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In our opinion, all of the phenomena that are inhibited by cytochalasin can be thought of as resulting from contractile activity of cellular organelles. Smooth muscle contraction, clot retraction, beat of heart cells, and shortening of the tadpole tail are all cases in which no argument of substance for alternative causes can be offered. The morphogenetic processes in epithelia, contractile ring function during cytokinesis, migration of cells on a substratum, and streaming in plant cells can be explained most simply on the basis of contractility being the causal event in each process. The many similarities between the latter cases and the former ones in which contraction is certain argue for that conclusion. For instance, platelets probably contract, possess a microfilament network, and behave like undulating membrane organelles. Migrating cells possess undulating membranes and contain a similar network. It is very likely, therefore, that their network is also contractile. In all of the cases that have been examined so far, microfilaments of some type are observed in the cells; furthermore, those filaments are at points where contractility could cause the respective phenomenon. The correlations from the cytochalasin experiments greatly strengthen the case; microfilaments are present in control and "recovered" cells and respective biological phenomena take place in such cells; microfilaments are absent or altered in treated cells and the phenomena do not occur. The evidence seems overwhelming that microfilaments are the contractile machinery of nonmuscle cells. The argument is further strengthened if we reconsider the list of processes insensitive to cytochalasin (Table 2). Microtubules and their sidearms, plasma membrane, or synthetic machinery of cells are presumed to be responsible for such processes, and colchicine, membrane-active drugs, or inhibitors of protein synthesis are effective at inhibiting the respective phenomena. These chemical agents would not necessarily be expected to affect contractile apparatuses over short periods of time, they either do not or only secondarily interfere with the processes sensitive to cytochalasin (Table 1). It is particularly noteworthy in this context that microtubules are classed as being insensitive to cytochalasin and so are not considered as members of the "contractile microfilament" family. The overall conclusion is that a broad spectrum of cellular and developmental processes are caused by contractile apparatuses that have at least the common feature of being sensitive to cytochalasin. Schroeder's important insight (3) has, then, led to the use of cytochalasin as a diagnostic tool for such contracile activity: the prediction is that sensitivity to the drug implies presence of some type of contractile microfilament system. Only further work will define the limits of confidence to be placed upon such diagnoses. The basis of contraction in microfilament systems is still hypothetical. Contraction of glycerol-extracted cells in response to adenosine triphosphate (53), extraction of actin-like or actomyosin-like proteins from cells other than muscle cells (54), and identification of activity resembling that of the actomyosin-adenosine triphosphatase system in a variety of nonmuscle tissues (40, 54) are consistent with the idea that portions of the complex, striated muscle contractile system may be present in more primitive contractile machinery. In the case of the egg cortex, calcium-activated contractions can be inhibited by cytochalasin. If, as seems likely, microfilaments are the agents activated by calcium, then it will be clear that they have the same calcium requirement as muscle. Biochemical analyses of primitive contractile systems are difficult to interpret. Ishikawa's important observation (31), that heavy meromyosin complexes with fine filaments oriented parallel to the surface of chondrocytes and perpendicular to the surface of intestinal epithelial cells, implies that both types of filaments are "actin-like" in this one respect. Yet, it is very likely that these actin-like filaments correspond respectively to the cytochalasin-insensitive sheath of glial and heart fibroblasts and the core filaments of oviduct microvilli. No evidence from our studies links contractility directly to these meromyosin-binding filaments. Apart from this problem, activity resembling that of the myosin-adenosine triphosphatase has been associated with the microtubule systems of sperm tails and cilia (55), but those organelles are insensitive to cytochalasin in structure and function. Clearly, a means must be found to distinguish between enzymatic activities associated with microfilament networks, microfilament bundles, microtubules, and the sheath filaments of migratory cells. Until such distinctions are possible, little of substance can be said about the molecular bases of primitive contractile systems. Three variables are important for the control of cellular processes dependent upon microfilaments: (i) which cells of a population shall manufacture and assemble the filaments; (ii) where filaments shall be assembled in cells; and (iii) when contractility shall occur. With respect to distribution among cells, the networks involved in cell locomotion are presumed to be present in all cells that have the potential to move in cell culture. In this respect, the networks can be regarded as a common cellular organelle in the sense that cytoplasmic microtubules are so regarded. In some developing systems, all cells of an epithelium possess microfilament bundles (7, 13), whereas, in others, only discrete subpopulations possess the bundles (5, 6). In these cases the filaments can be regarded as being differentiation products associated only with certain cell types. These considerations may be related to the fact that microfilament networks are associated with behavior of individual cells (such as migration, wound healing, and cytokinesis), whereas the bundles are present in cells that participate in coordinated changes in shape of cell populations. With respect to placement in cells, two alternatives are apparent, namely, localized or ubiquitous association with the plasma membrane. Microfilament bundles of epithelial cells are only found extending across the luminal and basal ends of cells. In this respect they contrast with desmosomal tonofilaments and with microtubules, each of which can curve in a variety of directions through the cell. The strict localization of microfilament bundles probably rests upon their association with special junctional complex insertion regions that are only located near the ends of cells. In the case of mitotically active cells, the orientation of the spindle apparatus may determine the site at which the contractile ring of microfilaments will form (4, 56); this raises the question of what sorts of cytoplasmic factors can influence the process of association between filament systems and plasma membranes. In contrast to such cases of localized distribution, contractile networks responsible for cell locomotion are probably found beneath all of the plasma membrane, just as the network of thrombosthenin may extend to all portions of the periphery of a blood platelet. This ubiquitous distribution probably accounts for the ability of a fibroblast or glial cell to establish an undulating membrane at any point on its edge, or of an axon to form lateral microspikes along its length. The third crucial aspect of control of these contractile apparatuses involves the choice of when contraction shall occur (and as a corollary the degree or strength of contraction that will occur). In the simplest situation, contraction would follow automatically upon assembly of the microfilament bundles or networks. In cleavage furrows of marine embryos (4), for instance, microfilaments are seen beneath the central cleavage furrow and at its ends, but not beyond, under the portion of plasma membrane that will subsequently become part of the furrow. This implies that the furrow forms very soon after the contractile filaments are assembled in the egg cortex. In other cases, microfilaments are apparently assembled but not in a state of (maximal?) contraction. Thus, networks are seen along the sides of migratory cells, although such regions are not then active as undulating membrane organelles. Similarly, microfilament bundles occur in all epithelial cells of the salivary gland (13), or pancreatic anlage (7), although only the ones at discrete points are thought to generate morphogenetic tissue movements. Likewise, bundles begin to appear as early as 12 hours after estrogen administration to oviduct, although visible tubular gland formation does not start until 24 to 30 hours. Finally, streaming in plant cells can wax and wane, depending upon external factors such as auxin (57). All of these cases imply a control mechanism other than mere assembly of the microfilament systems and even raise the possibility that within one cell some filaments may be contracting while others are not. In discussing this problem, it must be emphasized that different degrees of contraction or relaxation cannot as yet be recognized with the electron microscope. In fact, every one of the cases cited above could be explained by contraction following immediately upon some subtle sort of "assembly." Inclusive in the latter term are relations between individual filaments, relations of the filaments and their insertion points on plasma membrane, and quantitative alterations in filament systems. Furthermore, the critical role of calcium and high-energy compounds in muscle contraction suggest that equivalent factors may be part of primitive, cytochalasinsensitive systems. The finding that calcium-induced contraction in the cortex of eggs is sensitive to cytochalasin strengthens that supposition and emphasizes the importance of compartmentalization of cofactors as a means of controlling microfilaments in cells.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The National Cancer Institute (NCI) has recently decided to embark on an international partnership with the developing cancer programs on the Island of Ireland (Northern Ireland and the Republic of Ireland) in an attempt to further improve the quality and range of cancer services available for patients. This Transatlantic Partnership called the All Ireland-NCI Cancer Consortium offers exciting opportunities in cancer treatment, education and research as the cancer-caring communities from both the Republic of Ireland and Northern Ireland prepare to join with the U.S. NCI in this major endeavor. The inaugural event of the partnership will be the NCI All Ireland Cancer Conference to be held in Belfast, October 3-6, 1999. (See www.allirelandcancer.com, for information on the conference.) Cancer is a significant cause of mortality and morbidity on the Island of Ireland. There are approximately 28,000 new cases and approximately 11,000 deaths from cancer each year. Therefore, Northern Ireland and the Republic of Ireland have among the highest cancer incidence and mortality rates in the Western World. In recent years there has been a major restructuring of cancer services in both parts of the Island. This is the result of several government reports such as the Campbell Report in Northern Ireland and the National Strategy Document for Cancer in the Republic of Ireland. The National Strategy Document proposes that cancer treatment services should be centered around primary care services, regional services, supra-regional centers and a national coordinating structure whereby the supra-regional centers deliver specialist surgery, medical and radiation oncology, rehabilitation and specialist palliative care. Three supra-regional cancer centers are being established in the cities of Dublin, Cork and Galway and a National Cancer Forum, which has served as a multidisciplinary advisory board to the Government, has pushed the development and implementation of this plan. This has already resulted in a major expansion in the number of medical oncologists practicing in Ireland but further development is required to facilitate multidisciplinary care, to establish programs of education and training and to harness the scientific talent available to engage in the international effort against cancer. In Northern Ireland the Chief Medical Officer commissioned a report entitled "Cancer Services-Investing for the Future" whose key recommendations were that Northern Ireland should have one cancer center in Belfast and four smaller cancer units. This report also recommended the implementation of a multidisciplinary approach to cancer diagnosis, treatment and palliative care. As in the Republic, all the recommendations of the Report have been accepted and the planning and implementation of this plan are now well under way. Therefore, development of services for cancer patients is a top priority for both governments on the Island and, given the process of cancer service development, it is timely to bring international expertise such as the NCI on board as partners in this effort. The decision by the NCI to develop an agreement for cancer research and service development in Ireland is a major boost for those involved in cancer care and research and will, no doubt, help speed the process of redevelopment. There have already been several visits from senior NCI personnel to Ireland including Dr. Klausner, the Director of the NCI, to determine the potential impact of this agreement and to identify the most productive areas of interaction between the NCI and the Irish Cancer Community. As a result of these visits, the NCI has decided to focus on several areas of strategic importance whose objectives will be to enhance clinical services, improve patient care, promote North South collaboration and cement strategic Ireland-U.S. collaboration in cancer research and development. The agreement will build on existing informal links in U.S.-Irish scientific, medical education and training and also promote clinical trials and cancer epidemiology programs. Major components of the NCI Ireland Agreement will include some of the following: EDUCATION AND EXCHANGE OF SCHOLARS: Education will form one of the major platforms of this agreement through the support of educational programs for medical, nursing and scientific staff. These will include the exchange of scholars, including Ph.D., M.D. and nursing students. Particular emphasis will be given to the exchange of medical and nursing trainees focused on clinical research. This will have an immediate clinical impact and will naturally extend the support that has already been given to the training of medical and scientific trainees from the Island of Ireland. Further exchanges would include Ph.D. students, laboratory-based M.D.s in training, clinical visiting professors and investigators from the U.S. wishing to extend their studies in Ireland. CLINICAL TRIALS: Another major area for partnership will be the enhancement of a clinical trials infrastructure and clinical trial development. Modernization of cancer care requires that delivery of care should be in the context of evidence-based medicine. This requires a vigorous and contemporary clinical trials infrastructure which would center around the clinical trials infrastructure already established at the Northern Ireland Cancer Centre and the Irish Clinical Oncology Research Group (ICORG) in the Republic of Ireland. The NCI has already commissioned the development of a new Clinical Trials Information System (CTIS) which seeks as its goal to set international standards in the clinical trials process, and it has already committed significant resources to its implementation. The outcome of this element of partnership will be that clinical trials performed in Irish institutions will immediately be compatible for collation, analysis and presentation with studies performed in the U.S. Moreover, this system will allow participating centers to immediately conform to international standards. This proposal therefore permits participating institutions in Northern Ireland and the Republic of Ireland to quickly achieve data management standards of the highest quality. TELECONFERENCING: Teleconferencing capabilities are already established in both the NCI and in Ireland and indeed limited teleconferencing linkages have already been established between the partners. Further investment in this infrastructure will be vital to the success of major elements of this partnership. It will facilitate clinical trial development, education programs, patient services development and exchange of clinical and scientific ideas. Communication between sites will be essential to the success of this partnership. TUMOR REGISTRIES: Another area for major collaboration and partnership will be in the use of the Cancer Tumor Registries in both Northern Ireland and the Republic of Ireland. The monitoring of improvements in cancer care can only be undertaken with a reliable tumor registry that tracks population-based cancer incidence and mortality. These data are now available in both Northern Ireland and the Republic of Ireland, and both Governments recognize their importance. The NCI proposes to assist both Tumor Registries by developing a common database that can assist in consultation, informatic tools and quality control. Consolidation of the Registries, North and South, will improve the overall quality of data collection and provide information on a genetically stable population. This therefore will act as a major tool for epidemiological investigations and programs focused on screening and prevention. DEVELOPMENTS IN CANCER CLINICAL SERVICES: The NCI Ireland partnership also proposes to assist the further development of clinical service programs on the Island of Ireland. These will include the improvement and standardization of Radiation Oncology practice and the development of a consolidated Radiation Oncology program for research. There are a limited number of radiation facilities on the Island of Ireland and there are significant needs in terms of linking practice elements and the implementation of uniform standards of practice. Assistance in standardizing and driving the development of clinical services will also extend to elements of medical and surgical oncology practice as well as palliative care. The development of palliative care services is already at an advanced stage on the Island of Ireland and is one that the NCI will carefully evaluate in terms of its own developing programs. THE NCI ALL IRELAND CANCER CONFERENCE: An important event to highlight the commencement of this special relationship will be the NCI All Ireland Cancer Conference to be held in Belfast October 3-6, 1999. This Conference will address clinical, laboratory, epidemiological and political issues that are pertinent to the care of cancer patients. It will highlight important work by Irish, American and European scientists with further input from well-known international academic and biotechnology investigators from across the world. These international experts will not only be asked to speak on their areas of expertise but also to comment on clinical and scientific programs that may help improve North and South interaction and Transatlantic collaboration. Finally, it is hoped that the Conference will be a marker of a very special interaction on the Island of Ireland focused on the overall development of cancer services for patients. It will also signal the start of an important partnership between the NCI and those involved in cancer care and research in Ireland. This tripartite cooperative agreement is a most exciting venture and it will hopefully be an example of how an effort focused on a human problem common to all societies can generate a spirit of cooperation and help to eliminate strife.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Schizophrenia is a disease affecting the young adults and amounts to approximately 300,000 people in France. The French public psychiatric sector takes care of approximately 150,000 adults schizophrenics: 50% benefit from ambulatory care, 50% are in partial or full-time hospitalization care. Schizophrenia represents the first diagnosis that psychiatric sectors take in charge. The costs associated with schizophrenia, mainly hospital costs, are important and were estimated at 2% of the total medical costs in France. In the French social welfare system, the social costs (pensions, allowances, managements of custody or guardianship by social workers) are also to be taken into account: it amounts to a third of the global direct cost. Schizophrenia also generates indirect costs (losses of productivity and premature deaths) which would be at least equal, or even more important, than direct medical costs. The non-compliance to the antipsychotic treatment is a major problem with people suffering from schizophrenia. Indeed the lack of compliance to the treatment, estimated at 20 to 40%, is a major handicap for schizophrenic patient stabilization. The poor level of compliance is due to many various causes: adverse effects that are considered unbearable, medicine viewed as persecutory, negation of the disease, nostalgia for the productive phases of the disease, lack of social support, complexity of the prescription, relapse itself. Compliance is thus influenced by the patient's clinical features, local provision of health care and the specific nature of the drug (adverse effects, pharmaceutical formulation). The atypical antipsychotics present fewer extrapyramidal side effects and reduce the cognitive deficits associated with the disease, which results in improved compliance. Long-acting injectable antipsychotics allow a better therapeutic compliance and thus better efficacy of the treatment. Several studies have shown a significant improvement in compliance related to the pharmaceutical formulation of antipsychotics. Hospitalization and relapse risks are lower in compliant than in non-compliant patients. The main objective of this pharmacoeconomic analysis is to evaluate the impact in terms of medical benefits and costs of the following strategies: 1. Risperidone long-acting injection: first long-acting injectable atypical antipsychotic; 2. Haloperidol depot: long-acting injectable conventional neuroleptic; 3. Olanzapine: atypical antipsychotic available commercially in oral formulation. The target population defined for the study are young schizophrenic patients treated for at least 1 year and whose disorder has not been diagnosed for longer than 5 years. The time horizon is 2 years. A cost-effectiveness analysis is performed. The perspective adopted is the French Health System. The main hypothesis of the model is that an increase in compliance linked to the use of long-acting injectable formulation could lead to an increased efficacy and a modification of the cost-effectiveness ratio. A decision tree was built. Six periods of follow-up are identified with a duration of 4-months per period. The tree contains 3 principal arms, each one corresponding to a specific treatment: risperidone LA injection, haloperidol decanoate and olanzapine. For each arm, at the chance node, two health states are identified: either the patient responds favourably to the treatment or does not respond favourably and requires a switch to another drug treatment. After a period of response, the patient can either remain in the same state or experiences a clinical deterioration. If the patient presents a clinical deterioration, he can either go back to a positive response state after a period of intensive follow-up or remain in an insufficient response state; in this case, a change of antipsychotic treatment is necessary. In the model, a patient should receive four different treatments before a long-term hospitalization takes put in place. According to the market authorization labelling, clozapine is proposed only as a 2nd or 3rd line therapeutic option, so when at least one or two successive neuroleptics have failed. The efficacy data used in the model are provided by clinical research recently published. These studies estimate the efficacy of oral risperidone, LA risperidone, olanzapine, and treatment by haloperidol. When available data in the literature were insufficient, the opinion of experts was sought. The effectiveness criteria is the rate of patients treated successfully: patients responding to the initial treatment with the possibility of experiencing one or two episodes of clinical deterioration but without requiring a switch to another drug during 2 years of follow-up. The base case is as follows: efficacy for oral risperidone is used for the LA risperidone strategy, increased by 10% within the first 4 months of follow-up; efficacy for oral haloperidol is used for haloperidol depot, increased by 5% within the first 4 months of follow-up; for olanzapine, observed data in clinical trials were applied. The hypotheses for long acting forms are rather conservative because the increase of efficacy which can be expected for the long-acting injectable formulations varies between 5% to more than 30% according to the literature data. The analysis of sensibility includes three scenarios: scenario 1: for LA risperidone, 5% of patients treated successfully improvement in regard to oral risperidone instead of 10% in the base case; scenario 2: for haloperidol depot, 10% of patients treated successfully improvement in regard of oral haloperidol instead of 5% in the base case; scenario 3: the results of an open trial conducted within the framework of the LA risperidone license are used, leading to an increase of up to 13,3% of the rate of successfully treated patients, compared to oral risperidone literature data. As for the side effects, only extrapyramidal symptoms were considered. Other side effects are described in the literature such as the obesity or the occurrence of a diabetes; these effects were not taken into account in the model, their impact on the cove-rage of schizophrenic patients and on resources utilisation being poorly known. Only direct medical costs were considered in the pharmaco-economic analysis. Two types of costs were identified: hospital costs and community care costs. The stays in overnight hospitalisation and day hospitalisation were derived from the Disease Related Groups (DRG) and valued from the data of the National Cost Study (Etude Nationale de Coûts; 1999). The DRGs corresponding to the diagnosis of schizophrenia are the DRG 627 (complete hospitalization) and DRG 819 (day hospitalisation). Ambulatory care: procedures and visits, were valued in euros in reference with the tariffs for reimbursement issued in the Naming General of the Professional Acts (NGAP) and published by the French National Health Insurance (Year 2001). Medication consumption was quantified by using the daily dosage specified in the the MAA and the French prescription database IMS-Dorema. The cost of medicines was valued from tariffs 2001 (SEMPEX). LA risperidone price being not fixed to date, the reserved hypothesis is a 141,62 Euro retail price. As schizophrenia is listed among the diseases reimbursed at a 100% rate by the Health insurance, out of pocket expenses by patient are not considered in the analysis. The cost for the extrapyramidal effects was attributed to all the strategies. This cost was calculated according to the rates of extrapyramidal effects occurrence collected in the literature. Globally, in the published studies, the incidence of the side effects for the patients treated by olanzapine or risperidone is similar. It was thus decided by the experts to use the same rate of occurrence for extrapyramidal effects for olanzapine and risperidone (20%). This rate is 40% for haloperidol decanoate, 10% for oral clozapine. For the cost estimation, the expenses for treating a schizophrenic patient for two years were taken into account. The results show that in two years, LA risperidone is more effective than the two other antipsychotics. After 2 years, the rate of patients treated successfully is 82,7% for LA risperidone, 74,8% for olanzapine and 57,3% for haloperidol depot. The 2 year-cost per patient treated by LA risperidone is 14,055 Euro. This cost is 14,351 Euro and 17,203 Euro respectively for the strategies olanzapine and haloperidol depot. The cost-efficacy ratios per patient successfully treated are 16,995 Euro for the strategy LA risperidone, 19,186 Euro for olanzapine and 30,023 Euro for haloperidol depot. LA risperidone is a dominant strategy compared with both olanzapine and haloperidol depot. Scenario 1 shows that LA risperidone strategy remains the most effective. Indeed, this strategy allows a response increase of 3,5% regarding olanzapine strategy and of 21% regarding haloperidol depot strategy. Under the hypothesis tested in scenario 1, LA risperidone is a partial dominant strategy against olanzapine and a total dominant strategy against haloperidol depot. In scenario 2, as efficacy is improved for haloperidol decanoate (61,10%), a decrease of 1,763 Euro in the cost per patient treated is observed for this strategy. Cost per patient treated successfully and efficacy for LA risperidone and olanzapine are the same than in the base case. LA risperidone is a total dominant strategy against olanzapine and haloperidol decanoate. In scenario 3, the rate of patients treated successfully at 2 years is 88,6% for LA risperidone with a cost per patient of 12,347 Euro. LA risperidone is dominant against olanzapine and haloperidol depot. The schizophrenia is a relatively frequent disease. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
