem cell sources, such as umbilical cord blood or haploidentical donors, should be considered. Future of the myelodysplastic syndromes Advances in deep sequencing of both the genome and immune system will permit rapid evaluation of each individual for their specific mutation and immune profile. This will ultimately lead to refinements in disease classification and prognostication based on these findings. Furthermore, it will allow for therapies to be better targeted, either by predicting response to currently available therapies or by the use of novel treatments targeting specific dysregulated pathways. Hypomethylating drugs, such as azacitidine and decitabine, are well tolerated and can be administered in an outpatient setting. It is usually given subcutaneously, although trials of an oral formulation are underway. Epidemiology Multiple myeloma accounts for 1% of all malignancies and 12% of all haematological malignancies. Over 70% of patients are over the age of 65 years when diagnosed, although 1% of patients are less than 40 at presentation. It is twice as common in AfroCaribbeans, who are frequently diagnosed at a younger age than their Caucasian counterparts. Pathogenesis Myeloma results from a clonal proliferation of plasma cells derived from postgerminal centre terminally differentiated B cells. Multiple myeloma cells characteristically have cytogenetic abnormalities, most commonly hyperdiploidy and translocations involving the immunoglobulin (Ig) heavy chain gene (at 14q32). Additional cytogenetic changes, mutations and epigenetic abnormalities are also seen. These genetic abnormalities result in altered expression of adhesion molecules on plasma cells, allowing increased adherence to bone marrow stromal cells and haematopoietic cells. The complex autocrine and paracrine interactions between plasma cells and the bone marrow microenvironment result in tumour cell growth, angiogenesis and myeloma disease. The resulting imbalance between osteoclast and osteoblast activity results in bone resorption and hypercalcaemia (Figure 9. As the bone marrow is effaced with the clonal proliferation of plasma cells, normal haematopoiesis is suppressed, resulting in anaemia, and less commonly, other cytopenias. Plasma cells secrete monoclonal antibodies which are responsible for clinical complications such as hyperviscosity (especially IgA) and renal failure as a result of lightchain deposition in renal tubules. The excess production of monoclonal antibody results in a depression in the production of normal Ig, leaving patients susceptible to infections, particularly bacterial. Clinical features In the early stages, myeloma may be asymptomatic and may be diagnosed as an incidental finding on blood tests done for another reason. This results in increased osteoclastic activity and osteoblast inhibition, leading to bone resorption. Patients presenting with these symptoms 80­90% Symptom Bone pain Cause Lytic lesions Pathological fractures (Figure 9. Renal failure There are several factors that may contribute to renal failure in myeloma: · free light chains cause tubular damage (cast nephropathy) · hypercalcaemia · nephrotoxic drugs · infection · dehydration. They must be ascertained to be directly attributable to myeloma in order for the diagnosis of symptomatic myeloma to be made. There are several subtypes of myeloma, depending on the paraprotein detected: · IgG (60%) · IgA (20%) · lightchain only multiple myeloma (kappa or lambda) (15%) Figure 9. Patients with IgA myeloma are at greater risk of hyperviscosity complications due to their large dimeric Ig structure.

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