These studies have shown that the bones of guinea pigs given daily injections of parathormone from the age of 2 to 7 days to the age of 110 to 120 days, show relatively very little effect after receiving 20 units daily during the last 65 to 87 days of treatment. But it is probable that their bones underwent decalcification early in the treatment and that subsequently the parathormone, continued at the same dosage, did not maintain the effects on the bones. Healing finally occurred despite it. The bones of guinea pigs treated with intermittent injections of large doses of parathormone from the time they were 1 week old to the age of 95 to 145 days also showed relatively few changes at the end of the treatment. The injections were given at intervals of 7 to 11 days, and were stepped up from 60 units to 140 units. From our previous experience (1) we infer that the earlier injections of parathormone produced very extensive bone changes which healed in the intervals between the injections. As the guinea pigs became older the injections of parathormone did not produce as severe effects. We have found in our studies of experimental hyperparathyroidism that the bone changes after a single large dose of parathormone in young guinea pigs are soon healed. The study of a series of animals shows that healing begins at about the 48th hour after injection, and proceeds rapidly. Between the 8th and 14 days, callus may be observed at the costochondral junctions, where fractures had occurred. Now the endosteum may be lined by osteoblasts and the vessel canals by new formed bone. In adult guinea pigs extremely large single doses had little effect on the bones in 48 hours, even though the dose killed the animal. It was only when three doses pyramided over a period of 48 hours and totaling 2580 units of parathormone were given, that moderately severe bone resorption could be demonstrated in the adult. The elevation of serum calcium may be considered as one of the indices of calcium mobilization in experimental hyperparathyroidism. When the rate of calcium excretion exceeds the rate of its mobilization, or when the animal is on a low calcium diet, hypercalcemia may be absent. It is possible to raise the serum calcium of adult guinea pigs by large single doses of parathormone, but the resulting rise is not as great as in the young (2). This is confirmatory evidence of the fact that calcium is mobilized much less rapidly from the bones of old animals than from those of young ones. Collip pointed out that young normal dogs are more susceptible to parathormone (6). This observation was corroborated by Morgan and Garrison (7). We found that the same difference held also in experimental hyperparathyroidism produced in dogs by repeated doses of parathormone (8). In man, clinical experience likewise indicates the necessity of using relatively large doses of parathormone to raise the serum calcium of adults. The serum calcium of middle-aged or old adults does not rise significantly unless as much as 100 units or more of parathormone are given daily for a number of days. Charts VI and VII, in a recent paper by Merritt and Bauer (9), support our findings of the relative difficulty of obtaining a significant elevation of serum calcium in adults. If adult guinea pigs are given daily injections of parathormone which are rapidly stepped up, the animals may be killed by the ensuing acute hyperparathyroidism, only slight bone changes being produced. However, a careful avoidance of the induction of acute hyperparathyroidism by gradual stepping up of the parathormone dose permits the employment of doses continued over a long period of time that could not possibly have been tolerated otherwise. Furthermore, healing of the lesions thus produced may occur, in spite of the continuance of parathormone at this level. It seems likely that the difference in response of young and old guinea pigs to single doses of parathormone, as indicated by the bone changes, as well as by the serum calcium and phosphorus, is related to the more rapid rate of mineral metabolism in the young, actively growing animals. The calcium mobilizing effect of parathormone is most prominent in actively growing young animals, the calcium being withdrawn from the most readily available stores-the regions of most active new bone formation and most active bone reconstruction (10). In the adult animal the calcium reserves (in the formed bone) are less susceptible to the calcium mobilizing effect of parathormone. The adult guinea pig will show relatively slight bone changes even as a result of extremely large, fatal doses of parathormone. Repeated doses, as is well known, will produce, by pyramiding, greater effects than the entire amount administered at one time. In this type of experiment the young again show greater susceptibility of the bone than the adult. In time, however, some compensation takes place, and the effects of the same doses are decreased until finally healing may occur in spite of the continued treatment. Increase of the dose, however, again elicits the parathormone effects upon the bone, as well as upon the serum calcium and phosphorus, without toxic changes (1, 8). It would seem that some compensation sets in which may be overcome by increasing the dose. This compensation is especially evident in the experiments in which the parathormone doses were stepped up gradually from small amounts. In addition to the compensation observed in young and adult animals as a result of repeated injections of parathormone, we must also consider the possibility that there is a compensating mechanism in adult animals more effective than in the young. That compensation occurs is unquestionable but its nature is not clear. Apparently it is less effective during pregnancy, doses of parathormone which produce only slight bone changes in ordinary adults causing very severe lesions in advanced pregnancy (11). Parathormone has been shown to produce only one primary effect on bone, and that is decalcification. This may come about as the result of a change in the circulating tissue fluids, the salts being dissolved out of the organic matrix, and the latter disappearing secondarily. The process is most rapid in the vicinity of most active bone formation. The osteoblasts disappear from the surfaces of bone where dissolution is occurring, and at the same time the marrow connective tissue proliferates. Fusion of cells produces osteoclasts (12), which then proceed to remove the decalcified organic matrix, with the production of the deep lacunae of Howship. Frequently leucocytes are also observed actively phagocyting the decalcified organic matrix, and often leucocytes are observed within the osteoclasts (12). Healing is associated with the complete reversal of the process. The osteoclasts disappear, the connective tissue diminishes, osteoblasts reappear, and bone formation is resumed. As we have previously stated (13), parathormone produces a more continuous effect than experimental acidosis and greater changes than are seen in experimental osteoporosis. A pronounced decalcification results from it which, with its sequelae, simulates von Recklinghausen's disease. The emphasis which the older pathologists laid on osteoclasts as a special feature of ostitis fibrosa cystica is justified, for in the experimental condition the appearance of great numbers of osteoclasts is a constant feature, whenever decalcification occurs (13). There seems to be no doubt that the giant cell tumors found in ostitis fibrosa cystica are expressions of the same pathological response. The other features of the bone changes of hyperparathyroidism-marrow hemorrhage, cysts, fractures, and osteoid proliferation-are secondary to the primary decalcification. Progress of the pathological changes leads to circulatory stasis and cyst formation. Stresses and strains exerted on the progressively weakening bone may result in microscopical or gross fractures. Osteoid tissue is, as we have previously pointed out (13), merely reparative in nature, being laid down as support to the weakened or fractured bone, or as a part of healing. Osteoid borders appear on bone surfaces 48 hours after one large dose of parathormone. The mosaic picture which we have observed in the bones of some of our animals is produced by short and irregularly disposed cement lines resulting from rapid bone transformation. Schmorl (14) recently emphasized the mosaic-like appearance of the newly formed lamellar bone in Paget's disease (ostitis fibrosa deformans). The mosaic-like appearance of bone has also been described in local bone conditions, as e.g. syphilitic periostitis, and in bone in the vicinity of cysts and giant cell tumors in von Recklinghausen's disease (ostitis fibrosa cystica). However, Schmorl claims that in no disease is the mosaic appearance so constant and the arrangement of the cement lines so irregular as in Paget's disease. In chronic experimental hyperparathyroidism (von Recklinghausen's disease), the mosaic structure is not a prominent feature because of the progressive decalcification. But the bones of our young guinea pigs which received intermittent injections showed a mosaic-like appearance indicative of the periodic decalcifications and restorations which they had undergone.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The objective of this health technology policy assessment was to determine the clinical effectiveness and cost-effectiveness of IVF for infertility treatment, as well as the role of IVF in reducing the rate of multiple pregnancies. TARGET POPULATION AND CONDITION Typically defined as a failure to conceive after a year of regular unprotected intercourse, infertility affects 8% to 16% of reproductive age couples. The condition can be caused by disruptions at various steps of the reproductive process. Major causes of infertility include abnormalities of sperm, tubal obstruction, endometriosis, ovulatory disorder, and idiopathic infertility. Depending on the cause and patient characteristics, management options range from pharmacologic treatment to more advanced techniques referred to as assisted reproductive technologies (ART). ART include IVF and IVF-related procedures such as intra-cytoplasmic sperm injection (ICSI) and, according to some definitions, intra-uterine insemination (IUI), also known as artificial insemination. Almost invariably, an initial step in ART is controlled ovarian stimulation (COS), which leads to a significantly higher rate of multiple pregnancies after ART compared with that following natural conception. Multiple pregnancies are associated with a broad range of negative consequences for both mother and fetuses. Maternal complications include increased risk of pregnancy-induced hypertension, pre-eclampsia, polyhydramnios, gestational diabetes, fetal malpresentation requiring Caesarean section, postpartum haemorrhage, and postpartum depression. Babies from multiple pregnancies are at a significantly higher risk of early death, prematurity, and low birth weight, as well as mental and physical disabilities related to prematurity. Increased maternal and fetal morbidity leads to higher perinatal and neonatal costs of multiple pregnancies, as well as subsequent lifelong costs due to disabilities and an increased need for medical and social support. IVF was first developed as a method to overcome bilateral Fallopian tube obstruction. The procedure includes several steps: (1) the woman's egg is retrieved from the ovaries; (2) exposed to sperm outside the body and fertilized; (3) the embryo(s) is cultured for 3 to 5 days; and (4) is transferred back to the uterus. IFV is considered to be one of the most effective treatments for infertility today. According to data from the Canadian Assisted Reproductive Technology Registry, the average live birth rate after IVF in Canada is around 30%, but there is considerable variation in the age of the mother and primary cause of infertility. An important advantage of IVF is that it allows for the control of the number of embryos transferred. An elective single embryo transfer in IVF cycles adopted in many European countries was shown to significantly reduce the risk of multiple pregnancies while maintaining acceptable birth rates. However, when number of embryos transferred is not limited, the rate of IVF-associated multiple pregnancies is similar to that of other treatments involving ovarian stimulation. The practice of multiple embryo transfer in IVF is often the result of pressures to increase success rates due to the high costs of the procedure. The average rate of multiple pregnancies resulting from IVF in Canada is currently around 30%. An alternative to IVF is IUI. In spite of reported lower success rates of IUI (pregnancy rates per cycle range from 8.7% to 17.1%) it is generally attempted before IVF due to its lower invasiveness and cost. Two major drawbacks of IUI are that it cannot be used in cases of bilateral tubal obstruction and it does not allow much control over the risk of multiple pregnancies compared with IVF. The rate of multiple pregnancies after IUI with COS is estimated to be about 21% to 29%. Ontario Health Insurance Plan Coverage Currently, the Ontario Health Insurance Plan covers the cost of IVF for women with bilaterally blocked Fallopian tubes only, in which case it is funded for 3 cycles, excluding the cost of drugs. The cost of IUI is covered except for preparation of the sperm and drugs used for COS. DIFFUSION OF TECHNOLOGY: According to Canadian Assisted Reproductive Technology Registry data, in 2004 there were 25 infertility clinics across Canada offering IVF and 7,619 IVF cycles performed. In Ontario, there are 13 infertility clinics with about 4,300 IVF cycles performed annually. ROYAL COMMISSION REPORT ON REPRODUCTIVE TECHNOLOGIES: The 1993 release of the Royal Commission report on reproductive technologies, Proceed With Care, resulted in the withdrawal of most IVF funding in Ontario, where prior to 1994 IVF was fully funded. Recommendations of the Commission to withdraw IVF funding were largely based on findings of the systematic review of randomized controlled trials (RCTs) published before 1990. The review showed IVF effectiveness only in cases of bilateral tubal obstruction. As for nontubal causes of infertility, there was not enough evidence to establish whether IVF was effective or not. Since the field of reproductive technology is constantly evolving, there have been several changes since the publication of the Royal Commission report. These changes include: increased success rates of IVF; introduction of ICSI in the early 1990's as a treatment for male factor infertility; and improved embryo implantation rates allowing for the transfer of a single embryo to avoid multiple pregnancies after IVF. STUDIES AFTER THE ROYAL COMMISSION REPORT: REVIEW STRATEGY THREE SEPARATE LITERATURE REVIEWS WERE CONDUCTED IN THE FOLLOWING AREAS: clinical effectiveness of IVF, cost-effectiveness of IVF, and outcomes of single embryo transfer (SET) in IVF cycles. CLINICAL EFFECTIVENESS OF IVF: RCTs or meta-analyses of RCTs that compared live birth rates after IVF versus alternative treatments, where the cause of infertility was clearly stated or it was possible to stratify the outcome by the cause of infertility.COST EFFECTIVENESS OF IVF: All relevant economic studies comparing IVF to alternative methods of treatment were reviewedOUTCOMES OF IVF WITH SET: RCTs or meta-analyses of RCTs that compared live birth rates and multiple birth rates associated with transfer of single versus double embryos.OVID MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Cochrane Library, the International Agency for Health Technology Assessment database, and websites of other health technology assessment agencies were searched using specific subject headings and keywords to identify relevant studies. COMPARATIVE CLINICAL EFFECTIVENESS OF IVF: Overall, there is a lack of well composed RCTs in this area and considerable diversity in both definition and measurement of outcomes exists between trials. Many studies used fertility or pregnancy rates instead of live birth rates. Moreover, the denominator for rate calculation varied from study to study (e.g. rates were calculated per cycle started, per cycle completed, per couple, etc...). Nevertheless, few studies of sufficient quality were identified and categorized by the cause of infertility and existing alternatives to IVF. The following are the key findings: A 2005 meta-analysis demonstrated that, in patients with idiopathic infertility, IVF was clearly superior to expectant management, but there were no statistically significant differences in live birth rates between IVF and IUI, nor between IVF and gamete-intra-Fallopian transfer.A subset of data from a 2000 study showed no significant differences in pregnancy rates between IVF and IUI for moderate male factor infertility.In patients with moderate male factor infertility, standard IVF was also compared with ICSI in a 2002 meta-analysis. All studies included in the meta-analysis showed superior fertilization rates with ICSI, and the pooled risk ratio for oocyte fertilization was 1.9 (95% Confidence Interval 1.4-2.5) in favour of ICSI. Two other RCTs in this area published after the 2002 meta-analysis had similar results and further confirmed these findings. There were no RCTs comparing IVF with ICSI in patients with severe male factor infertility, mainly because based on the expert opinion, ICSI might only be an effective treatment for severe male factor infertility. COST-EFFECTIVENESS OF IVF: Five economic evaluations of IVF were found, including one comprehensive systematic review of 57 health economic studies. The studies compared cost-effectiveness of IVF with a number of alternatives such as observation, ovarian stimulation, IUI, tubal surgery, varicocelectomy, etc... The cost-effectiveness of IVF was analyzed separately for different types of infertility. Most of the reviewed studies concluded that due to the high cost, IVF has a less favourable cost-effectiveness profile compared with alternative treatment options. Therefore, IVF was not recommended as the first line of treatment in the majority of cases. The only two exceptions were bilateral tubal obstruction and severe male factor infertility, where an immediate offer of IVF/ICSI might the most cost-effective option. CLINICAL OUTCOMES AFTER SINGLE VERSUS DOUBLE EMBRYO TRANSFER STRATEGIES OF IVF: Since the SET strategy has been more widely adopted in Europe, all RCT outcomes of SET were conducted in European countries. The major study in this area was a large 2005 meta-analysis, followed by two other published RCTs. All of these studies reached similar conclusions: Although a single SET cycle results in lower birth rates than a single double embryo transfer (DET) cycle, the cumulative birth rate after 2 cycles of SET (fresh + frozen-thawed embryos) was comparable to the birth rate after a single DET cycle (~40%).SET was associated with a significant reduction in multiple births compared with DET (0.8% vs. 33.1% respectively in the largest RCT). (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The present studies explored whether faecal retention in the colon is a causative factor in functional bowel disease, appendicitis, and haemorrhoids. Faecal retention was characterized by colon transit time (CTT) after radio-opaque marker ingestion and estimation of faecal loading on abdominal radiographs at 48 h and 96 h. Specific hypotheses were tested in patients (n = 251 plus 281) and in healthy random controls (n = 44). A questionnaire was completed for each patient, covering abdominal and anorectal symptoms and without a priori grouping. Patients with functional bowel disorders, predominantly women, had a significantly increased CTT and faecal load compared to controls. The CTT was significantly and positively correlated with segmental and total faecal loading. The faecal load was equal at 48 h and 96 h, mirroring the presence of permanent faecal reservoirs. In these first clinical studies to correlate bowel symptoms with CTT and colon faecal loading, abdominal bloating was significantly correlated with faecal loading in the right colon, total faecal load, and CTT. Abdominal pain was significantly and positively correlated to distal faecal loading and significantly associated with bloating. A new phenomenon with a high faecal load and a normal CTT was observed in a subset of patients (n = 90), proving faecal retention as hidden constipation. The CTT and faecal load were significantly higher in the right-side compared to the left and distal segments. Within the control group of healthy persons, the right-sided faecal load was significantly greater than the left and distal load. The CTT and faecal load significantly positively correlated with a palpable mass in the left iliac fossa and meteorism. Cluster analysis revealed that CTT and faecal load positively correlated with a symptom factor consisting of bloating, proctalgia and infrequent defecation of solid faeces. On the other hand, CTT and faecal load negatively correlated with a symptom factor comprising frequent easy defecations, repetitiveness, and incompleteness with solid or liquid faeces. The majority of patients with a heavy faecal load but normal CTT had repetitive daily defecation, mostly with ease and with altering faecal consistence. Flue-like episodes co-existed in symptom factors with abdominal pain and meteorism, and these symptoms together with a palpable right iliac fossa mass and tenderness, and in other factors with seldom and difficult defecation, and with epigastric discomfort and halitosis. Patients with seldom and difficult defecation of solid faeces experienced abdominal pain significantly more often and presented a palpable mass in the right iliac fossa with tenderness and meteorism. The CTT was significantly prolonged and faecal load significantly increased. In patients with a normal CTT and increased faecal load, only patients with abdominal pain had a significant correlation between faecal loading and bloating. CTT and faecal load were shown for the first time to increase significantly with the number of colonic redundancies (colon length), which also resulted in significantly increased bloating and pain. Intervention with a bowel stimulation regimen combining a fibre-rich diet, fluid, physical activity, and a prokinetic drug was essential to proving that abdominal symptoms and defecation disorders are caused by faecal retention, with or without a prolonged CTT. The CTT was significantly reduced, as was faecal load. Bloating and pain were reduced significantly. The defecation became easy with solid faeces, towards one per day and with significant reductions in incompleteness and repetitiveness. Proctalgia and flue-like episodes were significantly reduced. The intervention significantly reduced the presence of a tender palpable mass in the right fossa and rectal constipation. In patients with a normal CTT but increased faecal load, the intervention did not significantly change the CTT or load, but bloating and pain were significantly reduced, just as defecation improved overall. The novel knowledge of faecal retention in the patients does not explain why faecal retention occurs. However, it may be inferred from the present results that a constipated or irritable bowel may belong to the same underlying disease dimension, where faecal retention is a common factor. Thus, measuring CTT and faecal load is suggested as a guide to a positive functional diagnosis of bowel disorders compared to the constellation of symptoms alone. Thirty-five patients underwent surgery after being refractory to the conservative treatment for constipation. They had a significantly prolonged CTT and heavy faecal loading, which was responsible for the aggravated abdominal and defaecatory symptoms. The operated patients presented with a redundant colon (dolichocolon) significantly more often. These patients also had an extremely high rate of previous appendectomy. Twenty-one patients underwent hemicolectomy, and 11 patients had a subtotal colectomy with an ileosigmoidal anastomosis; three patients received a stoma. However, some patients had to have the initial segmental colectomy converted to a final subtotal colectomy because of persisting symptoms. Six more subtotal colectomies have been performed and the leakage rate of all colectomies is then 4.9 % (one patient died). After a mean follow-up of 5 years, the vast majority of patients were without abdominal pain and bloating, having two to four defecations daily with control and their quality of life had increased considerably. A faecalith is often located in the appendix, the occlusion of which is responsible for many cases of acute appendicitis, which is infrequent in all except white populations. An effort to trace the origin of the faecalith to faecal retention in the colon was made in a case control study (56 patients and 44 random controls). The CTT was longer and faecal load greater in patients with appendicitis compared to controls, though the difference was not significant. Power calculations showed that more patients were needed to reach statistical significance for these parameters. The presence of a faecalith was most often associated with a gangrenous or perforated appendix. No significant differences were found between the CTT and faecal load of patients who had or did not have a faecalith. However, the right-sided faecal load was significantly higher than the left and distal load. Haemorrhoids are often a consequence of constipation and defaecatory disorders and were found in every second patient with functional bowel disorders. The present studies are the first Danish reports of a novel operation to cure this disease, stapled haemorrhoidopexy (n = 40 and 258 patients). The majority of patients had prolapsed haemorrhoids, and the durability of procedure was confirmed with a follow-up of up to 5 years, meaning a normal anus. The operation time was short, post-operative pain was low, and recovery was rapid. No incontinence was observed, and patient satisfaction was high and significantly correlated with the appearance of a normal anus without prolapse. The cumulative risk of re-operation was greatest in the first 2 years after the stapled haemorrhoidopexy. Patients with persisting haemorrhoidal prolapse had the procedure repeated with results as good as those obtained in the rest of the patients. It was shown in a statistical model that the preoperative severity of haemorrhoidal disease and the immediate postoperative result contributed significantly to predicting the outcome that is the durability of the operation. The most frequent post-operative complication was bleeding requiring surgical haemostasis. One serious complication occurred after an anastomotic leak from a highly placed anastomosis, resulting in retro rectal, retro- and intra-peritoneal, and mediastinal gas. The patient recovered after conservative treatment and without surgical intervention. The stapling technique now used has revolutionized the surgical treatment of prolapsing haemorrhoids. Finally, a common cause may be suspected for diseases constantly associated with one another. Epidemiological evidence has recognized that constipation, diverticulosis and IBS increase the risk of colon cancer (and adenomas), diseases exceedingly rare in communities exempt from appendicitis. Haemorrhoids are a colonic co-morbidity as well. Notably, the patients with a functional bowel disorder had a much higher rate of a previous appendectomy than the background population. In addition, the patients who had previously had an appendectomy had a significantly longer CTT compared to patients, who had not. The data points to the involvement of faecal retention in the origin of faecaliths and, thus, acute appendicitis. Faecal reservoirs were shown in the right and left colon segments in both patients and controls, which are the same areas bearing the highest incidences of adenomateous polyps and malignancies. Familial colorectal cancer occurred significantly more often in patients who had a higher faecal load than the controls. Four malignancies and 25 adenomas were identified. An increased faecal load in the colon with or without delayed transit will increase bacterial counts and create a chronic inflammation of the colonic mucosa, which is a risk factor for cancer onset. A functional bowel disorder is then likely to occur with gradually transition from a primary functional disease into specific organic diseases. A diet rich in fibre and regular physical activity have a therapeutic and preventive effect on colorectal diseases associated with faecal retention. A “common cause” was earlier proposed for constipation, colon diverticula, cancer, appendicitis, and haemorrhoids. The actual results of the present studies support this unifying theory for these diet-related diseases, in which the functional retention of faeces maybe the common cause.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
N,N-dimethyl-p-toluidine was nominated for toxicology and carcinogenesis studies by the National Cancer Institute based on the potential for human exposure through its use in dental materials and bone cements and the lack of toxicity and carcinogenicity data. Male and female F344/N rats and B6C3F1/N mice were administered N,N-dimethyl-p-toluidine (greater than 99% pure) in corn oil by gavage for 3 months or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli, mouse peripheral blood, and mouse and rat liver. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered 0, 62.5, 125, 250, 500, or 1,000 mg N,N-dimethyl-p-toluidine/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. Additional groups of 10 male and 10 female rats (clinical pathology study) were administered the same doses, 5 days per week for 25 days. On day 88, blood was collected from core study rats for hemoglobin and methemoglobin analyses only. All 1,000 mg/kg male and female rats and one 500 mg/kg male rat died by study day 3. Mean body weights of all surviving dosed groups of males and females were significantly less than those of the vehicle controls. Clinical findings associated with exposure to N,N-dimethyl-p-toluidine included cyanosis, abnormal breathing, and lethargy in groups administered 250 mg/kg or greater. Methemoglobinemia appeared to be the primary hematologic toxic response, and many other lesions could be explained as secondary to methemoglobin formation including Heinz body formation; a macrocytic, hypochromic, responsive anemia; and increased hematopoietic cell proliferation in the spleen and bone marrow. In general, hematologic changes were dose-related and occurred at both evaluated timepoints in all dosed groups. Anemia was evidenced by decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts; erythrocyte macrocytosis was characterized by increases in mean cell volume and mean cell hemoglobin values; erythrocyte hypochromia was evidenced by decreases in mean cell hemoglobin concentration values; and an erythropoietic response to the anemia was characterized by substantially increased reticulocyte and nucleated erythrocyte counts. Liver weights of all surviving dosed groups of males and females were significantly greater than those of the vehicle controls. Kidney weights of all surviving dosed groups of females were significantly greater than those of the vehicle controls. There were significant decreases in left cauda epididymis and left epididymis weights in 250 mg/kg males. There was a dose-related decrease in the number of cycling females, with only four females in the 250 mg/kg group having regular cycles and females in the 125 and 250 mg/kg groups spending a significantly higher proportion of time in extended diestrus compared to the vehicle control group. In the surviving groups of rats, there were significantly increased incidences of pigmentation in the liver of all dosed groups, hepatocyte hypertrophy in groups administered 125 mg/kg or greater, and hepatocyte necrosis in 62.5, 250, and 500 mg/kg females. In the olfactory epithelium of the nose, there were dose-related increases in the incidences and severities of degeneration in all dosed groups and significantly increased incidences of metaplasia in the 250 and 500 mg/kg groups. In the respiratory epithelium of the nose, there were significantly increased incidences of hyperplasia and squamous metaplasia in all of the groups administered 125 mg/kg or greater. The incidences of glandular hyperplasia of the nose were significantly increased in males and females administered 125, 250, or 500 mg/kg. In the spleen, there were significantly increased incidences of capsule fibrosis, congestion, mesothelial hypertrophy, and lymphoid follicle atrophy primarily in groups administered 125 mg/kg or greater. Hematopoietic cell proliferation and pigmentation were increased in severity in treated groups. In the kidney, there were significantly increased incidences of nephropathy (females), pigmentation (males and females), papillary necrosis (males and females), and mineralization (males). Other treatment-related lesions included inflammation of the forestomach in males, mesenteric lymph node atrophy in females, and bone marrow hyperplasia in males and females. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered 0, 15, 30, 60, 125, or 250 mg N,N-dimethyl-p-toluidine/kg body weight in corn oil by gavage, 5 days per week for 14 weeks. All 250 mg/kg male and female mice (except for one male mouse) died before day 10, and three males and two females administered 125 mg/kg died before the end of the study. The final mean body weight of 125 mg/kg males and the mean body weight gains of 125 mg/kg males and females were significantly less than those of the vehicle controls. Clinical findings associated with administration of N,N-dimethyl-p-toluidine included abnormal breathing, thinness, lethargy, cyanosis, and ruffled fur in 125 and 250 mg/kg males and females. Methemoglobinemia appeared to be the primary hematologic toxic response; however there were less severe erythron changes compared to the 3-month study in rats. In females, no erythron changes were detected up to 125 mg/kg. In males, inconsistent and minor decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts, and increased reticulocyte counts occurred in groups administered 60 mg/kg or greater. Methemoglobin values were minimally increased in males and females administered 30 mg/kg or greater. Heinz bodies were slightly increased in 60 mg/kg females, 125 mg/kg males and females, and the one surviving 250 mg/kg male; Heinz body formation was considered secondary to methemoglobin formation. Liver weights of all dosed groups of mice were significantly greater than those of the vehicle controls. In the surviving groups of mice, there were significantly increased incidences of bronchiolar epithelium degeneration, bronchiolar epithelium regeneration, and peribronchiolar chronic active inflammation in the lung of 125 mg/kg groups, and histiocytic infiltrates of the alveoli in 125 mg/kg females. In the nose, there were significantly increased incidences of glandular hyperplasia and olfactory epithelium metaplasia in the 125 mg/kg groups and olfactory epithelium degeneration in 60 mg/kg females and 125 mg/kg males and females. In the thymus, the incidences of thymocyte necrosis in the 125 mg/kg groups were significantly increased. In the liver, the severities of cytoplasmic vacuolization of the hepatocytes were increased in dosed groups of males and females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were administered 0, 6, 20, or 60 mg N,N-dimethyl-p-toluidine/kg body weight in corn oil by gavage, 5 days per week for 104 or 105 weeks. Additional groups of 10 male and 10 female rats (clinical pathology study) were administered the same doses for 86 days. Survival of 60 mg/kg males was significantly less than that of the vehicle controls. Mean body weights of 60 mg/kg males and females were more than 10% less than those of the vehicle controls after week 61 and week 33, respectively. Clinical findings included signs of pallor in 60 mg/kg females and hyperactivity and boxing behavior in 20 mg/kg females and 60 mg/kg males and females. The hematology findings at the 3-month timepoint were consistent with those in the 3-month study in rats which indicated that methemoglobinemia was the primary hematologic toxic response. In the 20 and 60 mg/kg groups, there were dose-related decreases in hematocrit values, hemoglobin concentrations, and erythrocyte counts. There were similar trends toward erythrocyte macrocytosis and hypochromia and increased erythropoiesis as seen in the 3-month study. While the magnitudes of the erythron decreases were not sufficient to classify the responses as anemias, the patterns of the erythron changes were identical to those in the 3-month study. In the liver of 60 mg/kg males and females, there were significantly increased incidences of hepatocellular carcinoma and hepatocellular adenoma or hepatocellular carcinoma (combined). Numerous nonneoplastic liver lesions occurred in dosed males and females primarily in the 20 and 60 mg/kg groups. In the nose, there were significantly increased incidences of transitional epithelium adenoma and transitional epithelium adenoma or carcinoma (combined) in 60 mg/kg males; transitional epithelium adenoma also occurred in female rats administered 6 or 60 mg/kg. In the nose, there were significantly increased incidences of nonneoplastic lesions in the olfactory, respiratory, and transitional epithelia of dosed rats. These lesions occurred with the greatest incidence and severity in the 60 mg/kg groups. The incidences of inflammation and nerve atrophy were significantly increased in males and females administered 60 mg/kg. There were increased incidences of follicular cell adenoma or carcinoma (combined) of the thyroid gland in all dosed groups of males, and an increased incidence of follicular cell adenoma in 20 mg/kg females. In the spleen, there were significantly increased incidences of hematopoietic cell proliferation in all dosed groups of males and females. The incidences of congestion and mesothelial hypertrophy of the capsule were significantly increased in 60 mg/kg males and all dosed groups of females. There were also significantly increased incidences of capsular fibrosis and atrophy of the lymphoid follicle in the 60 mg/kg groups. The incidences of pigmentation were significantly increased in all dosed groups of males and in 60 mg/kg females. In all dosed groups of female rats, there were significantly increased incidences of nephropathy. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The suicide rates in Denmark have been declining during the last two decades. The decline was relatively larger among women than among men. All age groups experienced a decline except the very young with stable rates and the very old with increasing rates. The Universal, Selective, Indicated (USI) model recommended by Institute of Medicine was used as a framework for the thesis. Universal preventive interventions are directed toward the entire population; selective interventions are directed toward individuals who are at greater risk for suicidal behaviour; and indicated preventions are targeted at individuals who have already begun self-destructive behaviour. At the universal level, a review was carried out to highlight the association between availability of methods for suicide and suicide rate. There were mostly studies of firearms, and the conclusion of the review was that there was clear indication of restricted access to lethal means was associated with decline in suicide with that specific method, and in many cases also with overall suicide mortality. Restricting access is especially important for methods with high case fatality rate. Our own study indicated a beneficial effect on suicide rates of restrictions in access to barbiturates, dextropropoxyphen, domestic gas and car exhaust with high content of carbon monoxide. Although a range of other factors in the society might also be of importance, it was concluded that restrictions in access to dangerous means for suicide were likely to play an important role in reducing suicide rates in Denmark, especially for women. At the selective level, there are several important risk groups such as psychiatric patients, persons with alcohol and drug abuse, persons with newly diagnosed severe physical illness, all who previously attempted suicide, and groups of homeless, institutionalized, prisoners and other socially excluded persons. The thesis focused on homeless persons and psychiatric patients, especially patients with schizophrenia and related disorders. The thesis contains a review of the risk of suicide in homeless. In all the studies included, increased suicide mortality was found, and in the studies that evaluated suicide risk in different age groups, the excess suicide mortality was most dominant in younger age groups. Our own study revealed an increased risk of suicide, and in univariate analysis, significant predictors for suicide were found to be associated with shortest stay in hostel less than 11 days and more than one stay during one year. The thesis also contains a review of the risk of suicide in first-episode patients with schizophrenia, and it was concluded on the basis of the identified studies that long-term risk of suicide was not 10 percent as previously accepted, but lower. Risk factors for suicide among patients with schizophrenia were evaluated in case control studies, in nested case control studies, and in prospective studies. The following risk factors were the most important and frequently observed predictors: male gender, young age, short duration of illness, many admissions during last year, current inpatient, short time since discharge, previous and recent suicide attempt, co-morbid depression, drug abuse, poor compliance with medication, poor adherence to treatment, high IQ, and suicidal ideations. The results of analyses of psychotic symptoms as risk factor for suicide were contradictory, but a recent meta-analysis concluded that both hallucinations and delusions seemed to be protective; however, there was a non-significant tendency that command hallucinations were associated with higher suicide risk. Prevention of suicide in schizophrenia must especially focus on improving assessment of risk of suicide during inpatient treatment and the first week after discharge, and special attention must be paid to patients with one or more of the identified risk factors. There is a need for large randomised clinical trials evaluating the effect on suicide and suicide attempt of psychosocial and pharmacological treatment in schizophrenia. In our own study, we did not find any effect of integrated treatment on attempted suicide, but there was an effect on hopelessness and a trend toward lower prevalence of depression among patients in the integrated treatment. There were four suicides and one probable suicide (drowning) in standard treatment and one suicide in integrated treatment at two-year follow-up, but the study did not have sufficient power to detect these differences in proportion to who committed suicide; more than one thousand patients should have been in each treatment condition in order for these differences in proportion to be significant. At the indicated prevention level, a literature review was carried out regarding risk of suicide attempt and suicide in short-term, medium-term and long-term follow-up of persons who attempted suicide. It was concluded that the risk of repetition in short- and medium-term follow-up studies was approximately 16 percent, with lower risk among "first-evers" compared to repeaters. There was a large variation in repetition rate. The proportion who committed suicide in medium-term follow-up studies was 2.8 percent and in long-term follow-up studies was 3.5 percent (weighted mean) with clearly higher proportions in the Nordic studies than in the studies from UK. Risk factors for attempted suicide were previous suicide attempt, alcohol and drug abuse, depression, schizophrenia, previous inpatient treatment, self-discharge before evaluation, sociopathy, unemployment, frequent change of address, hostility, and living alone. Several of the predictors are overlapping and most of them were already identified in early studies of factors predictive of repetition of suicide attempt. Predictors of suicide were male gender, increasing age, previous suicide attempt, serious suicide attempt, alcohol and substance abuse, somatic disease, mental illness, and planning of suicide attempt, high suicidal intent score, violent suicide attempt or suicide attempt with severe lethality, and ongoing or previous psychiatric treatment. In our follow-up study from Bispebjerg Hospital, we found that the risk of suicide during a ten-year follow-up period among patients admitted in 1980 after self-poisoning was 30 times greater than in the general population. We also found increased mortality by all other causes of death. Predictors of suicide were several previous suicide attempts, living alone and increasing age. There are not many randomised clinical trials of psychosocial interventions aiming to reduce risk of repetition among suicide attempters. A Cochrane review concluded that evidence was lacking to indicate the most effective forms of treatment for deliberate self-harm patients. A recent randomised controlled trial showed a positive influence of cognitive behavioural therapy on repetition rate. Our own quasi-experimental study of effectiveness of two weeks' inpatient treatment in a special unit of young persons who had severe suicidal thoughts or who had attempted suicide showed that risk of repetition was reduced in the intervention group, and that the intervention group obtained a significantly greater improvement in Beck's Depression Inventory, Hopelessness Scale, Rosenberg Self-Esteem Scale and CAGE-score. The study of emergency outreach indicates that there are many persons in the community that experience a suicidal crisis, and that this group is an important target group for psychiatric emergency outreach. In our study of registration and referral practice in Copenhagen Hospital Cooperation, we conclude that not all suicide attempts were registered as such in the National Patient Register - in fact, only 37 percent. It must be concluded that the quality of the Danish Patient Register must be improved with regard to registration of suicide attempt. We found that psychiatric evaluation was planned in relation to almost all suicide attempts, but that it must be recommended to pay attention to escorting patients to psychiatric emergency in order to ensure that the patient actually attends the planned consultation. We found that patients who were referred after psychiatric evaluation to psychiatric treatment at outpatient facilities only received the planned treatment in approximately two-thirds of the cases; therefore, like Hawton et al. [Hawton et al., 1998; Hawton et al., 1999], we recommend that outpatient facilities adopt an assertive approach to patients who have attempted suicide. Danish suicide research is strong, primarily due to the possibilities for linking complete national registers providing detailed data and large sample sizes for suicide research, which is so far unique for the Nordic countries. This, combined with skilful use of epidemiological methods, had resulted in a remarkable series of papers highlighting risk of suicide in different risk groups, risk factors and protective factors. This activity must continue. In this work it is important to be aware of limitations in naturalistic studies such as the risk of interchanging cause and effect and the necessity to carry out control for confounders. Meta-analysis is a strong tool for summing up results of previous research. Meta-analyses can be used in reporting the evidence for effectiveness of interventions, but also for determining risk or identifying risk factors. A meta-analysis of risk factors of repetition of suicide attempt has not been carried out, and the quality of the identified studies did not allow a formal meta-analysis. Large randomised clinical trials examining the effectiveness of interventions on reducing rate of suicide attempt and suicide should have high priority. Suicide is a major public health problem and should be given high priority with regard to prevention and research. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. Due to their lipophilicity and persistence, once internalized, they accumulate in body tissue, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always involves a complex mixture, the toxic equivalency factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD, which is the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally related polychlorinated biphenyls (PCBs) and mixtures of these compounds. TCDD is not manufactured commercially other than for scientific research purposes. The main sources of TCDD releases into the environment are from combustion and incineration; metal smelting, refining, and processing; chemical manufacturing and processing; biological and photochemical processes; and existing reservoir sources that reflect past releases. TCDD (dioxin) was selected for study by the National Toxicology Program as a part of the dioxin TEF evaluation to assess the cancer risk posed by complex mixtures of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and PCBs. The dioxin TEF evaluation includes conducting multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLCs, structurally related PCBs, and mixtures of these compounds. While one of the aims of the dioxin TEF evaluation was a comparative analysis across studies, in this Technical Report, only the TCDD results are presented and discussed. TCDD was included because it is the reference compound for the dioxin TEF methodology. Female Harlan Sprague-Dawley rats were administered TCDD (at least 98% pure) in corn oil:acetone (99:1) by gavage for 14, 31, or 53 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, Drosophila melanogaster, and mouse bone marrow cells. 2-YEAR STUDY: Groups of 81 or 82 female rats were administered 3, 10, 22, 46, or 100 ng TCDD/kg body weight in corn oil:acetone (99:1) by gavage, 5 days per week, for up to 105 weeks; a group of 81 vehicle control female rats received the corn oil/acetone vehicle alone. Up to 10 rats per group were evaluated at 14, 31, or 53 weeks. A stop-exposure group of 50 female rats was administered 100 ng/kg TCDD in corn oil:acetone (99:1) by gavage for 30 weeks and then just the vehicle for the remainder of the study. Survival of dosed groups was similar to that of the vehicle control group. Mean body weights of 100 ng/kg core study and stop-exposure groups were less than those of the vehicle control group after week 13 of the study. Mean body weights of 46 ng/kg rats were less than those of the vehicle controls during year 2 of the study, and those of 22 ng/kg rats were less than those of the vehicle controls the last 10 weeks of the study. THYROID HORMONE CONCENTRATIONS: Alterations in serum thyroid hormone levels were evaluated at the 14-, 31- and 53-week interim evaluations. At 14 weeks, there were significant decreases in serum total and free thyroxine (T4) levels and increases in serum total triiodothyronine (T3) and thyroid stimulating hormone (TSH). At 31 weeks, there were significant decreases in serum total and free T4 levels and increases in serum total T3 but no significant effect on TSH. At 53 weeks, there were significant decreases in serum total T4 levels and increases in serum total T3. There were no significant effects on total T4 or TSH levels. HEPATIC CELL PROLIFERATION DATA: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the 14-, 31-, and 53-week interim evaluations. The hepatocellular labeling index was significantly higher in the 22 ng/kg group compared to vehicle controls at 14 weeks. At the 31-week interim evaluation, the labeling indices in hepatocytes were significantly higher in all dosed groups than in the vehicle controls. At 53 weeks, labeling indices were significantly higher in the 46 and 100 ng/kg groups than in the vehicle controls. CYTOCHROME P450 ENZYME ACTIVITIES: To evaluate the expression of known dioxin-responsive genes, CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activity were evaluated at 14, 31, and 53 weeks. In addition, pentoxyresorufin-O-deethylase (PROD) activity was analyzed. Hepatic EROD, PROD, and A4H activities were significantly higher in all dosed groups relative to vehicle controls at the 14-, 31-, and 53-week interim evaluations. Pulmonary EROD was also significantly higher in all dosed groups compared to vehicle controls at 14, 31, and 53 weeks. DETERMINATIONS OF TCDD CONCENTRATIONS IN TISSUES: The tissue disposition of TCDD was analyzed in the liver, lung, fat, and blood of all animals in each group at the 14-, 31-, and 53-week interim evaluations and in 10 animals per group at the end of the 2-year study (105 weeks). The highest concentrations of TCDD were observed in the liver, followed by fat tissue. Liver and fat tissue concentrations of TCDD increased with increasing doses of TCDD. No measurable concentrations of TCDD were observed in blood from vehicle control or treated rats at any of the interim evaluations. Mean levels of TCDD in the liver and fat in the 100 ng/kg group at the end of the 2-year study were 9.3 and 3.2 ng/g, respectively. In liver tissue from the stop-exposure group, TCDD concentrations were slightly higher than those observed in the 3 ng/kg group. In the stop-exposure group, TCDD concentrations in fat were below the limits of quantitation. PATHOLOGY AND STATISTICAL ANALYSES: Absolute and/or relative liver weights were increased at 14, 31, and 53 weeks, with more severe effects occurring in the higher dosed groups. Increased liver weights correlated with increased incidences of hepatocyte hypertrophy at 14, 31, and 53 weeks. Exposure led to a treatment-related increase in hepatic toxicity with a broad spectrum of lesions. Incidences and severities of lesions increased at higher doses and longer durations of exposure. The earliest effects were increased incidences and severities of hepatocyte hypertrophy at 14 weeks. At 2 years, there was a significant increase in toxic hepatopathy characterized by increased incidences of numerous nonneoplastic liver lesions including hepatocyte hypertrophy, multinucleated hepatocytes, altered hepatocellular foci, inflammation, pigmentation, diffuse fatty change, necrosis, portal fibrosis, oval cell hyperplasia, bile duct hyperplasia, bile duct cysts, cholangiofibrosis, and nodular hyperplasia At 2 years, the incidence of hepatocellular adenoma was significantly increased in the 100 ng/kg core study group. Dose-related increased incidences of cholangiocarcinoma were seen in core study rats administered 22 ng/kg or greater. The highest incidence of cholangiocarcinoma was seen in the 100 ng/kg core study group and included a significant number of animals with multiple cholangiocarcinomas. Two cholangiocarcinomas and two hepatocellular adenomas were seen in the 100 ng/kg stop-exposure group. Two hepatocholangiomas were seen in the 100 ng/kg core study group, and one cholangioma was seen in the 100 ng/kg stop-exposure group. In the lung, the incidence of cystic keratinizing epithelioma of the lung was significantly increased at 2 years in the 100 ng/kg core study group. Nonneoplastic effects in the lung included increased incidences of bronchiolar metaplasia. The incidence of gingival squamous cell carcinoma of the oral mucosa was significantly increased in the 100 ng/kg core study group at 2 years and was accompanied by an increased incidence of gingival squamous hyperplasia. At 2 years, the incidence of squamous cell carcinoma of the uterus in the 46 ng/kg group was significantly increased, and there were two squamous cell carcinomas in the 100 ng/kg stop-exposure group. At 2 years, one acinar adenoma and two acinar cell carcinomas of the pancreas were seen in the 100 ng/kg core study group; one acinar carcinoma was seen in the 100 ng/kg stop-exposure group. The incidences of acinar cell adenoma or carcinoma (combined) exceeded the historical vehicle control range. Nonneoplastic effects in the lung included acinar cytoplasmic vacuolization, chronic active inflammation, acinar atrophy, and arterial chronic active inflammation. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. Due to their lipophilicity and persistence, once internalized, they accumulate in body tissues, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always involves a complex mixture, the toxic equivalency factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD, which is the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals, based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally related polychlorinated biphenyls (PCBs) and mixtures of these compounds. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), 2,3,4,7,8-pentachlorodibenzofuran (PeCDF), and 3,3',4,4',5-pentachlorobiphenyl (PCB 126) are not manufactured commercially other than for scientific research purposes. The main sources of TCDD and PeCDF releases into the environment are from metal smelting, refining, and processing; combustion and incineration sources; chemical manufacturing and processing; biological and photochemical processes; and existing reservior sources that reflect past releases. PCB mixtures were commercially produced and used in the electric power industry as dielectric insulating fluids in transformers and capacitors and used in hydraulic fluids, plastics, and paints. TCDD, PeCDF, and PCB 126 were selected for study by the National Toxicology Program as part of the dioxin TEF evaluation to assess the cancer risk posed by complex mixtures of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and PCBs. The dioxin TEF evaluation includes conducting multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLC's, structurally related PCBs, and mixtures of these compounds. Female Harlan Sprague-Dawley rats were administered a mixture of TCDD, PeCDF, and PCB 126 (henceforth referred to as the TEF mixture) in corn oil:acetone (99:1) by gavage for 14, 31, or 53 weeks or 2 years. While one of the aims of the dioxin TEF evaluation was a comparative analysis across studies, in this Technical Report only the results of the present study of the mixture of TCDD, PeCDF, and PCB 126 are presented and discussed. 2-YEAR STUDY: Groups of 81 female rats were administered 10, 22, 46, or 100 ng toxic equivalents (TEQ)/kg body weight in corn oil:acetone (99:1) by gavage, 5 days per week, for up to 105 weeks; a group of 81 vehicle control female rats received the corn oil/acetone vehicle alone. Actual doses used for each compound in the mixture were: for 10 ng TEQ/kg: 3.3 ng/kg TCDD, 6.6 ng/kg PeCDF, and 33.3 ng/kg PCB 126; for 22 ng TEQ/kg: 7.3 ng/kg TCDD, 14.5 ng/kg PeCDF, and 73.3 ng/kg PCB 126; for 46 ng TEQ/kg: 15.2 ng/kg TCDD, 30.4 ng/kg PeCDF, and 153 ng/kg PCB 126; and for 100 ng TEQ/kg: 33 ng/kg TCDD, 66 ng/kg PeCDF, and 333 ng/kg PCB 126. Up to 10 rats per group were evaluated at 14, 31, or 53 weeks. Survival of all dosed groups of rats was similar to that of the vehicle control group. Mean body weights of the 22 and 46 ng TEQ/kg groups were less than those of the vehicle control groups after week 69 of the study. Mean body weights of the 100 ng TEQ/kg group were less than those of the vehicle control group after week 37 of the study. Thyroid Hormone Concentrations: Alterations in serum thyroid hormone concentrations were evaluated at the 14-, 31-, and 53-week interim evaluations. At 14, 31, and 53 weeks, there were dose-dependent reductions in total serum and free thyroxine concentrations. There were dose-dependent increases in serum triiodothyronine concentrations at 14 and 31 weeks. No changes in serum thyroid stimulating hormone concentrations were observed at any time point. Hepatic Cell Proliferation Data: To evaluate hepatocyte replication, analysis of labeling of replicating hepatocytes with 5-bromo-2'-deoxyuridine was conducted at the interim evaluations. At 14 weeks, no effects on the hepatocellular labeling index were observed in the dosed groups compared to the vehicle controls. At 31 and 53 weeks, the hepatocellular labeling index was significantly higher in the 46 and 100 ng TEQ/kg groups compared to the vehicle controls. Cytochrome P450 Enzyme Activities: To evaluate the expression of known dioxin-responsive genes, CYP1A1-associated 7-ethoxyresorufin-O-deethylase (EROD) activity and CYP1A2-associated acetanilide-4-hydroxylase (A4H) activity were evaluated at the interim time points. Liver and lung EROD (CYP1A1) activities and hepatic A4H (CYP1A2) activities were significantly greater in all dosed groups than in the vehicle controls at all interim evaluations (14, 31, and 53 weeks). Determinations of TCDD, PeCDF, and PCB 126 Concentrations in Tissues: Tissue concentrations of TCDD, PeCDF, and PCB 126 were analyzed in the fat, liver, lung, and blood at each interim evaluation and at the end of the 2-year study (105 weeks). The highest concentrations of TCDD, PeCDF, and PCB 126 were observed in the liver followed by fat. Liver and fat concentrations of TCDD, PeCDF, and PCB 126 at each interim evaluation and at 105 weeks were higher in groups with increasing doses of the mixture and generally increased with duration of dosing. In the lung, PeCDF was present at detectable concentrations in the 46 and 100 ng TEQ/kg groups at 14 and 31 weeks. Measurable concentrations of TCDD and PCB 126 were observed at 14 and 31 weeks in the lung of rats in all dosed groups with the highest concentrations observed in the 100 ng TEQ/kg group. At 53 weeks, concentrations of TCDD, PeCDF, and PCB 126 in the lung generally increased with increasing dose. At 105 weeks, detectable concentrations of TCDD, PeCDF, and PCB 126 in the lung were observed in all dosed groups. In blood, TCDD and PCB 126 concentrations at 14 and 31 weeks generally increased with increasing dose. Blood concentrations of PeCDF were detectable in the 46 and 100 ng TEQ/kg groups at 14 weeks and at 22 ng TEQ/kg or greater at 31 weeks. At 53 and 105 weeks, concentrations of TCDD, PeCDF, and PCB 126 in blood generally increased with increasing dose and duration of dosing. Pathology and Statistical Analyses: Relative liver weights were significantly increased in all dosed groups at 14, 31, and 53 weeks and correlated with increased incidences of hepatocellular hypertrophy. Increasing duration of exposure led to an increase in the spectrum, incidence, and severity of nonneoplastic effects. The only significant effect at 14 weeks was increased incidences of hepatocellular hypertrophy. At 53 weeks, there was a significant effect on the incidences of hepatocellular hypertrophy, multinucleated hepatocytes, pigmentation, focal fatty change, bile duct hyperplasia, and toxic hepatopathy. At 2 years, there were significant increases in the incidences of hepatocellular adenoma and cholangiocarcinoma of the liver. There was an increase in hepatic toxicity characterized by increases in the incidences of numerous nonneoplastic lesions including hepatocyte hypertrophy, multinucleated hepatocytes, pigmentation, inflammation, diffuse fatty change, bile duct hyperplasia, oval cell hyperplasia, nodular hyperplasia, eosinophilic focus, cholangiofibrosis, bile duct cysts, necrosis, portal fibrosis, mixed cell focus, and toxic hepatopathy. In the lung, there were dose-dependent increases in the incidences of bronchiolar metaplasia of the alveolar epithelium at 53 weeks and at 2 years and squamous metaplasia at 2 years. At 2 years, there was a dose-dependent increase in the incidences of cystic keratinizing epithelioma. In the pancreas, there were increases in the incidences of numerous nonneoplastic lesions including arterial chronic active inflammation, acinar cytoplasmic vacuolization, acinar atrophy, chronic active inflammation, and duct dilatation. At 2 years, incidences of acinar adenoma or acinar carcinoma that exceeded the historical control ranges were seen in all dosed groups except the 100 ng TEQ/kg group. Treatment-related increases in the incidences of nonneoplastic lesions were seen in other organs including hyperplasia, cystic degeneration, atrophy, and cytoplasmic vacuolization of the adrenal cortex; gingival squamous hyperplasia of the oral mucosa; squamous metaplasia of the uterus; atrophy of the thymus (incidence and severity); chronic active inflammation of the ovary; nephropathy of the kidney (incidence and severity); cardiomyopathy; bone marrow hyperplasia; transitional epithelium of the urinary bladder; chronic active inflammation of the mesenteric artery; and follicular cell hypertrophy of the thyroid gland. (ABSTRACT TRUNCATED).	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
To assess the effectiveness, safety and cost-effectiveness of extracorporeal photophoresis (ECP) for the treatment of refractory erythrodermic cutaneous T cell lymphoma (CTCL) and refractory chronic graft versus host disease (cGvHD). CUTANEOUS T CELL LYMPHOMA: Cutaneous T cell lymphoma (CTCL) is a general name for a group of skin affecting disorders caused by malignant white blood cells (T lymphocytes). Cutaneous T cell lymphoma is relatively uncommon and represents slightly more than 2% of all lymphomas in the United States. The most frequently diagnosed form of CTCL is mycosis fungoides (MF) and its leukemic variant Sezary syndrome (SS). The relative frequency and disease-specific 5-year survival of 1,905 primary cutaneous lymphomas classified according to the World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification (Appendix 1). Mycosis fungoides had a frequency of 44% and a disease specific 5-year survival of 88%. Sezary syndrome had a frequency of 3% and a disease specific 5-year survival of 24%. Cutaneous T cell lymphoma has an annual incidence of approximately 0.4 per 100,000 and it mainly occurs in the 5(th) to 6(th) decade of life, with a male/female ratio of 2:1. Mycosis fungoides is an indolent lymphoma with patients often having several years of eczematous or dermatitic skin lesions before the diagnosis is finally established. Mycosis fungoides commonly presents as chronic eczematous patches or plaques and can remain stable for many years. Early in the disease biopsies are often difficult to interpret and the diagnosis may only become apparent by observing the patient over time. The clinical course of MF is unpredictable. Most patients will live normal lives and experience skin symptoms without serious complications. Approximately 10% of MF patients will experience progressive disease involving lymph nodes, peripheral blood, bone marrow and visceral organs. A particular syndrome in these patients involves erythroderma (intense and usually widespread reddening of the skin from dilation of blood vessels, often preceding or associated with exfoliation), and circulating tumour cells. This is known as SS. It has been estimated that approximately 5-10% of CTCL patients have SS. Patients with SS have a median survival of approximately 30 months. CHRONIC GRAFT VERSUS HOST DISEASE: Allogeneic hematopoietic cell transplantation (HCT) is a treatment used for a variety of malignant and nonmalignant disease of the bone marrow and immune system. The procedure is often associated with serious immunological complications, particularly graft versus host disease (GvHD). A chronic form of GvHD (cGvHD) afflicts many allogeneic HCT recipients, which results in dysfunction of numerous organ systems or even a profound state of immunodeficiency. Chronic GVHD is the most frequent cause of poor long-term outcome and quality of life after allogeneic HCT. The syndrome typically develops several months after transplantation, when the patient may no longer be under the direct care of the transplant team. Approximately 50% of patients with cGvHD have limited disease and a good prognosis. Of the patients with extensive disease, approximately 60% will respond to treatment and eventually be able to discontinue immunosuppressive therapy. The remaining patients will develop opportunistic infection, or require prolonged treatment with immunosuppressive agents. Chronic GvHD occurs in at least 30% to 50% of recipients of transplants from human leukocyte antigen matched siblings and at least 60% to 70% of recipients of transplants from unrelated donors. Risk factors include older age of patient or donor, higher degree of histoincompatibility, unrelated versus related donor, use of hematopoietic cells obtained from the blood rather than the marrow, and previous acute GvHD. Bhushan and Collins estimated that the incidence of severe cGvHD has probably increased in recent years because of the use of more unrelated transplants, donor leukocyte infusions, nonmyeloablative transplants and stem cells obtained from the blood rather than the marrow. The syndrome typically occurs 4 to 7 months after transplantation but may begin as early as 2 months or as late as 2 or more years after transplantation. Chronic GvHD may occur by itself, evolve from acute GvHD, or occur after resolution of acute GvHD. The onset of the syndrome may be abrupt but is frequently insidious with manifestations evolving gradually for several weeks. The extent of involvement varies significantly from mild involvement limited to a few patches of skin to severe involvement of numerous organ systems and profound immunodeficiency. The most commonly involved tissues are the skin, liver, mouth, and eyes. Patients with limited disease have localized skin involvement, evidence of liver dysfunction, or both, whereas those with more involvement of the skin or involvement of other organs have extensive disease. CUTANEOUS T CELL LYMPHOMA: The optimal management of MF is undetermined because of its low prevalence, and its highly variable natural history, with frequent spontaneous remissions and exacerbations and often prolonged survival. Nonaggressive approaches to therapy are usually warranted with treatment aimed at improving symptoms and physical appearance while limiting toxicity. Given that multiple skin sites are usually involved, the initial treatment choices are usually topical or intralesional corticosteroids or phototherapy using psoralen (a compound found in plants which make the skin temporarily sensitive to ultraviolet A) (PUVA). PUVA is not curative and its influence on disease progression remains uncertain. Repeated courses are usually required which may lead to an increased risk of both melanoma and nonmelanoma skin cancer. For thicker plaques, particularly if localized, radiotherapy with superficial electrons is an option. "Second line" therapy for early stage disease is often topical chemotherapy, radiotherapy or total skin electron beam radiation (TSEB). Treatment of advanced stage (IIB-IV) MF usually consists of topical or systemic therapy in refractory or rapidly progressive SS. Bone marrow transplantation and peripheral blood stem cell transplantation have been used to treat many malignant hematologic disorders (e.g., leukemias) that are refractory to conventional treatment. Reports on the use of these procedures for the treatment of CTCL are limited and mostly consist of case reports or small case series. CHRONIC GRAFT VERSUS HOST DISEASE: Patients who develop cGvHD require reinstitution of immunosuppressive medication (if already discontinued) or an increase in dosage and possibly addition of other agents. The current literature regarding cGvHD therapy is less than optimal and many recommendations about therapy are based on common practices that await definitive testing. Patients with disease that is extensive by definition but is indolent in clinical appearance may respond to prednisone. However, patients with more aggressive disease are treated with higher doses of corticosteroids and/or cyclosporine. Numerous salvage therapies have been considered in patients with refractory cGvHD, including ECP. Due to uncertainty around salvage therapies, Bhushan and Collins suggested that ideally, patients with refractory cGvHD should be entered into clinical trials. Two Ontario expert consultants jointly estimated that there may be approximately 30 new erythrodermic treatment resistant CTCL patients and 30 new treatment resistant cGvHD patients per year who are unresponsive to other forms of therapy and may be candidates for ECP. Extracorporeal photopheresis is a procedure that was initially developed as a treatment for CTCL, particularly SS. CURRENT TECHNIQUE: Extracorporeal photopheresis is an immunomodulatory technique based on pheresis of light sensitive cells. Whole blood is removed from patients followed by pheresis. Lymphocytes are separated by centrifugation to create a concentrated layer of white blood cells. The lymphocyte layer is treated with methoxsalen (a drug that sensitizes the lymphocytes to light) and exposed to UVA, following which the lymphocytes are returned to the patient. Red blood cells and plasma are returned to the patient between each cycle. Photosensitization is achieved by administering methoxsalen to the patient orally 2 hours before the procedure, or by injecting methoxsalen directly ino the leucocyte rich fraction. The latter approach avoids potential side effects such as nausea, and provides a more consistent drug level within the machine. In general, from the time the intravenous line is inserted until the white blood cells are returned to the patient takes approximately 2.5-3.5 hours. For CTCL, the treatment schedule is generally 2 consecutive days every 4 weeks for a median of 6 months. For cGvHD, an expert in the field estimated that the treatment schedule would be 3 times a week for the 1(st) month, then 2 consecutive days every 2 weeks after that (i.e., 4 treatments a month) for a median of 6 to 9 months. The UVAR XTS Photopheresis System is licensed by Health Canada as a Class 3 medical device (license # 7703) for the "palliative treatment of skin manifestations of CTCL." It is not licensed for the treatment of cGvHD. UVADEX (sterile solution methoxsalen) is not licensed by Health Canada, but can be used in Canada via the Special Access Program. (Personal communication, Therakos, February 16, 2006) According to the manufacturer, the UVAR XTS photopheresis system licensed by Health Canada can also be used with oral methoxsalen. (Personal communication, Therakos, February 16, 2006) However, oral methoxsalen is associated with side effects, must be taken by the patient in advance of ECP, and has variable absorption in the gastrointestinal tract. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Since the first U.S. infant conceived with Assisted Reproductive Technology (ART) was born in 1981, both the use of advanced technologies to overcome infertility and the number of fertility clinics providing ART services have increased steadily in the United States. ART includes fertility treatments in which both eggs and embryos are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). Women who undergo ART procedures are more likely to deliver multiple-birth infants than those who conceive naturally because more than one embryo might be transferred during a procedure. Multiple births pose substantial risks to both mothers and infants, including pregnancy complications, preterm delivery, and low birthweight infants. This report provides state-specific information on U.S. ART procedures performed in 2011 and compares infant outcomes that occurred in 2011 (resulting from procedures performed in 2010 and 2011) with outcomes for all infants born in the United States in 2011. 2011. In 1996, CDC began collecting data on all ART procedures performed in fertility clinics in the United States as mandated by the Fertility Clinic Success Rate and Certification Act of 1992 (FCSRCA) (Public Law 102-493). Data are collected through the National ART Surveillance System (NASS), a web-based data collecting system developed by CDC. In 2011, a total of 151,923 ART procedures performed in 451 U.S. fertility clinics were reported to CDC. These procedures resulted in 47,818 live-birth deliveries and 61,610 infants. The largest numbers of ART procedures were performed among residents of six states: California (18,808), New York (excluding New York City) (14,576), Massachusetts (10,106), Illinois (9,886), Texas (9,576), and New Jersey (8,698). These six states also had the highest number of live-birth deliveries as a result of ART procedures and together accounted for 47.2% of all ART procedures performed, 45.3% of all infants born from ART, and 45.1% of all multiple live-birth deliveries, but only 34% of all infants born in the United States. Nationally, the average number of ART procedures performed per 1 million women of reproductive age (15-44 years), which is a proxy indicator of ART use, was 2,401. In 11 states (Connecticut, Delaware, Hawaii, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, and Virginia), the District of Columbia, and New York City, this proxy measure was higher than the national rate, and of these, in three states (Massachusetts, New Jersey, and New York) and the District of Columbia, it exceeded twice the national rate. Nationally, among ART cycles with patients using fresh embryos from their own eggs in which at least one embryo was transferred, the average number of embryos transferred increased with increasing age (2.0 among women aged <35 years, 2.3 among women aged 35-40 years, and 2.9 among women aged >40 years). Elective single-embryo transfer (eSET) rates decreased with increasing age (12.2% among women aged <35 years, 4.7% among women aged 35-40 years, and 0.7% among women aged >40 years). Rates of eSET also varied substantially between states (range: 0.7% in Idaho to 53% in Delaware among women aged <35 years). The number of ART births as a percentage of total infants born in the state is considered as another measure of ART use. Overall, ART contributed to 1.5% of U.S. births (range: 0.2% in Puerto Rico to 4.5% in Massachusetts) with the highest rates (≥3.5% of all infants born) observed in four states (Connecticut, Massachusetts, New Jersey, and New York state), and the District of Columbia. Infants conceived with ART comprised 20% of all multiple-birth infants (range: 4.7% in Puerto Rico to 41.3% in New York state), 19% of all twin infants (range: 4.1% in Mississippi to 39.7% in Massachusetts), and 32% of triplet or higher order infants (range: 0 in several states to 71.4% in Hawaii). Among infants conceived with ART, 45.6% were born in multiple-birth deliveries (range: 23.1% in Delaware to 61.3% in Wyoming), compared with only 3.4% of infants among all births in the general population (range: 1.9% in Puerto Rico to 4.8% in New Jersey). Approximately 43% of ART-conceived infants were twins, and 3% were triplets and higher order infants. Nationally, infants conceived with ART comprised 5.7% of all low birthweight (<2,500 grams) infants (range: 0.6% in Puerto Rico to 15% in Massachusetts) and 5.9% of all very low birthweight (<1,500 grams) infants (range: 0.8% in Mississippi to 17.3% in Massachusetts). Overall, among ART-conceived infants, 31% were low birthweight (range: 18% in District of Columbia to 44.6% in Puerto Rico), compared with 8.1% among all infants (range: 6% in Alaska to 12.5% in Puerto Rico); 5.7% of ART infants were very low birthweight (range: 0 in North Dakota to 8.5% in Hawaii), compared with 1.4% among all infants (range: 0.9% in Alaska to 2.2% in Mississippi). Finally, ART-conceived infants comprised 4.6% of all infants born preterm (<37 weeks; range: 0.5% in Puerto Rico to 13% in Massachusetts) and 5.2% of all infants born very preterm (<32 weeks; range: 0 in Wyoming to 17.1% in Massachusetts). Overall, among infants conceived with ART, 36.2% were born preterm (range: 12.5% in Vermont to 56.9% in Puerto Rico), compared with 11.8% among all infants born in the general population (range: 8.8% in Vermont to 17.6% in Puerto Rico); 6.7% of ART infants were born very preterm (range: 0 in Wyoming to 12.5% in Alaska), compared with 1.9% among all infants born in the general population (range: 1.3% in Wyoming to 3.0% in Puerto Rico). The percentage of infants conceived with ART who were low birthweight varied from 8.8% (range: 3.9% in the District of Columbia to 17.9% in Puerto Rico) among singletons, to 56.4% (range: 34.6% in Vermont to 70.4% in Mississippi) among twins, and 95.7% (range: 79.5% in North Carolina to 100% in several states) among triplets or higher-order multiples; comparable percentages for all infants were 6.4% (range: 4.5% in Idaho and Oregon to 11.3% in Puerto Rico), 56.3% (range: 47.7% in Vermont to 72.1% in Puerto Rico), and 93.9% (range: 50% in Wyoming to 100% in several states), respectively. The percentage of ART infants who were preterm varied from 13.2% (range: 7.3% in the District of Columbia to 28.6% in Puerto Rico) among singletons, to 61.8% (range: 46% in the District of Columbia to 82.7% in Oklahoma) among twins, and 97.1% (range: 76.9% in Iowa to 100% in several states) among triplets or higher-order multiples; comparable percentages for all infants were 10.1% (range:7.5% in Oregon to 16.6% in Puerto Rico), 57.3% (range: 46.8% in New Hampshire to 68.8% in Louisiana), and 93.4% (range: 73.3% in Rhode Island to 100% in several states), respectively. Only nonsuppressed values from reporting areas are provided to protect confidentiality. The percentage of infants conceived with ART varied considerably by state (range: 0.2% to 4.5%). In most states, multiples from ART comprised a substantial proportion of all twin, triplet, and higher-order infants born in the state, and the rates of low birthweight and preterm infants were disproportionately higher among ART infants than in the birth population overall. Even among women aged <35 years, for whom elective single embryo transfers should be considered (particularly in patients with a favorable prognosis), on average, two embryos were transferred per cycle in ART procedures, influencing the overall multiple infant rates in the United States. Compared with ART singletons, ART twins were approximately 5 times more likely to be born preterm, and approximately six times more likely to be low birthweight. Singleton infants conceived with ART had slightly higher rates of preterm delivery and low birthweight than among all singleton infants born in the United States. However, all multiple-birth infants, regardless of whether they were ART-conceived or not, were more likely to be preterm and low birthweight compared with singletons. Further, ART use per population unit was distributed disproportionately in the United States, with 11 states showing ART use above the national rate. Of the four states (Illinois, Massachusetts, New Jersey, and Rhode Island) with comprehensive statewide-mandated health insurance coverage for ART procedures (e.g., coverage for at least four cycles of in vitro fertilization, three states (Illinois, Massachusetts, and New Jersey) also had rates of ART use >1.5 times the national level. This type of mandated insurance has been associated with greater use of ART and might account for the differences in per capita ART use observed among states. Reducing the number of embryos transferred per ART procedure and promoting eSET procedures, when clinically appropriate, are needed to reduce multiple births and related adverse consequences of ART. Improved patient education and counseling on the health risks of having twins might be useful in reducing twin births given that twins account for the majority of ART-conceived multiple births. Although ART contributes to increasing rates of multiple births, it does not explain all of the increases, and therefore other explanations for multiple births not investigated in this report, such as the possible role of non-ART fertility treatments, warrants further study.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The demographic structure of a country changes dramatically with increasing trends toward general population aging and declining birth rates. In Japan, the percentage of the elderly population (aged ≥65 years) reached 25% in 2013; it is expected to exceed 30% in 2025 and reach 39.9% in 2060. The national total population has been decreasing steadily since its peak reached in 2008, and it is expected to fall to the order of 80 million in 2060. Of the total population, those aged ≥75 years accounted for 12.3% as of 2013, and this is expected to reach 26.9% in 2060. As the demographic structure changes, the disease structure changes, and therefore the medical care demand changes. To accommodate the medical care demand changes, it is necessary to secure a system for providing medical care. Japan has thus far attained remarkable achievements in medical care, seeking a better prognosis for survival; however, its medical care demand is anticipated to change both qualitatively and quantitatively. As diseases in the elderly, particularly in the old-old population, are often intractable, conventional medical care must be upgraded to one suitable for an aged society. What is required to this end is a shift from "cure-seeking medical care" focusing on disease treatment on an organ-specific basis to "cure and support-seeking medical care" with treatments reprioritized to maximize the quality of life (QOL) for the patient, or a change from "hospital-centered medical care" to "community-oriented medical care" in correlation with nursing care and welfare. (1) Necessity for a paradigm shift to "cure-and-support seeking medical care" In addition to the process of aging with functional deterioration of multiple organs, the elderly often suffer from systemically disordering diseases, such as lifestyle-related diseases, as well as geriatric syndrome and daily activity dysfunction; therefore, integrated and comprehensive medical care is required. In addition, with regard to diseases in the elderly, not only their acute stage, but also their chronic and intermediate stages must be emphasized in their treatment. Aiming to achieve a complete cure of disease by exploring the cause and implementing radical treatment, the conventional medical care model is difficult to apply to the medical care of the elderly; medical care suitable for the elderly is required. (2) Spread of home-based care and the necessity for human resources development Many elderly people want to continue to live in their house and their community where they have been living for a long time, even with disease. There are increasing needs for QOL-emphasizing home-based care for patients in the intermediate stage after completion of acute stage treatment, or for end-of-life care. Hence, there is a demand for a shift to "community-oriented medical care" for providing comprehensive care supported with medical and nursing resources available in the community. As the percentage of the elderly population (aged ≥65 years) and the availability of medical care resources vary considerably among different regions, it is important that specialists in the fields of public health, medical care, nursing care, and welfare work on establishing a collaborative system suitable for the local characteristics of each region by making the best use of their own specialties. (3) Necessity for establishing a department of gerontology or geriatric medicine at each medical school In line with the increasing number of elderly people, it is necessary to upgrade the systems for educating and nurturing physicians engaged in healthcare and nursing care for the elderly. It is also necessary to develop the organic cooperation with other medical and nursing care professionals, such as registered nurses and care workers. At present, just approximately 30% of medical schools in Japan have a department specializing in medical care for the elderly and relevant medical education; there is an urgent need to improve the situation, as the majority of universities do not provide any such education. (4) Necessity for establishing a medical center for promoting medical care provider collaboration, multidisciplinary training and a means to increase public awareness In the medical care for the elderly, comprehensive care must be provided from the viewpoints of both healthcare and nursing care; to improve the quality of such care services, multidisciplinary collaboration and team-based medicine are indispensable. Therefore, physicians, nurses, therapists, pharmacists, dieticians, care managers, and other health care professionals who have thorough knowledge about medical care for the elderly are of utmost necessity. In reality, however, the collaboration of these health care professionals is unsatisfactory, and the degree of understanding of team-based medicine by each medical professional is low. Therefore, as in the case of the establishment of cancer centers within individual regions to promote medical care for cancer, there is a demand to nurture professionals engaged in medical care for the elderly, and to establish a core facility for the promotion of multidisciplinary collaboration and team-based medicine for each region. (5) Do the people understand the paradigm shift? Currently, not only healthcare professionals, but also many citizens seek "cure-seeking medical care" aiming at a restoration of organ function; however, surveys of the elderly often show that they want to restore independent daily activity, rather than to achieve a "cure." In contrast, in the actual medical care setting, contradictory situations prevail in which the public awareness of the shift to "cure-and-support seeking medical care" is unsatisfactory, including the fact that the majority of recipients of tertiary emergency care are elderly patients. The Science Council of Japan has the task to propose future visions for the Japanese aging society not only from the viewpoint of the health of each individual, but also from a broader perspective, taking into account the relationship between humans and society. Various issues related to general population aging are posing serious problems, which require prompt resolution. Although we made a number of proposals at the 21st Subcommittee for Aging, the situation has not changed satisfactorily. Accordingly, the present proposals on specific solutions were designed. (1) In a super-aged society, a paradigm shift to "cure-and-support seeking medical care" should be implemented A super-aged society will consist of an unprecedented demographic structure in which the percentage of only those people aged ≥75 years will increase in the entire population. Therefore, there is an urgent need to prepare for increasing populations of persons in need of long-term care and those who are likely to become in need of long-term care. Given the consideration that "patients are not merely sick persons, but rather living persons," a paradigm shift from conventional "cure-seeking medical care" to "cure and support-seeking medical care" must be implemented. (2) Facilitate a paradigm shift to community-oriented medical care, and promote the activity of female physicians in the medical care for the elderly A paradigm shift should be promptly facilitated by reorganizing hospital functions and establishing a community comprehensive care system for home-based care to promote the participation of the elderly by themselves in care-supporting society. To further promote the collaboration of medical care and welfare, not only persons in charge of actual regional settings, but also university schools of medicine and regional core medical institutions experienced in medical care for the elderly should take the initiative to promote home-based care and facilitate a paradigm shift to community-oriented medical care. In addition, programs should also be developed to re-educate female physicians who became housewives in order to nurture them to become facilitators of geriatric medicine. (3) Physicians who are required at local medical facilities must be nurtured through the establishment of a department of gerontology or geriatric medicine at each medical school To facilitate efficient medical care services, medical education and research, and human resources development in support of expected paradigm shifts, it is considered that a department of gerontology or geriatric medicine should be established at each medical school. Furthermore, it is necessary to allocate dedicated teachers of medical care for the elderly to all medical schools, as well as to upgrade practice-participatory drills and to collaborate with a broad range of entities, including local medical institutions, and welfare and nursing care facilities. Efforts must be made to nurture locally wanted physicians through specific efforts concerning team-based medicine. (4) Promote the establishment of centers for geriatrics and gerontology (provisional name) for medical care collaboration, multidisciplinary training, and a means to increase public awareness To promote the uniform accessibility of expertise on efficient medical care that is best suited for a super-aged society, it is necessary to build a post-graduation educational system under the initiatives of the Japan Geriatrics Society and the National Center for Geriatrics and Gerontology across the nation in cooperation with regional medical schools and the Japan Medical Association. Furthermore, at least one hospital serving as a center for geriatrics and gerontology should be established in each regional block (Hokkaido, Tohoku, Koshinetsu, Hokuriku/Tokai, Kinki, Chushikoku and Kyushu/Okinawa) by making the best use of existing hospitals. By establishing these centers, uniform accessibility for the quality of medical care for the elderly in each region is expected. (ABSTRACT TRUNCATED).	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Furosemide is a diuretic used in human and veterinary medicine. Toxicology and carcinogenesis studies were conducted by feeding diets containing furosemide (99% pure, USP grade) to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day and Thirteen-Week Studies: Dietary concentrations of furosemide used in the 14-day studies for rats and mice ranged up to 46,000 ppm. Two of five male and 3/5 female rats that received 46,000 ppm furosemide died before the end of the studies. Rats that received 15,300 or 46,000 ppm lost weight over the course of the studies. The final mean body weights of rats that received 1,700 or 5,100 ppm were 12% or 23% lower than that of controls for males and 8% or 16% lower for females. Nephrosis was dose related in rats. All five male and 1/5 female mice that received 46,000 ppm furosemide died before the end of the 14-day studies. Male mice that received 15,300 ppm and female mice that received 46,000 ppm lost weight. The final mean body weights of male mice that received 1,700 or 5,100 ppm were 16% or 14% lower than that of controls. The final mean body weight of females that received 15,300 ppm was 13% lower than that of controls. Slight dilatation of the renal cortical tubules and/or nephrosis were dose related in mice. Dietary concentrations of furosemide used in the 13-week studies were 0 and 625-10,000 ppm for male rats and 0 and 938-15,000 ppm for female rats and male mice. Concentrations for female mice were 0 and 1,250-20,000 ppm. None of the rats died before the end of the studies. The final mean body weights of male rats that received 2,500, 5,000, or 10,000 ppm furosemide were 11%, 22%, or 44% lower than that of controls. The final mean body weights of female rats that received 3,750, 7,500, or 15,000 ppm were 18%, 26%, or 35% lower than that of controls. Minimal-to-mild nephrosis occurred in the two highest dose groups of male and female rats. Mineralization of minimal to mild severity was observed at the renal corticomedullary junction in dosed male rats receiving 625 ppm or more; the severity and incidence of the mineralization increased with increased dose. No compound-related deaths occurred in mice. The final mean body weights of male mice that received 3,750, 7,500, or 15,000 were 12%, 22%, or 17% lower than that of controls. Final mean body weights of dosed and control female mice were comparable. Compound-related lesions in mice induced minimal-to-mild nephrosis. Because of the lower body weights and the kidney lesions in the 13-week studies, doses selected for the 2-year studies were 0, 350, or 700 ppm furosemide in the diet for groups of 50 F344/N rats of each sex. Groups of 50 B6C3F1 mice of each sex were fed diets containing 0, 700, or 1,400 ppm furosemide for 104 weeks. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed and control rats were comparable throughout the studies. No significant differences in survival were observed between any groups of rats of either sex (final survival--male: control, 17/50; low dose, 17/50; high dose, 20/50; female: 35/50; 31/50; 34/50). The final survival of all groups of male rats was low, reflecting the large number of moribund animals killed after week 91. Survival at week 90 was 35/50, 28/50, and 34/50. Mean body weights of high dose male mice were up to 17% lower than those of controls, and mean body weights of low dose male mice were about 5%-10% lower than those of controls after week 31. Mean body weights of high dose female mice were up to 22% lower than those of controls. Mean body weights of low dose female mice were 5%-13% lower than those of controls after week 82. The survival of the high dose group of female mice was significantly lower than that of controls after week 99 (final survival--male: 31/50; 24/50; 26/50; female: 36/50; 29/50; 18/50). Feed consumption by dosed rats was similar to that by controls. The estimateer week 99 (final survival--male: 31/50; 24/50; 26/50; female: 36/50; 29/50; 18/50). Feed consumption by dosed rats was similar to that by controls. The estimated average amount of furosemide consumed per day was approximately 14-16 or 29-31 mg/kg for low dose or high dose rats. Feed consumption by dosed mice was approximately 5&percnt;-7&percnt; greater than that by controls. The average amount of furosemide consumed per day was approximately 91-99 or 191-214 mg/kg for low dose or high dose mice. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nephropathy occurred at similar incidences in all groups of rats, but the severity was greater in dosed male rats. Tubular cell hyperplasia was observed in 4/50 control, 2/50 low dose, and 4/50 high dose male rats. Tubular cell adenomas of the kidney occurred in 1/50 control, 3/50 low dose, and 1/50 high dose male rats. Tubular cell adenocarcinomas were seen in a fourth low dose male rat and in a second high dose male rat (adenomas or adenocarcinomas, combined: control, 1/50; low dose, 4/50; high dose, 2/50). The historical incidence of renal tubular cell adenomas or adenocarcinomas (combined) in untreated male F344/N rats is 9/1,928 (0.5&percnt;), and the highest incidence observed in controls is 3/50. Malignant meningiomas of the brain occurred in 3/50 low dose male rats; none was observed in other groups. The historical incidence of meningiomas in untreated male F344/N rats is 2/1,928 (0.1&percnt;). C-Cell adenomas of the thyroid gland in female rats occurred with a positive trend; the incidence in the high dose group was not statistically greater than that in the controls (4/50; 6/50; 11/50). A C-cell carcinoma occurred in another low dose female rat. The incidence of adenomas of the anterior pituitary gland in low dose male rats was marginally greater than that in controls (4/50; 11/50; 8/50). Neither of these marginal increases was considered to be chemically related. Malignant mixed tumors (adenocarcinoma, type C) of the mammary gland occurred in dosed female mice (0/50; 1/50; 5/48). One mammary gland acinar cell carcinoma occurred in a second low dose female mouse. The historical incidence of all malignant mammary gland neoplasms in untreated female B6C3F1 mice is 40/2,040 (2&percnt;). Compound-related nonneoplastic lesions of the kidney in mice included nephropathy and dilatation of the renal pelvis for males and females and tubular cysts, suppurative inflammation, and epithelial hyperplasia of the renal pelvis for males. Kidney lesions may have contributed to the low survival of high dose female mice. Mucosal epithelial hyperplasia and submucosal chronic focal inflammation of the urinary bladder were observed at increased incidences in dosed male mice. Suppurative inflammation of the prostate was observed at an increased incidence in high dose male mice. Fighting may have contributed to urogenital lesions in male mice. Suppurative inflammation of the ovary or uterus was observed at an increased incidence in high dose female mice. Hematopoiesis was observed at increased incidences in the spleen and liver of dosed male and high dose female mice and in the adrenal cortex of high dose female mice. Genetic Toxicology: Furosemide was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 when tested with or without exogenous metabolic activation. In the mouse lymphoma assay for trifluorothymidine (Tft) resistance, furosemide produced an equivocal response in the absence of metabolic activation and a positive response in the presence of activation. Furosemide induced sister chromatid exchanges and chromosomal aberrations in CHO cells in both the presence and absence of exogenous metabolic activation. Audit: The data, documents, and pathology materials from the 2-year studies of furosemide have been audited. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusion: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of furosemide for male F344/N rats, as shown by marginal increases in uncommon tubular cell neoplasms of the kidney and meningiomas of the brain. There was no evidence of carcinogenic activity of furosemide for female F344/N rats fed diets containing 350 or 700 ppm furosemide for 2 years. There was no evidence of carcinogenic activity for male B6C3F1 mice fed diets containing 700 or 1,400 ppm furosemide for 2 years. There was some evidence of carcinogenic activity of furosemide for female mice, as shown by an increase in malignant tumors of the mammary gland. Nephropathy was more severe in the kidney of male rats and of male and female mice fed diets containing furosemide than in controls. Synonyms: 5-(aminosulfonyl)-4-chloro-2-[(2-furanylmethyl)amino]benzoic acid; frusemide; fursemide Trade Names: Aisemide; Aluzine; Beronald; Desdemin; Diural; Dryptal; Errolon; Frusemin; Fulsix; Fuluvamide; Furosemide "Mita"; Katlex; Lasilix; Lasix; Lowpstron; Rosemide; Transit; Urosemide	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Evidence is increasing that long-term exposure to ambient air pollution is associated with deaths from cardiopulmonary diseases. In a 2002 pilot study, we reported clear indications that traffic-related air pollution, especially at the local scale, was related to cardiopulmonary mortality in a randomly selected subcohort of 5000 older adults participating in the ongoing Netherlands Cohort Study (NLCS) on diet and cancer. In the current study, referred to as NLCS-AIR, our objective was to obtain more precise estimates of the effects of traffic-related air pollution by analyzing associations with cause-specific mortality, as well as lung cancer incidence, in the full cohort of approximately 120,000 subjects. Cohort members were 55 to 69 years of age at enrollment in 1986. Follow-up was from 1987 through 1996 for mortality (17,674 deaths) and from late 1986 through 1997 for lung cancer incidence (2234 cases). Information about potential confounding variables and effect modifiers was available from the questionnaire that subjects completed at enrollment and from publicly available data (including neighborhood-scale information such as income distributions). The NLCS was designed for a case-cohort approach, which makes use of all the cases in the full cohort, while data for the random subcohort are used to estimate person-time experience in the study. Full information on confounders was available for the subjects in the random subcohort and for the emerging cases of mortality and lung cancer incidence during the follow-up period, and in NLCS-AIR we used the case-cohort approach to examine the relation between exposure to air pollution and cause-specific mortality and lung cancer. We also specified a standard Cox proportional hazards model within the full cohort, for which information on potential confounding variables was much more limited. Exposure to air pollution was estimated for the subjects' home addresses at baseline in 1986. Concentrations were estimated for black smoke (a simple marker for soot) and nitrogen dioxide (NO2) as indicators of traffic-related air pollution, as well as nitric oxide (NO), sulfur dioxide (SO2), and particulate matter with aerodynamic diameter < or = 2.5 microm (PM2.5), as estimated from measurements of particulate matter with aerodynamic diameter < or = 10 microm (PM10). Overall long-term exposure concentrations were considered to be a function of air pollution contributions at regional, urban, and local scales. We used interpolation from data obtained routinely at regional stations of the National Air Quality Monitoring Network (NAQMN) to estimate the regional component of exposure at the home address. Average pollutant concentrations were estimated from NAQMN measurements for the period 1976 through 1996. Land-use regression methods were used to estimate the urban exposure component. For the local exposure component, geographic information systems (GISs) were used to generate indicators of traffic exposure that included traffic intensity on and distance to nearby roads. A major effort was made to collect traffic intensity data from individual municipalities. The exposure variables were refined considerably from those used in the pilot study, but we also analyzed the data for the full cohort in the current study using the exposure indicators of the pilot study. We analyzed the data in models with the estimated overall pollutant concentration as a single variable and with the background concentration (the sum of regional and urban components) and the local exposure estimate from traffic indicators as separate variables. In the full-cohort analyses adjusted for the limited set of confounders, estimated overall exposure concentrations of black smoke, NO2, NO, and PM2.5 were associated with mortality. For a 10-microg/m3 increase in the black smoke concentration, the relative risk (RR) (95% confidence interval [CI]) was 1.05 (1.00-1.11) for natural-cause (nonaccidental) mortality, 1.04 (0.95-1.13) for cardiovascular mortality, 1.22 (0.99-1.50) for respiratory mortality, 1.03 (0.88-1.20) for lung cancer mortality, and 1.04 (0.97-1.12) for noncardiopulmonary, non-lung cancer mortality. Results were similar for NO2, NO, and PM2.5. For a 10-microg/m3 increase in PM2.5 concentration, the RR for natural-cause mortality was 1.06 (95% CI, 0.97-1.16), the same as in the results of the American Cancer Society Study reported by Pope and colleagues in 2002. The highest relative risks were found for respiratory mortality, though confidence intervals were wider for this less-frequent cause of death. No associations with mortality were found for SO2. Some of the associations between the traffic indicator variables used to assess traffic intensity near the home and mortality reached statistical significance in the full cohort. For an increase in traffic intensity of 10,000 motor vehicles in 24 hours (motor vehicles/day) on the road nearest a subject's residence, the RR was 1.03 (95% CI, 1.00-1.08) for natural-cause mortality, 1.05 (0.99-1.12) for cardiovascular mortality, 1.10 (0.95-1.26) for respiratory mortality, 1.07 (0.96-1.19) for lung cancer mortality, and 1.00 (0.94-1.06) for noncardiopulmonary, non-lung cancer mortality. Results were similar for traffic intensity in a 100-m buffer around the subject's residence and living near a major road (a road with more than 10,000 motor vehicles/day). Distance in meters to the nearest major road and traffic intensity on the nearest major road were not associated with any of the mortality outcomes. We did not find an association between cardiopulmonary mortality and living near a major road as defined using the methods of the pilot study. In the case-cohort analyses adjusted for all potential confounders, we found no associations between background air pollution and mortality. The associations between traffic intensity and mortality were weaker than in the full cohort, and confidence intervals were wider, consistent with the smaller number of subjects. The lower relative risks of mortality associated with traffic variables in the case-cohort study population could be related to the particular subcohort that was randomly selected from the full cohort, as the risks estimated with the actual subcohort were well below the average estimates obtained for 100 new case-cohort analyses with 100 alternative subcohorts of 5000 subjects each that we randomly selected from the full cohort. Differences in adjusted relative risks between the full-cohort and the case-cohort analyses could be explained by random error introduced by sampling from the full cohort and by a selection effect resulting from the relatively large number of missing data for variables in the extensive confounder model used in the case-cohort analyses. More complete control for confounding probably did not contribute much to the lower relative risks in the case-cohort analyses, especially for the traffic variables, as results were similar when the limited confounder model for the full cohort was used in analyses of the subjects in the case-cohort study population. In additional analyses using black smoke concentrations as the exposure variables, we found that the association between overall black smoke and cardiopulmonary mortality was somewhat stronger for case-cohort subjects who did not change residence during follow-up, and in the full cohort, there was a tendency for relative risks to be higher for subjects living in the three major cities included in the study. Adjustment for estimated exposure to traffic noise did not affect the associations of background black smoke and traffic intensity with cardiovascular mortality. There was some indication of an association between traffic noise and cardiovascular mortality only for the 1.6% of the subjects in the full cohort who were exposed to traffic noise in the highest category of > 65 A-weighted decibels (dB(A); decibels with the sound pressure scale adjusted to conform with the frequency response of the human ear). Examination of sex, smoking status, educational level, and vegetable and fruit intake as possible effect modifiers showed that for overall black smoke concentrations, associations with mortality tended to be stronger in case-cohort subjects with lower levels of education and those with low fruit intake, but differences between strata were not statistically significant. For lung cancer incidence, we found essentially no relation to exposure to NO2, black smoke, PM2.5, SO2, or several traffic indicators. Associations of overall air pollution concentrations and traffic indicator variables with lung cancer incidence were, however, found in subjects who had never smoked, with an RR of 1.47 (95% CI, 1.01-2.16) for a 10-microg/m3 increase in overall black smoke concentration. In the current study, the mortality risks associated with both background air pollution and traffic exposure variables were much smaller than the estimate previously reported in the pilot study for risk of cardiopulmonary mortality associated with living near a major road (RR, 1.95; 95% CI, 1.09-3.51). The differences are most likely due to the extension of the follow-up period in the current study and to random error in the pilot study related to sampling from the full cohort. Though relative risks were generally small in the current study, long-term average concentrations of black smoke, NO2, and PM2.5 were related to mortality, and associations of black smoke and NO2 exposure with natural-cause and respiratory mortality were statistically significant. Traffic intensity near the home was also related to natural-cause mortality. The highest relative risks associated with background air pollution and traffic variables were for respiratory mortality, though the number of deaths was smaller than for the other mortality categories. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Both the landforms and the vegetation of the earth develop to states that are maintained in dynamic equilibrium. Short-term equilibrium of a hillslope or river valley results from intersection between erosional and depositional tendencies, controlled by gravitational force and the efficiency of the transporting medium. Long-term equilibrium of major landforms depends on crustal uplift and the resistance of the rock to weathering. In most parts of the world landscape evolves toward a peneplain, but the reduction rate approaches zero as the cycle progresses, and the counteracting force of crustal uplift intercedes before the end form is reached. Davis described this theoretical model in elegant terms. Leopold and Hack have provided a new and quantitative understanding of short-range geomorphic interactions that tend to discredit the Davisian model in the eyes of many. However, the substitute models of quasi-equilibrium or dynamic equilibrium merely describe short-range situations in which this or that Davisian stage is maintained despite uplift or downwasting. Given crustal stability and an unchanging climate, landforms would presumably still evolve through Davisian stages. However, the Davis model cannot be tested, for despite tremendous inventions in geochronology and impressive advances in stratigraphic knowledge, we cannot yet establish the rates or even the fact of crustal uplift in most areas. We are left with an unresolvable problem, for the sedimentary records of erosional history are largely inaccessible, undatable, and indecipherable, at least in the detail necessary to describe long-term evolution of the landscape. We know more about the evolution and maintenance of vegetation assemblages than about landform evolution, for even long-term vegetation sequences are within the scope of radiocarbon dating, and the biostratigraphic record is detailed. Even here, however, distinctions between short-term and long-term situations must be made, so that Clements' grand scheme of vegetational climax-created soon after Davis's model of landform development-can be evaluated in terms of modern knowledge. Disillusion with the climax model paralleled disillusion with Davis's model in the 1950's, but the climax model can be tested, because the record of vegetational history is accessible, datable, and decipherable. In the short term of a few decades, successional vegetation stages occur in variety of situations, as confirmed by observation or by techniques such as tree-ring analysis. The successional vegetation stages are reactions to nutrients, weather, competition, and consumption. Such succession implies long-term disequilibrium, or at least unidirectional development. The long-term controlling factor in Clements' model of vegetation development is climate. With climatic stability the succession will proceed to a climax. In the Appalachian Mountains, geomorphic, microclimatic, and edaphic conditions limit climax development, producing a polyclimax, which is generally sustained by the dominance of these factors. Death and regeneration of single forest trees is controlled mostly by windstorms. The distributional pattern may be locally transected by lightning fires, major windstorms, or washouts. However, the long-term stability of Appalachian forests is demonstrated by pollen stratigraphy. Although we can infer the long-term stability of Appalachian forests, the trends and mechanics of short-term vegetational succession are not fully understood, because lack of sizable areas of virgin forest limits investigations of natural conditions. In this respect, the eastern United States is already much like western Europe, where climatic and disturbance factors in vegetational history cannot be disentangled. In the Great Lakes region, a large area of virgin forest exists in the BWCA of northeastern Minnesota. Here short- and long-term studies show that for at least 9000 years the principal stabilizing factor has been the frequent occurrence of fire. Major fires occur so often that the vegetation pattern is a record of fire history. All elements in the forest mosaic are in various stages of postfire succession, with only a few approaching climax. Fire interrupts the successful sequence toward climax. Geomorphic and edaphic factors in vegetational distribution are largely submerged by the fire regime, except for bog and other lowland vegetation. Fire recycles nutrients and renews succession. Nevertheless, despite the fire regime, the resulting long-term equilibrium of the forest mosaic, characterized by severe and irregular fluctuations of individual elements, reflects regional climate. In the BWCA and the western mountains, large virgin forests can be preserved for study and wilderness recreation. These wilderness areas must be managed to return them to the natural equilibrium which has been disturbed by 50 to 70 years of fire suppression. The goal should be to maintain virgin forests as primeval wilderness. This can be done by management that permits fire and other natural processes to determine the forest mosaic. Mechanized tree-felling and other human disturbances should be kept to an absolute minimum. Natural landforms also should be preserved for study and for certain nondestructive recreational activities. It is somewhat late for the Colorado River and other rivers of the West, because natural balances are upset by drainagebasin disturbances. Modification of plant cover on hillslopes changes infiltration and erosion rates and thus the stream discharge and sediment load, so the stream balance is altered from primeval conditions. Scenic Rivers legislation should thus be used to restore certain river systems and their drainage basins. Mountain meadows, badlands, desert plains, and patterned permafrost terrain are extremely fragile and sensitive. Intricate stream and weathering processes leave patterns easily obliterated by mechanized vehicles. Tire tracks can last for decades or centuries. The mineral patina or lichen cover on desert or alpine rocks are records of long stability, and slight differences in their development record the relative ages of landforms, to the year in the case of lichens. Delicate color differences in a talus slope or desert fan show long-term effects just as does the arboreal vegetation mosaic in another climatic setting. Preservation of virgin wilderness for study is viewed by some as a selfish goal of scientists, to be achieved at the expense of commercial and recreational development. However, scientific study and nonmechanized recreational uses are compatible in wilderness areas. Furthermore, the public does appreciate intellectual stimulation from natural history, as witnessed by massive support for conservation, the Wilderness Act, and a dozen magazines like National Geographic. Finally, no knowledgeable American today is unaware that ecological insights are necessary to preserve the national heritage. Western dust bowls, deforested slopes, gullied fields, silted rivers, strip mine waste-lands, and the like might have been avoided had long-term problems been balanced against short-term profits. Many economic questions cannot be answered intelligently without detailed knowledge of extensive virgin ecosystems. Long-term values are enhanced by those uses of natural resources that are compatible with the preservation of natural ecosystems. Esthetically, virgin wilderness produced by nature is comparable to an original work of art produced by man. One deserves preservation as much as the other, and a copy of nature has as little value to the scientist or discerning layman as a reproduction of a painting has to an art scholar or an art collector. Nature deserves its own display, not just in tiny refuges but in major landscapes. Man is only one of literally countless species on the earth. Man developed for a million years in a world ecosystem that he is now in danger of destroying for short-term benefits. For his long-term survival and as an expression of his rationality and morality, he should nurture natural ecosystems. Some people believe that human love of nature is self-protective. For many it is the basis of natural religion. The opposition of many Americans to the Alaska pipeline is a manifestation of almost religious feeling; most never expect to see the Alaskan wilderness, but they are heartened to realize that it exists and is protected. The same can be said of those who contribute to save the redwoods in California. Here cost analysis fails to account for the enormous value people place on nature and on the idea of nature as contrasted to the private gain of a few developers. Americans admire European preservation of works of art. Europeans admire American foresight in setting aside national parks. However, the distribution of protected natural areas in America is uneven and inadequate, and vast areas continue to be developed or badly managed despite widespread new knowledge about long-term human interest in wilderness preservation. Darwin turned nature study into the study of natural history. He could observe natural features in vast undisturbed areas with no thought that human interference had been a factor in their development. Today such natural landscapes have practically vanished. Those that remain should be preserved as extensively as possible, and managed with scientific knowledge of the natural processes that brought them to being. At the present accelerating rate of exploitation, massive disturbance, and unscientific management, soon no natural areas will be left for research or wilderness recreation. Some say that scientific curiosity and the ability for recreation define man. This is reason enough for wilderness preservation. However, a more ominous conclusion that the survival of man may depend on what can be learned from the study of extensive natural ecosystems.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
In our part of the world invasive fungal infections include invasive yeast infections with Candida as the absolutely dominating pathogen and invasive mould infections with Aspergillus as the main organism. Yeasts are part of our normal micro-flora and invasive infections arise only when barrier leakage or impaired immune function occurs. On the contrary, moulds are ubiquitous in the nature and environment and their conidia inhaled at a daily basis. Hence invasive mould infections typically arise from the airways whereas invasive yeast infections typically enter the bloodstream causing fungaemia. Candida is by far the most common fungal blood stream pathogen; hence this genus has been the main focus of this thesis. As neither the Danish epidemiology nor the susceptibility of fungal pathogens was well described when we initiated our studies we initially wanted to be able to include animal models in our work. Therefore, a comprehensive animal study was undertaken comparing the virulence in a haematogenous mouse model of eight different Candida species including the five most common ones in human infections (C. albicans, C. glabrata, C. krusei, C. parapsilosis and C. tropicalis and in addition three rarer species C. guilliermondii, C. lusitaniae and C. kefyr). We found remarkable differences in the virulence among these species and were able to group the species according to decreasing virulence in three groups I: C. albicans and C. tropicalis, II: C. glabrata, C. lusitaniae and C. kefyr, and III: C. krusei, C. parapsilosis and C. guilliermondii. Apart from being necessary for our subsequent animal experiments exploring in vivo antifungal susceptibility, these findings also helped us understand at least part of the reason for the differences in the epidemiology and the pitfalls associated with the establishment of genus rather than species specific breakpoints. In example, it was less surprising that C. albicans has been the dominant pathogen and associated with a significantly higher mortality than C. parapsilosis and that C. glabrata and C. krusei mainly emerged in the post fluconazole era and in settings with azole selection pressure. Moreover, it was less surprising that infections due to mutant C. albicans isolates with echinocandin MICs of 1-2 mg/l were not good targets for the echinocandins despite the fact that the outcome for infections involving wild type C. parapsilosis for which similar echinocandin MICs were similar was not inferior. This last observation highlights the importance of providing optimal, reproducible and sensitive reference susceptibility testing methods and notably accompanied by appropriate breakpoints that allow a separation and detection of susceptible and resistant isolates against which the commercial tests can be validated. Correct detection of resistant isolates is for obvious reasons crucial in order to avoid inappropriate treatment. And if the test method cannot correctly identify resistant isolates it makes little sense performing susceptibility testing at all. On the other hand misclassification of susceptible isolates as resistant is also an issue as the patient is thereby deprived an appropriate treatment option among the few available. These comments may seem very basic; nevertheless, it has taken a lot of effort and patience to optimise the susceptibility tests, understand the variability issue for caspofungin testing, to provide appropriate breakpoints that reduced misclassifications to a minimum and not the least to facilitate a harmonisation of breakpoints across the Atlantic sea. We initially realised that the CLSI method and echinocandin breakpoint misclassified resistant isolates. This was due to the endorsement of a single susceptibility breakpoint across all Candida species and the three echinocandins and therefore set as high as 2 mg/l in order to include and not bisect the C. parapsilosis population. Through our comprehensive comparisons of echinocandin susceptibility testing using EUCAST, CLSI, Etest, disk diffusion and agardilution with different media with and without the supplementation of bovine serum albumin we provided data that supported the current reference methodologies, provided that drug and species specific breakpoints were selected. Moreover, the issues of caspofungin variability and of overlap between micafungin MICs for wild type and mutant C. glabrata populations were handled and understood. Anidulafungin EUCAST breakpoints are now published and publically available at the www.eucast.org website and anidulafungin testing recommended as a marker for the echinocandin class. Our antifungal EUCAST breakpoint setting approach has been adopted by the CLSI leading to revision and harmonisation of breakpoints for the three echinocandins, fluconazole and voriconazole. Our epidemiological studies developed gradually over the years following our observation of a notably high incidence rate of fungaemia compared to our Nordic neighbours. Initially, we anticipated that our high incidence was at least in part related to the fact that the capture area for our initial studies was skewed with dominance of university hospitals and inclusion of all centres performing solid organ or bone marrow transplantation. However, when the surveillance was extended to the entire country, the high incidence remained a consistent finding and we even demonstrated that the incidence rate is still increasing. Additionally we demonstrated a changing epidemiology as a high and increasing proportion of the cases involved fluconazole resistant isolates and that this proportion also was significantly higher than in the other Nordic countries. This appears to be related to a significantly higher and increasing fluconazole use in Denmark than in the other Nordic countries. Exploring the incidence rate for the individual hospitals and age groups we demonstrated not unexpectedly that the incidence rate was highest at the university centres, but also that whereas the age specific incidence rate was comparable in children and the younger adults with that in the other Nordic countries it was notably higher in the elderly population. This in combination with the fact that it is increasing specifically in the elderly men and that the incidence rates in the Nordic countries were comparable two decades back suggest that host specific factors including antifungal consumption rather than genetic differences in susceptibility to fungaemia account for the differences, and hence that it is possibly modifiable by implementing relevant measures. Hence, it was important to investigate the underlying clinical conditions and diagnostic factors and the outcome in Danish patients with fungaemia. In this study we demonstrated that two thirds of the patients had received abdominal surgery or intensive care treatment prior to the development of the fungaemia, a proportion that is higher than in most other studies. We also demonstrated that unless surveillance cultures are handled with careful attention the detection of non-C. albicans may go unnoticed which imply a risk of inappropriate treatment in cases involving intrinsically resistant species. Finally, we demonstrated the necessity of using a fungal blood culture flask in addition to the conventional aerobic and anaerobic ones if all C. glabrata infections (BACTEC) and all polymicrobial infections (BacT/ALERT) are to be diagnosed. Hence close monitoring with the use of improved diagnostic options (such as frequent BC including a mycosis bottle, surveillance cultures and mannan antigen and antibody screening) of particularly ICU and abdominal surgery patients may help better identify patients with fungaemia and allow early treatment. With respect to treatment and outcome we found that the fluconazole resistant species C. glabrata, C. krusei and S. cerevisiae were significantly more common in patients exposed to at least 7 days of antifungal prophylaxis (mainly fluconazole). We also demonstrated that a significant proportion of the patients initially received inappropriate antifungal treatment and that the outcome was significantly improved when patients with C. glabrata received caspofungin as their first line agent. This has today been incorporated in the Danish and international treatment guidelines. The prevalence of acquired antifungal resistance remained very low throughout the study period, however, we may only have detected the tip of the resistance iceberg due to the study design, where for epidemiological purposes only the initial isolate was included with the lowest antifungal exposure, and as the susceptibility tests and breakpoints were not optimal for the detection of resistance at all centres. Most Danish laboratories either do not susceptibility test or use commercial tests such as the Etest and later the VITEK system. These are FDA approved with the CLSI breakpoints which, as we have shown, have been far too high to reliably detect resistance and which despite having now been revised and harmonised are not yet in formal CLSI print and hence not incorporated in the product inserts for the commercial tests on the market. Finally, even for laboratories aware of these issues challenges are still ahead as the official breakpoints not always lead to a correct classification for MIC endpoints obtained using the commercial systems or as the commercial tests do not include a relevant concentration range for all drug bug combinations. I thus believe, the studies included in this thesis have contributed significantly to the understanding of the interplay between the Candida virulence, epidemiology and susceptibility and the importance of appropriate diagnostics and treatment choice. It is my hope that we thereby have contributed to the improved options and outcome for patients with candidaemia.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Dear Editor, The Covid-19 pandemic affected human life globally, inducing much stress on daily living (Çakıroğlu et al. 2020). Although assessments of general mental health during the Covid-19 pandemic have been widely reported, there is not adequate research on how schizophrenia patients have been affected. According to the World Health Organization (2020), individuals with chronic diseases who do not pay attention to their personal hygiene and the rules of protection from COVID-19 have a higher risk of getting infected than the healthy individuals who observe these measures. It is well known that the risk of Covid-19 infection is raised among schizophrenia patients due to negligence on the requisite control of personal hygiene and health conditions related to smoking and diabetes ( Cohn et al., 2004; Dinan et al., 2004; Krieger et al. 2019). The cognitive impairment in this disorder which reduces the perceptions on the necessity of self protection and the awareness of the risks proposed to underlie this raised risk of COVID-19 positivity (Yao et al. 2020). These patients have difficulty in following the preventive regulations (Palomar-Ciria et al., 2020). Apart from the risk of infection, there is also the risk of pandemic related development of auditory or visual hallucinations and delusional symptoms by acute and chronic psychosis patients during and after the pandemic (Brown et al. 2020, Cowan 2020). Therefore, this survey has been organised to evaluate the reaction developed by schizophrenia patients to the pandemic conditions. The first Covid-19 case was reported in Turkey on 11 March 2020 (Anadolu Agency, 11.03.2020) which was followed by the gradual increase in case numbers. In order to prevent the spread of Covid-19 and maintain the existing public health, the Republic of Turkey Ministry of Health established a 'Scientific Committee'' and prepared effective strategies including social isolation, quarantine, school closures, social distancing and wearing face mask in the community. During this process, the approximately 250 schizophrenia and schizoaffective disorder patients followed up by the Psychosis Outpatient Unit of Dokuz Eylul University Hospital Psychiatry Department (DEUPD) were instructed to visit the outpatient unit only in emergency conditions. It was determined that there were 176 schizophrenia patients whose follow up visit appointments for the period of April 1 - June 22, 2020, scheduled before the announcement of the pandemic, were cancelled. Therefore, the survey reported here was conducted with the schizophrenia patients of the DEUPD online and by telephone connections during 10- 20 May, 2020, the 9th and the 10th weeks of the pandemic. Only 76 (43.19%) of the 176 patients joined the survey, since 4 (2.27%) refused to participate and 96 (54.4%) could not be contacted. The survey aimed to determine the incidence of Covid-19 diagnosis among these schizophrenia patients and their attitude to the preventive measures against the infection during the first 2 months of the pandemic, together with how they felt and their needs for psychiatric consultation on outpatient basis during this period. The surveyed 76 patients consisted of 49 (64%) males and 27 (35%) females, with 73 (96.1%) dwelling in urban and 3 (3.9%) in suburban areas; and only 11 (14.5%) employed while 65 (85.5%) were not working. Only two patients reported consulting emergency services for Covid-19 symptoms. The rest of the patients did not report consulting a healthcare facility for suspecting Covid-19 symptoms or Table 1. Data on the demographic, clinical and social features of the schizophrenia patients during the COVID-19 pandemic n=76 Mean SD Gender (F/M) 27 (35.5%) / 49 (64.5%) Age 44.54 12.21 Disease duration 16.62 9.96 Patients living /with Alone 3 (3.9%) Parent(s) 43 (56.6%) Spouse/children 25 (32.9%) Sibling (s) 1 (1.3%) Relative(s) 2 (2.6%) Friend(s) 2 (2.6%) Yes No Need to see a psychiatrist 23 (30.3%) 53 (69.7%) Subjective psychiatric complaints 32 (42.1%) 44 (57.9%) Consultation with an emergency service 2 (2.6%) 74 (97.4%) Planning to go to the hospital in the post-quarantine period 58 (76.3%) 18 (23.7%) Wearing a mask in community 67 (88.2%) 4 (5.3%) Keeping social distancing 68 (89.5%) 3 (3.9%) Expressed feeling Loneliness 26 (34.2%) 49 (64.5%) Depressed 31 (40.8%) 44 (57.9%) Despaired 22 (28.9%) 52 (68.4%) Anxious 25 (32.9%) 49 (64.5%) Difficulty of going to the hospital in the quarantine period 53 (69.7%) 23 (30.3%) hospital admission for Covid-19 infection or psychotic attack or incidences of Covid-19 related hallucination or delusions. During this 2-month period, 4 patients had experienced fatigue, 2 had episodes of dry cough and 7 had experienced shortness of breath, which can be associated with the nature of schizophrenia, the sedentary life style.and cigarette smoking. Medication was prescribed by a psychiatrist for 10 patients and by a family doctor for 16 patients or supplied directly by pharmacies for 45 patients on the basis of prescriptions with 1-year validity issued by the hospital* (Table 1). Much as it had been aimed to contact all patients with cancelled appointments, this objective was not attainable The patients who were not reached are likely to include those with low awareness and difficulty of adapting to infection prevention strategies. On the other hand, regardless of the level of awareness of the pandemic and compliance with the rules, phone use by these patients might have been limited by economic and environmental reasons, as well as the difficulties imposed by the pandemic. In conclusion, it is possible to say that most of the patients with schizophrenia were aware of the risk of COVID-19 infection, and understood and mostly obeyed the general health rules and advices of healthcare professionals even if they had difficulty in doing so. This could also have resulted from the nature of schizophrenia with preference for social isolation even if this can worsen the prognosis. On the other hand, patients need to be in contact with a mental healthcare professional in extraordinary situations of a pandemic. This survey did not find a remarkable increase in positive symptom severity in association with COVID-19 as most patients included in the survey had not seen a psychiatrist or mental healthcare professional for two months with 53 patients stating that they did not have to need. However, 58 patients also stated that despite planning to make a consultation after normalization of the quarantine measures, the anxiety of contagion outweighed the option of visiting outpatient clinics. This anxiety over Covid-19 infection, however, may make it difficult for patients to understand the level of the need to see a psychiatrist and may be associated with the assumption that the pandemic would be taken under control in the normalization process with a decrease in the risk of contagion. On the results of this survey, it may be concluded that strategies for prevention of COVID-19 spread were effective among schizophrenia patients and that there is need to develop a system that reaches all patients and keeps them socially connected during the COVID-19 pandemic. *In Turkey, prescription reports with 1-year validity are issued for patients with chronic disorders. The medications can only be prescribed by a specialist, and in the case of pyshchiatric disorders, by a consultant psychiatrist. When the report is confirmed by a hospital committee of specialists, a family doctor is able to issue prescriptions. According to the decision of the Ministry of Health, patients who have medication prescription reports valid for one year would be able to get their medicines directly from pharmacies without having to consult a psychiatrist or family doctor during the pandemic. REFERENCES Anadolu Agency (2020, Mach 11). Sağlık Bakanı Koca Türkiye'de ilk koronavirüs vakasının görüldüğünü açıkladı, https://www.aa.com.tr/tr/kor onavir us/ saglik-bakani-koca-turkiyede-ilk-koronavirus-vakasinin-goruldugunu- acikladi/1761466. Accessed 28 May 2020. Brown E, Gray R, Lo Monaco S et al (2020) The potential impact of COVID-19 on psychosis: A rapid review of contemporary epidemic and pandemic research. Schizophr Res 222:79-87. Cohn T, Prud'homme D, Streiner D et al (2004) Characterizing coronary heart disease risk in chronic schizophrenia: High prevalence of the metabolic syndrome. Can J Psychiatry 49:753-60. Cowan, HR (2020) Is schizophrenia research relevant during the COVID-19 pandemic?. Schizophr Res 220:271-2. Çakıroğlu S, Ertaş E, and Alyanak B (2020) Letter To The Editor - The Covid-19 Pandemic And Mental Health As Issues Considered Within The Context Of Adjustment Disorder And Psychosocial Interventions. Turk Psikiyatri Derg 31:148-50. Dinan T, Holt R, Kohen D et al (2004) "Schizophrenia and diabetes 2003" expert consensus meeting, Dublin, 3-4 october 2003: Consensus summary. Br J Psychiatry 184 (Suppl. 47): 0-2. Krieger I, Bitan DT, Comaneshter D et al (2019) Increased risk of smoking- related illnesses in schizophrenia patients: A nationwide cohort study. Schizophr Res 212:121-5. Palomar-Ciria N, del Valle PB, Hernández-Las Heras MÁ et al (2020) Schizophrenia and COVID-19 delirium. Psychiatry Res 290:113137. Yao H, Chen JH, and Xu YF (2020) Patients with mental health disorders in the COVID-19 epidemic. Lancet Psychiatry 7: e21. World Health Organization (2020, Mart 25). Covid-19: Vulnerable and High Risk Group, Geneva, Switzerland: World Health Organization, https:// www.who.int/westernpacific/emergencies/covid-19/information/high-risk- groups. Accessed 28 May 2020.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Dear Editor, The Covid-19 pandemic affected human life globally, inducing much stress on daily living (Çakıroğlu et al. 2020). Although assessments of general mental health during the Covid-19 pandemic have been widely reported, there is not adequate research on how schizophrenia patients have been affected. According to the World Health Organization (2020), individuals with chronic diseases who do not pay attention to their personal hygiene and the rules of protection from COVID-19 have a higher risk of getting infected than the healthy individuals who observe these measures. It is well known that the risk of Covid-19 infection is raised among schizophrenia patients due to negligence on the requisite control of personal hygiene and health conditions related to smoking and diabetes ( Cohn et al., 2004; Dinan et al., 2004; Krieger et al. 2019). The cognitive impairment in this disorder which reduces the perceptions on the necessity of self protection and the awareness of the risks proposed to underlie this raised risk of COVID-19 positivity (Yao et al. 2020). These patients have difficulty in following the preventive regulations (Palomar-Ciria et al., 2020). Apart from the risk of infection, there is also the risk of pandemic related development of auditory or visual hallucinations and delusional symptoms by acute and chronic psychosis patients during and after the pandemic (Brown et al. 2020, Cowan 2020). Therefore, this survey has been organised to evaluate the reaction developed by schizophrenia patients to the pandemic conditions. The first Covid-19 case was reported in Turkey on 11 March 2020 (Anadolu Agency, 11.03.2020) which was followed by the gradual increase in case numbers. In order to prevent the spread of Covid-19 and maintain the existing public health, the Republic of Turkey Ministry of Health established a 'Scientific Committee'' and prepared effective strategies including social isolation, quarantine, school closures, social distancing and wearing face mask in the community. During this process, the approximately 250 schizophrenia and schizoaffective disorder patients followed up by the Psychosis Outpatient Unit of Dokuz Eylul University Hospital Psychiatry Department (DEUPD) were instructed to visit the outpatient unit only in emergency conditions. It was determined that there were 176 schizophrenia patients whose follow up visit appointments for the period of April 1 - June 22, 2020, scheduled before the announcement of the pandemic, were cancelled. Therefore, the survey reported here was conducted with the schizophrenia patients of the DEUPD online and by telephone connections during 10- 20 May, 2020, the 9th and the 10th weeks of the pandemic. Only 76 (43.19%) of the 176 patients joined the survey, since 4 (2.27%) refused to participate and 96 (54.4%) could not be contacted. The survey aimed to determine the incidence of Covid-19 diagnosis among these schizophrenia patients and their attitude to the preventive measures against the infection during the first 2 months of the pandemic, together with how they felt and their needs for psychiatric consultation on outpatient basis during this period. The surveyed 76 patients consisted of 49 (64%) males and 27 (35%) females, with 73 (96.1%) dwelling in urban and 3 (3.9%) in suburban areas; and only 11 (14.5%) employed while 65 (85.5%) were not working. Only two patients reported consulting emergency services for Covid-19 symptoms. The rest of the patients did not report consulting a healthcare facility for suspecting Covid-19 symptoms or Table 1. Data on the demographic, clinical and social features of the schizophrenia patients during the COVID-19 pandemic n=76 Mean SD Gender (F/M) 27 (35.5%) / 49 (64.5%) Age 44.54 12.21 Disease duration 16.62 9.96 Patients living /with Alone 3 (3.9%) Parent(s) 43 (56.6%) Spouse/children 25 (32.9%) Sibling (s) 1 (1.3%) Relative(s) 2 (2.6%) Friend(s) 2 (2.6%) Yes No Need to see a psychiatrist 23 (30.3%) 53 (69.7%) Subjective psychiatric complaints 32 (42.1%) 44 (57.9%) Consultation with an emergency service 2 (2.6%) 74 (97.4%) Planning to go to the hospital in the post-quarantine period 58 (76.3%) 18 (23.7%) Wearing a mask in community 67 (88.2%) 4 (5.3%) Keeping social distancing 68 (89.5%) 3 (3.9%) Expressed feeling Loneliness 26 (34.2%) 49 (64.5%) Depressed 31 (40.8%) 44 (57.9%) Despaired 22 (28.9%) 52 (68.4%) Anxious 25 (32.9%) 49 (64.5%) Difficulty of going to the hospital in the quarantine period 53 (69.7%) 23 (30.3%) hospital admission for Covid-19 infection or psychotic attack or incidences of Covid-19 related hallucination or delusions. During this 2-month period, 4 patients had experienced fatigue, 2 had episodes of dry cough and 7 had experienced shortness of breath, which can be associated with the nature of schizophrenia, the sedentary life style.and cigarette smoking. Medication was prescribed by a psychiatrist for 10 patients and by a family doctor for 16 patients or supplied directly by pharmacies for 45 patients on the basis of prescriptions with 1-year validity issued by the hospital* (Table 1). Much as it had been aimed to contact all patients with cancelled appointments, this objective was not attainable The patients who were not reached are likely to include those with low awareness and difficulty of adapting to infection prevention strategies. On the other hand, regardless of the level of awareness of the pandemic and compliance with the rules, phone use by these patients might have been limited by economic and environmental reasons, as well as the difficulties imposed by the pandemic. In conclusion, it is possible to say that most of the patients with schizophrenia were aware of the risk of COVID-19 infection, and understood and mostly obeyed the general health rules and advices of healthcare professionals even if they had difficulty in doing so. This could also have resulted from the nature of schizophrenia with preference for social isolation even if this can worsen the prognosis. On the other hand, patients need to be in contact with a mental healthcare professional in extraordinary situations of a pandemic. This survey did not find a remarkable increase in positive symptom severity in association with COVID-19 as most patients included in the survey had not seen a psychiatrist or mental healthcare professional for two months with 53 patients stating that they did not have to need. However, 58 patients also stated that despite planning to make a consultation after normalization of the quarantine measures, the anxiety of contagion outweighed the option of visiting outpatient clinics. This anxiety over Covid-19 infection, however, may make it difficult for patients to understand the level of the need to see a psychiatrist and may be associated with the assumption that the pandemic would be taken under control in the normalization process with a decrease in the risk of contagion. On the results of this survey, it may be concluded that strategies for prevention of COVID-19 spread were effective among schizophrenia patients and that there is need to develop a system that reaches all patients and keeps them socially connected during the COVID-19 pandemic. *In Turkey, prescription reports with 1-year validity are issued for patients with chronic disorders. The medications can only be prescribed by a specialist, and in the case of pyshchiatric disorders, by a consultant psychiatrist. When the report is confirmed by a hospital committee of specialists, a family doctor is able to issue prescriptions. According to the decision of the Ministry of Health, patients who have medication prescription reports valid for one year would be able to get their medicines directly from pharmacies without having to consult a psychiatrist or family doctor during the pandemic. REFERENCES Anadolu Agency (2020, Mach 11). Sağlık Bakanı Koca Türkiye'de ilk koronavirüs vakasının görüldüğünü açıkladı, https://www.aa.com.tr/tr/kor onavir us/ saglik-bakani-koca-turkiyede-ilk-koronavirus-vakasinin-goruldugunu- acikladi/1761466. Accessed 28 May 2020. Brown E, Gray R, Lo Monaco S et al (2020) The potential impact of COVID-19 on psychosis: A rapid review of contemporary epidemic and pandemic research. Schizophr Res 222:79-87. Cohn T, Prud'homme D, Streiner D et al (2004) Characterizing coronary heart disease risk in chronic schizophrenia: High prevalence of the metabolic syndrome. Can J Psychiatry 49:753-60. Cowan, HR (2020) Is schizophrenia research relevant during the COVID-19 pandemic?. Schizophr Res 220:271-2. Çakıroğlu S, Ertaş E, and Alyanak B (2020) Letter To The Editor - The Covid-19 Pandemic And Mental Health As Issues Considered Within The Context Of Adjustment Disorder And Psychosocial Interventions. Turk Psikiyatri Derg 31:148-50. Dinan T, Holt R, Kohen D et al (2004) "Schizophrenia and diabetes 2003" expert consensus meeting, Dublin, 3-4 october 2003: Consensus summary. Br J Psychiatry 184 (Suppl. 47): 0-2. Krieger I, Bitan DT, Comaneshter D et al (2019) Increased risk of smoking- related illnesses in schizophrenia patients: A nationwide cohort study. Schizophr Res 212:121-5. Palomar-Ciria N, del Valle PB, Hernández-Las Heras MÁ et al (2020) Schizophrenia and COVID-19 delirium. Psychiatry Res 290:113137. Yao H, Chen JH, and Xu YF (2020) Patients with mental health disorders in the COVID-19 epidemic. Lancet Psychiatry 7: e21. World Health Organization (2020, Mart 25). Covid-19: Vulnerable and High Risk Group, Geneva, Switzerland: World Health Organization, https:// www.who.int/westernpacific/emergencies/covid-19/information/high-risk- groups. Accessed 28 May 2020.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Furfuryl alcohol-based resins are used as binding agents in foundry sand and as corrosion inhibitors in mortar, grout, and cement. Because of their heat resistance, furan resins are used in the manufacture of fiberglass-reinforced plastic equipment. Furfuryl alcohol was selected for evaluation because of the absence of data on its carcinogenic potential and its large production volume, widespread use in manufacturing, and ubiquitous presence in consumer goods. Male and female F344/N rats and B6C3F1 mice were exposed to furfuryl alcohol (greater than 98% pure) by inhalation for 16 days, 14 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse bone marrow cells. 16-DAY STUDY IN RATS: Groups of five male and five female rats were exposed to concentrations of 0, 16, 31, 63, 125, or 250 ppm furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 16 days. All male and female rats exposed to 250 ppm died by day 2 of the study, and one male rat exposed to 125 ppm died on day 5. Final mean body weights of male and female rats exposed to 125 ppm were significantly less than those of the chamber control groups. Male rats exposed to 31, 63, or 125 ppm and female rats exposed to 125 ppm gained less weight than the chamber control groups. Clinical findings included dyspnea, hypoactivity, and nasal and ocular discharge in males and females exposed to 63, 125, or 250 ppm. All exposed animals developed lesions in the nasal respiratory epithelium and olfactory epithelium, and the severities of these lesions generally increased with increasing exposure concentration. 16-DAY STUDY IN MICE: Groups of five male and five female mice were exposed to concentrations of 0, 16, 31, 63, 125, or 250 ppm furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 16 days. All male and female mice exposed to 250 ppm died by day 4 of the study, and one female mouse exposed to 125 ppm died on day 14. Mean body weights of male and female mice exposed to 63 or 125 ppm were significantly less than those of the chamber control groups. All exposed animals except one 16 ppm male developed lesions in the nasal respiratory epithelium and/or olfactory epithelium, and the severities of these lesions generally increased with increasing exposure concentration. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to furfuryl alcohol at concentrations of 0, 2, 4, 8, 16, or 32 ppm, 6 hours per day, 5 days per week for 14 weeks. All rats survived to the end of the study. The mean body weight gain of females exposed to 32 ppm was less than that of the chamber control group. Exposure-related increases in the incidences of squamous metaplasia of the respiratory and transitional epithelium, goblet cell hyperplasia of the respiratory epithelium, and hypertrophy of the respiratory epithelium lining the nasopharyngeal duct were observed in the nose of male and female rats. The incidences of degeneration, hyperplasia, metaplasia, and surface exudate of the olfactory epithelium generally increased with increasing exposure concentration in males and females. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to furfuryl alcohol at concentrations of 0, 2, 4, 8, 16, or 32 ppm, 6 hours per day, 5 days per week for 14 weeks. All mice survived to the end of the study. Heart weights of 32 ppm males were significantly less than those of the chamber controls. Exposure-related histologic changes included degeneration, metaplasia, and chronic inflammation of the olfactory epithelium; hyaline droplets of the respiratory epithelium; and squamous metaplasia of the submucosal gland of the cuboidal epithelium in males and females. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were exposed to furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 105 weeks, at concentrations of 0, 2, 8, or 32 ppm. Survival and Body Weights All male rats exposed to 32 ppm died by week 99; survival of all other exposed groups of male and femald female rats was similar to that of the chamber control groups. Mean body weights of 32 ppm males were less than those of the chamber control group beginning at week 19. Pathology Findings All groups of exposed male and female rats had significantly increased incidences of nonneoplastic histologic changes of the nose compared to the chamber control groups. An adenoma of the lateral wall of the nose was observed in one 2 ppm male and one 8 ppm female, an adenoma of the respiratory epithelium was observed in one 8 ppm male and one 32 ppm female, one carcinoma of the respiratory epithelium was observed in a 32 ppm male, and squamous cell carcinomas of the nose were observed in three 32 ppm males. Renal tubule adenomas were present in one chamber control male, one 2 ppm male, two 8 ppm males, and two 32 ppm females. One 2 ppm female had a renal tubule carcinoma. Additional histologic sections from the kidney revealed the presence of additional hyperplasias in all groups of males and females; one additional renal tubule adenoma was observed in each of the chamber control, 2 ppm, and 8 ppm male groups, and four additional adenomas were observed in 32 ppm males. In females, two additional adenomas were found in the 8 ppm group, one adenoma in the 32 ppm group, and one carcinoma in the 2 ppm group. The severities of nephropathy relative to the chamber controls were increased in 32 ppm males and females. Males exposed to 32 ppm had extrarenal signs indicative of marked nephropathy including parathyroid gland hyperplasia and fibrous osteodystrophy. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were exposed to furfuryl alcohol by inhalation, 6 hours per day, 5 days per week for 105 weeks, at concentrations of 0, 2, 8, or 32 ppm. Survival, Body Weights, and Clinical Findings Survival of exposed males and females was similar to that of the chamber control groups. Mean body weights of exposed males were generally similar to those of the chamber control group throughout the study. Mean body weights of exposed females were less than those of the chamber control group during year 2 of the study. Female mice exposed to 32 ppm developed focal corneal opacities. Pathology Findings The incidences of renal tubule neoplasms were increased in 32 ppm male mice compared to the chamber control group and exceeded the historical control range for inhalation studies. Step sectioning revealed the presence of additional hyperplasias in the chamber control and exposed groups and one adenoma in 32 ppm males. The severity of nephropathy increased with increasing exposure concentration in male mice. The incidence of renal tubule degeneration in male mice exposed to 32 ppm was significantly greater than in the chamber control group. Incidences of a variety of nonneoplastic lesions of the nose were significantly greater in all exposed groups of male and female mice than in the chamber control groups. The incidence of degeneration of the cornea was significantly greater in 32 ppm female mice compared to the chamber control group. GENETIC TOXICOLOGY: Furfuryl alcohol was not mutagenic in Salmonella typhimurium strain TA98, TA100, TA1535, or TA1537, with or without S9. It did induce sister chromatid exchanges in cultured Chinese hamster ovary cells in the absence of S9, but not in the presence of S9. No induction of chromosomal aberrations was noted in cultured Chinese hamster ovary cells treated with furfuryl alcohol in the absence of S9, but in the presence of S9 an equivocal result was obtained. In vivo, no induction of sister chromatid exchanges, chromosomal aberrations, or micronuclei was noted in bone marrow cells of male mice after treatment with furfuryl alcohol. CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was some evidence of carcinogenic activity of furfuryl alcohol in male F344/N rats based on increased incidences of combined neoplasms of the nose. There was equivocal evidence of carcinogenic activity of furfuryl alcohol in female F344/N rats based on marginally increased incidences of neoplasms of the nose and renal tubule neoplasms. There was some evidence of carcinogenic activity of furfuryl alcohol in male B6C3F1 mice based on increased inci dences of renal tubule neoplasms. There was no evidence of carcinogenic activity of furfuryl alcohol in female B6C3F1 mice exposed to 2, 8, or 32 ppm. Exposure of male and female rats and male mice to furfuryl alcohol was associated with increased incidences of nonneoplastic lesions of the nose and increased severities of nephropathy. Exposure of female mice to furfuryl alcohol was associated with increased incidences of nonneoplastic lesions of the nose and corneal degeneration. Synonyms: 2-Furancarbinol; 2-furanmethanol, furfuralcohol, a-furylcarbinol; 2-hydroxymethylfuran	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
If we now consider briefly the principal results of our investigation, we can, in comparing the behavior of the thyroid after auto- and homeoplastic transplantation, in general recognize three stages. In the first stage, comprising the first 4 to 5 days after transplantation, there is no noticeable difference between the auto- and homeograft; both corresponding pieces behave in the main alike; large parts of both grafts become necrotic in the center; the necrosis begins shortly after the transplantation and concerns only a part of the periphery; here a narrow zone of thyroid tissue is left; it consists of one to two rows of partly well recognizable follicles. After 48 hours the first fibroblasts, polynuclear leucocytes, and lymphocytes appear in the tissue surrounding the grafts. After 72 hours these elements are present also in the center of the thyroid tissue. At the same date the first mitoses appear in the follicular epithelium; their number is, however, as yet small, but it increases markedly during the following days. After 4 days are found the first newly formed follicles, and from now on their number is increasing. Colloid is present only in small amounts in the old follicles. The central necrotic area still persists, but the masses of detritus are becoming smaller, while the number of fibroblasts and lymphocytes in the necrotic part is increasing; new blood vessels are also visible in the necrotic center. The second stage, the stage of transition, extends over the next seven days. The earliest, at first slight, differences between the auto- and homeograft appear after 5 days; the difference is usually very definite after 12 days. During this time there is an increase in the number of follicles in the autograft and correspondingly a decrease in the size of the necrotic central area, which is caused by a gradually progressing removal of the necrotic material in the center of the piece. The follicles are lined with a high cylindrical epithelium, which contains numerous mitoses. The number of mitoses increases markedly after the 4th day and reaches a maximum between the 7th and 9th days. Newly produced colloid is always present in the autograft after the 8th day; in the newly formed follicles the colloid contains numerous vacuoles and is almost never retracted, in contradistinction to the solid retracted colloid in the old follicles, which probably was present in the follicles at the time of transplantation. At the end of this period the central part is almost entirely freed from the necrotic masses and is filled with loosely arranged connective tissue cells, between which isolated lymphocytes and polynuclear leucocytes can be found. It contains also numerous blood vessels and brown blood pigment cells. After 5 days, with the beginning of the second stage, the first as yet rather insignificant differences become noticeable in the homeotransplants. They are as follows: (1) The number of lymphocytes is much larger in the homeo- than in the autograft. (2) The fibroblasts are increased in the central area and these fibroblasts form here very soon firm connective tissue bundles; they surround also the individual follicles or small groups of follicles and form fibrous bands, which are at this stage still very small. During the following days the number of lymphocytes increases and the fibrous connective tissue becomes more prominent, so that 7, 9, 10, and 11 days after transplantation numerous follicles are not only destroyed by the surrounding and invading lymphocytes, but in addition a part of the follicles is encircled and compressed by wide connective tissue bands. This compression is especially distinct in the central parts of the homeografts. At this stage the absence of a well developed vascular system is already noticeable in the central parts of the homeografts. It is especially noteworthy that the follicles of the homeograft which escaped destruction by the lymphocytes and connective tissue are as well preserved as in the autograft. Colloid is usually present in smaller amounts than in the autografts, even in the well preserved follicles of the homeografts. It must, however, be stated that some variations occur in this stage in the degree of destruction of the homeotransplanted pieces. Side by side with pieces in which a marked destruction has taken place, there are other pieces which suffered as yet relatively little. But some of the above mentioned differences between the auto- and homeotransplants are always present to a smaller or larger extent. There are also certain variations in the relative strength, with which lymphocytes and connective tissue injure the follicles; in some homeotransplants the attacks on the part of the lymphocytes prevail, while in others those on the part of the connective tissue are more prominent. The homeotransplants, which are relatively little injured at this stage are spared only to be subject to a stronger attack on the part of the lymphocytes and connective tissue during the following stage. The third stage begins approximately with the 12th day. From now on the difference between auto- and homeograft is sharply defined. In the autografts the regeneration of the thyroid tissue is steadily progressing and is nearly complete after 21 days. After this date the autograft represents throughout the picture of the normal thyroid gland; well developed follicles filled with colloid are surrounded by a very scant connective tissue. Mitoses, which begin already to decrease after the 9th day, are still present at the end of 17 days, but absent after this date. The small amount of loosely built, usually centrally located connective tissue, has no tendency to undergo a fibrous or hyaline change and does nowhere exert a compression on the follicles. It contains always a large number of blood vessels and only a few lymphocytes. In the homeograft the secondary destruction of the follicles is progressing with great intensity after the 12th day. In contradistinction to a primary degeneration of the follicles, due to the action of substances circulating in the body fluids, which might have been expected to take place, but which in reality does not occur, and which would be followed only secondarily by a connective tissue proliferation and lymphocytic invasion, we may speak of the destruction by means of lymphocytes and connective tissue, which actually does take place, as a secondary destruction of the follicles. This secondary mode of destruction of the follicles through lymphocytes and connective tissue is found exclusively in the homeotransplant. Following this destruction the larger part of the homeografts is occupied by a fibrous, hyaline connective tissue, in which remnants of destroyed follicles in the form of clefts filled with lymphocytes are seen. In several cases the destruction of follicles through lymphocytes, which accumulate in large numbers around the follicles and destroy them very actively, prevails; in other cases the compression of the follicles through fibrous, hyaline connective tissue predominates; in other cases both factors may be about equally active. The few peripheral follicles which escaped destruction are small, probably as a result of compression through the connective tissue; but they may still show normal epithelium and nuclei and may occasionally contain traces of colloid. Newly formed colloid is not present in the homeotransplants at the third stage. It should also be mentioned that the blood supply of the homeografts, especially after the 12th day, is very much restricted and that the blood vessels are mainly located in the connective tissue surrounding the graft, and not in the central connective tissue, which exists here in a much larger quantity and is much denser than in the autograft. At this stage also we find considerable variations in the extent of the injuries, in the individual follicles. But no piece escapes the attack entirely, and those which remain relatively well preserved for a certain period will be attacked at a later date by the connective tissue, as well as by the lymphocytes of the host. To summarize briefly, the principal result: For a short period of time after operation no difference is seen in the behavior of the thyroid after auto- and homeotransplantation. Very soon, however, a destruction of follicles begins to take place in the homeografts. This destruction is not caused by a direct primary disintegration or solution of follicles, but depends on the destructive activity of (1) the lymphocytes, and (2) of the connective tissue of the host tissue. The former invade the follicles and destroy them directly; the latter grows into the homeografts in larger quantity than into the autografts. In the former it soon becomes fibrous and hyaline; in the latter it remains cellular. The fibrous connective tissue surrounds and compresses and thus destroys the follicles. In some homeografts destruction by means of lymphocytes, in others by connective tissue, preponderates. The rapidity with which the destruction takes place in different homeotransplants also varies. A much better blood vessel supply develops in the autograft than in the homeograft.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
DIOXIN TOXIC EQUIVALENCY FACTOR EVALUATION OVERVIEW: Polyhalogenated aromatic hydrocarbons such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have the ability to bind to and activate the ligand-activated transcription factor, the aryl hydrocarbon receptor (AhR). Structurally related compounds that bind to the AhR and exhibit biological actions similar to TCDD are commonly referred to as "dioxin-like compounds" (DLCs). Ambient human exposure to DLCs occurs through the ingestion of foods containing residues of DLCs that bioconcentrate through the food chain. Due to their lipophilicity and persistence, once internalized, they accumulate in body tissue, mainly adipose, resulting in chronic lifetime human exposure. Since human exposure to DLCs always involves a complex mixture, the toxic equivalency factor (TEF) methodology has been developed as a mathematical tool to assess the health risk posed by complex mixtures of these compounds. The TEF methodology is a relative potency scheme that ranks the dioxin-like activity of a compound relative to TCDD, which is the most potent congener. This allows for the estimation of the potential dioxin-like activity of a mixture of chemicals based on a common mechanism of action involving an initial binding of DLCs to the AhR. The toxic equivalency of DLCs was nominated for evaluation because of the widespread human exposure to DLCs and the lack of data on the adequacy of the TEF methodology for predicting relative potency for cancer risk. To address this, the National Toxicology Program conducted a series of 2-year bioassays in female Harlan Sprague-Dawley rats to evaluate the chronic toxicity and carcinogenicity of DLCs and structurally related polychlorinated biphenyls (PCBs) and mixtures of these compounds. 2,2',4,4',5,5'-Hexachlorobiphenyl (PCB 153) was produced as a component of some commercial PCB mixtures before 1977 for the electric industry as a dielectric insulating fluid for transformers and capacitors. Manufacture and use of the chemical was stopped due to increased PCB residues in the environment, but it continues to be released into the environment through the use and disposal of products containing PCBs, as by-products during the manufacture of certain organic chemicals, and during the combustion and biodegradation of some waste materials. Bioaccumulation of PCB 153 results in persistent levels in animal and human tissues. PCB 153 was selected for study by the National Toxicology Program as a part of the dioxin TEF evaluation to assess the cancer risk posed by complex mixtures of polychlorinated dibenzodioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs). The dioxin TEF evaluation includes conducting multiple 2-year rat bioassays to evaluate the relative chronic toxicity and carcinogenicity of DLCs, structurally related PCBs, and mixtures of these compounds. PCB 153 was included since it is present at the highest PCB concentrations in human samples on a molar basis. PCB 153 was also included in a mixture study with PCB 126, since previous studies have demonstrated interactions between PCB 153 and DLCs on pharmacokinetic and biological effects. While one of the aims of this study was a comparative analysis of effects seen with PCB 126 and the mixture of PCB 126 and PCB 153, in this Technical Report only the results of the present study of PCB 153 are presented and discussed. 2-YEAR STUDY: Female Harlan Sprague-Dawley rats were administered PCB 153 (greater than 99% pure) in corn oil:acetone (99:1) by gavage for 14, 31, or 53 weeks or 2 years. Groups of 80 (3,000 microg PCB 153/kg body weight), 81 (100, 300, and 1,000 microg/kg), or 82 (10 microg/kg) female rats received PCB 153 in corn oil:acetone (99:1) by gavage at doses of 10, 100, 300, 1,000, or 3,000 microg/kg 5 days per week for up to 105 weeks; a group of 81 female rats received the corn oil:acetone (99:1) vehicle alone. A stop-exposure group of 50 female rats was administered 3,000 microg/kg for 30 weeks and then the vehicle for the remainder of the study. Dose selection for the PCB 153 study was based on the range of PCB 153 doses used in the mixture study of PCB 126 and PCB 153 (10 to 3,000 microg/kg). Survival of dosed groups was similar to that of the vehicle control group. Mean body weights of 3,000 microg/kg core study rats were less than those of the vehicle controls after week 69 of the study. Thyroid Hormone Concentrations: Serum total thyroxine (T4), free T4, and total triiodothyronine (T3) concentrations in the 3,000 microg/kg group were significantly lower than those in the vehicle controls at the 14-week interim evaluation. At the 31-week interim evaluation, no significant differences were observed in serum total T4, free T4, T3, or thyroid stimulating hormone concentrations. At the 53-week interim evaluation, serum total T4 and free T4 concentrations in the 3,000 microg/kg group were significantly lower than in the vehicle controls. Hepatic Cell Proliferation Data: No significant differences in hepatocellular labeling index were observed between the vehicle control and dosed groups at any of the interim evaluations. Cytochrome P450 Enzyme Activities Hepatic pentoxyresorufin-O-deethylase activities were highly and significantly elevated relative to the vehicle control groups. Maximum increases over controls at 14, 31, and 53 weeks were 136-, 140-, and 40-fold, respectively. Hepatic 7-ethoxyresorufin-O-deethylase (EROD) and acetanilide-4-hydroxylase (A4H) activities were significantly elevated over controls at 14 and 31 weeks; increases were less than twofold. At 14 weeks, EROD activities in the lung were dose-dependently reduced compared to vehicle controls. Determinations of PCB 153 Concentrations in Tissues: In the fat from vehicle controls, detectable levels of PCB 153 were observed at 14, 31, and 53 weeks and at the end of the 2-year study. Fat concentrations of PCB 153 increased with increasing doses of PCB 153 and tended to increase with the longer exposure durations. In the fat of the 3,000 microg/kg stop-exposure group, PCB 153 concentrations were between the levels observed in the 300 and 1,000 microg/kg groups. In the liver of vehicle controls, no measurable concentrations of PCB 153 were observed at any time point. In dosed groups, hepatic concentrations of PCB 153 increased with increasing dose and longer exposure duration. Measurable concentrations of PCB 153 were observed in the lungs of vehicle control rats at 31 and 53 weeks and at 2 years. At all time points, PCB 153 lung and blood concentrations increased with increasing dose, and blood concentrations increased with duration of exposure. In liver, lung, and blood of rats from the 3,000 microg/kg stop-exposure group, PCB 153 concentrations were slightly above or below the levels observed in the 1,000 microg/kg group. Organ Weights: Absolute liver weights of 1,000 microg/kg rats and absolute and relative liver weights of 3,000 microg/kg rats were significantly greater than those of vehicle controls at week 14. At week 31, relative liver weights of 1,000 microg/kg rats and absolute and relative liver weights of 3,000 microg/kg rats were significantly greater than those of vehicle controls. At week 53, absolute and relative liver weights were significantly greater in rats administered 100 microg/kg or greater compared to vehicle controls. Absolute kidney weights of all exposed groups and the relative kidney weight of 3,000 microg/kg rats were significantly increased at week 53. Pathology and Statistical Analyses: The incidences of hepatocyte hypertrophy were significantly increased in the 1,000 and 3,000 microg/kg groups at 14 weeks and in all groups administered 300 microg/kg or greater at 31 and 53 weeks. At 2 years, the incidences of hepatocyte hypertrophy were significantly increased in all dosed groups. The incidences of diffuse fatty change in the 300 microg/kg or greater groups and bile duct hyperplasia of the liver in 300 microg/kg and 3,000 microg/kg (core and stop-exposure) groups were significantly increased. The incidences of oval cell hyperplasia and pigmentation of the liver were significantly increased in the 3,000 microg/kg core study group. At 2 years, two cholangiomas were seen in the 1,000 microg/kg group and two cholangiomas were seen in the 3,000 microg/kg stop-exposure group. A single hepatocellular adenoma was observed in the 3,000 microg/kg core study group. At 53 weeks, sporadic incidences of minimal to mild follicular cell hypertrophy of the thyroid gland occurred in all groups (except 10 microg/kg). At 2 years, the incidences of minimal to mild follicular cell hypertrophy were significantly increased in the 300 microg/kg and 3,000 microg/kg (core and stop-exposure) groups. At 2 years, significantly increased incidences of chronic active inflammation in the ovary and oviduct occurred in the 1,000 and 3,000 microg/kg core study groups. Incidences of suppurative inflammation of the uterus in the 1,000 microg/kg group and chronic active inflammation in the 3,000 microg/kg core study group were significantly greater than those in the vehicle control group. Under the conditions of this 2-year gavage study there was equivocal evidence of carcinogenic activity of PCB 153 in female Harlan Sprague-Dawley rats based on the occurrences of cholangioma of the liver. PCB 153 administration caused increased incidences of nonneoplastic lesions of the liver, thyroid gland, ovary, oviduct, and uterus in female rats.	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In a global culture that is increasingly interested in ecological interventions, probiotics, 'friendly bacteria', microbiome preservation/restoration and long-term health, there is growing awareness of the idea of seeding the vaginal microbiome in the new born after caesarean section. It is postulated as a way of restoring helpful missing microbes and preventing long term non-communicable diseases of babies delivered by caesarean section. Currently, there is a deluge of evidence being published on the human microbiome, which can be challenging to digest and absorb by scientists, clinicians and patients. The specific evidence base around this technique is at its early stages. This commentary discusses what advice is currently available from a feminist and a person-centred care perspective. Det er en voksende interesse internasjonalt for økologiske intervensjoner, probiotika, 'snille bakterier', bevaring/gjenoppretting av. mikrobiomet og helse i et langtidsperspektiv. I denne sammenhengen er det en økende interesse for tanken om å så det vaginale mikrobiomet (vaginal seeding) på den nyfødte etter et keisersnitt. Dette er postulert som en måte å gjenopprette manglende normalflora/mikrobiom og forebygge langvarige ikke-smittsomme sykdommer hos barn født med keisersnitt. For tiden publiseres det mye forskning om menneskets mikrobiom, noe som kan være utfordrende å fordøye og ta til seg for forskere, klinikere og pasienter. Forskningen på denne spesifikke metoden er i sin begynnelse. Denne kommentaren drøfter hvilke råd som for øyeblikket er tilgjengelige, fra et feministisk og personsentrert omsorgsperspektiv. POPULARISERT SAMMENDRAG På NORSK: Det menneskelige mikrobiomet er summen av alle bakteriene som dekker den menneskelige kroppen og det hjelper kroppen i å fungere optimalt. Når mikrobiomet forstyrres, vil kroppen kunne få betennelsesreaksjoner og allergier. I fødsel finnes de «gode» bakteriene i kvinnens vagina. (det vaginale mikrobiomet) som man tror vil være fordelaktig for babyens evne til å utvikle et sunt immunsystem. Babyer som er født med keisersnitt vil ikke bli eksponert for disse «gode» bakteriene og det kan påvirke barnets immunforsvar negativt og potensielt øke sjansen for allergier og betennelsesreaksjoner i kroppen på lang sikt. Vaginal seeding (et forsøk på å gjenopprette balansen og noen av de gode bakterier i spedbarnet gjennom å tilføre mors vaginale bakterier via en kompress som strykes over spedbarnets ansikt) Vaginal seeding er en metode som noen forskere sier muligens delvis gjenoppretter de manglende «gode» bakteriene etter et keisersnitt. Forskningen er på et tidlig stadium. Det har vært avisartikler og en film om emnet og mødre har funnet ut om vaginal seeding som en måte å gjenopprette denne delen av babyens mikrobiom. Foreldre ønsker å diskutere vaginal seeding, men på nåværende tidspunkt er helsevesenet avventende og helsepersonell er ikke godt nok informert. Denne artikkelen vil se på den pågående diskusjonen. RéSUMé: Dans une culture mondiale qui s'intéresse de plus en plus aux interventions écologiques, aux probiotiques, aux «bactéries amicales», à la préservation / restauration du microbiome et à la santé à long terme, on commence à prendre conscience de l'idée d'ensemencer le microbiome vaginal chez le nouveau-né après une césarienne. Il est postulé comme un moyen de restaurer les microbes manquants et d'aider à prévenir les maladies non transmissibles à long terme des bébés mis au monde par césarienne. Il existe actuellement un déluge de preuves sur le microbiome humain, qui peuvent être difficiles à digérer et à absorber par les scientifiques, les cliniciens et les patients. La base de preuves spécifique autour de cette technique en est à ses débuts. Ce commentaire discute des conseils actuellement disponibles dans une perspective de soins féministe et centrée sur la personne. RéSUMé SIMPLIFIé: Le microbiome humain est constitué de tous les microbes qui recouvrent le corps humain et qui aident le corps à bien fonctionner. Lorsque le microbiome est perturbé, le corps devient plus inflammatoire et est sujet aux allergies. Lors de l'accouchement, le vagin d'une mère (le microbiome vaginal) contient des "bactéries amicales" qui pourraient être bénéfiques pour l'enfant et aider le bébé à développer un système immunitaire en bonne santé. Les bébés nés par césarienne ne sont généralement pas exposés à ces «bactéries bénéfiques», ce qui pourrait affecter négativement le système immunitaire du bébé et potentiellement augmenter le risque d'allergies et d'inflammation à long terme. Selon certains scientifiques, l'ensemencement vaginal pourrait partiellement restaurer les «bactéries amies» manquantes après la césarienne. La recherche en est à ses débuts. Il y a eu des articles de journaux et un film à ce sujet, et les mères ont découvert l'existence d'un ensemencement vaginal (où une compresse placée dans le vagin de la mère pourrait être appliquée sur l'enfant après la césarienne) afin de restaurer une partie du microbiome du bébé. Les parents souhaitent discuter de l'ensemencement vaginal, mais à l'heure actuelle, les organisations médicales sont prudentes et les praticiens ne sont pas suffisamment informés. Cet article examine le débat en cours. Numa cultura global que está cada vez mais interessada em intervenções ecológicas, probióticos, "bactérias amigáveis", preservação/restauração do microbioma e saúde a longo prazo, há uma crescente consciência sobre a ideia de semear o microbioma vaginal no recém-nascido após uma cirurgia cesariana. Isso está sendo postulado como uma forma de restaurar micróbios úteis que lhe faltariam e prevenir doenças não transmissíveis em longo prazo para bebês que nasceram pela via cirúrgica. Atualmente, há um aumento massivo de evidências sendo publicadas sobre o microbioma humano cuja absorção e digestão pode ser desafiadora para cientistas, clínicos e pacientes. A base específica da evidência que cerca essa técnica ainda está em estágios preliminares. Este comentário discute o aconselhamento atualmente disponível numa perspectiva feminista e centrada na pessoa. SíNTESE SIMPLIFICADA: O microbioma humano está composto por todos os micróbios que cobrem o corpo humano e que ajudam o corpo a funcionar bem. Quando o microbioma é perturbado, o corpo tem mais inflamações e maior propensão a desenvolver alergias. Ao nascimento, há "bactérias amigáveis" na vagina materna (o microbioma vaginal) que podem ser benéficas à criança e ajudar o bebê a desenvolver um sistema imunológico saudável. Bebês que nascem por cesariana usualmente não são expostos a essas "bactérias amigáveis" e isso poderá afetar negativamente o sistema imunológico do bebê, aumentando potencialmente a probabilidade de alegrias e inflamações no longo prazo. A semeadura de bactéria vaginais é um método que alguns cientistas afirmam que poderá restaurar parcialmente as "bactérias amigáveis" faltantes depois de uma cesariana. Essa pesquisa está em fase preliminar. Houve alguns artigos em jornais e um filme sobre isso, e as mães descobriram a possibilidade da semeadura vaginal (quando é feito um swab da vagina materna que é esfregado no bebê após a cesárea) para restaurar parte do microbioma do bebê. Pais desejam discutir a semeadura vaginal, mas, no momento, as organizações médicas têm sido cautelosas e os profissionais não estão adequadamente informados. Este artigo aborda o debate em andamento. En una cultura global que está cada vez más interesada en las intervenciones ecológicas, los probióticos, las "bacterias amigables", la conservación/restauración de microbiomas y la salud a largo plazo, hay una creciente conciencia de la idea de sembrar el microbioma vaginal en el recién nacido después de la cesárea. Se postula como una forma de restaurar los microbios útiles faltantes y prevenir las enfermedades no transmisibles a largo plazo de los bebés nacidos por cesárea. Actualmente, se está publicando una gran cantidad de pruebas sobre el microbioma humano, que pueden ser difíciles de digerir y absorber por parte de científicos, clínicos y pacientes. La base de la evidencia específica en torno a esta técnica se encuentra en sus primeras etapas. Este artículo analiza qué consejos están disponibles actualmente desde una perspectiva feminista y de atención centrada en la persona. El microbioma humano está hecho de todos las bacterias que cubren el cuerpo humano y que ayudan al cuerpo a funcionar bien. Cuando se altera el microbioma, el cuerpo se inflama más y es propenso a las alergias. En el parto, hay "bacterias amigables" en la vagina de la madre (el microbioma vaginal) que podrían ser beneficiosas para el niño y ayudar al bebé a desarrollar un sistema inmunológico saludable. Los bebés que nacen por cesárea generalmente no se exponen a estas "bacterias amigables" y esto podría afectar negativamente el sistema inmunológico del bebé, lo que podría aumentar la probabilidad de alergias e inflamación a largo plazo. La siembra vaginal es un método que algunos científicos dicen que podría restaurar parcialmente las "bacterias amigables" que faltan después de la cesárea. La investigación se encuentra en sus primeras etapas. Han habido artículos periodísticos y una película sobre esto, y las madres se han enterado de la siembra vaginal (donde se puede frotar el niño con una torunda de la vagina de la madre después de la cesárea) para restaurar la parte del microbioma del bebé. Los padres quieren hablar sobre la siembra vaginal, pero en la actualidad las organizaciones médicas son cautelosas y los profesionales no están informados adecuadamente. Este artículo analiza el debate en curso.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
D&C Yellow No. 11 is used to color topical drug preparations and cosmetics. It is also used in spirit lacquers, polystyrenes, polycarbonates, polyamides, acrylic resins, colored smokes, and hydrocarbon solvents. D&C Yellow No. 11 was nominated to the NTP for toxicity and carcinogenesis studies as part of a larger regulatory effort mandated by Congress and undertaken by the Food and Drug Administration to determine the safety of a number of provisionally listed dyes. D&C Yellow No. 11 is currently regulated for external use. The recommendation to study D&C Yellow No. 11 by dietary exposure was based on the fact that it is a contaminant of D&C Yellow No. 10, a candidate for permanent listing as a chemical for which there is a potential for ingestion. First-generation (F(0)) male and female F344/N rats were given D&C Yellow No. 11 (approximately 99% pure) in feed for up to 19 weeks and then mated, and exposure of second-generation (F(1)) males and females began in utero and continued for 2 years after weaning at 28 days of age. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood. REPRODUCTIVE TOXICITY STUDY: Groups of 60 male and 60 female F(0) rats were given 0, 500, 1,700, or 5,000 ppm D&C Yellow No. 11 in feed for up to 19 weeks, which resulted in average daily doses of 35, 120, or 350 mg D&C Yellow No. 11/kg body weight to males and 35, 120, or 370 mg/kg to females. All F(0) males and females survived until the end of the study. Prior to cohabitation, mean body weight gains of males given 500, 1,700, or 5,000 ppm and of females given 5,000 ppm were significantly lower than those of the controls. The mean body weight gains of exposed females during gestation and lactation were generally similar to those of the controls. Feed consumption by exposed groups of rats was generally similar to that by the control groups prior to cohabitation. The duration of gestation, the average litter size, the number of live pups on days 4 (precull) and 21, and the percentage of male pups for each exposure group were similar to those of the controls. The mean body weights of exposed litters were significantly less than those of the control litters on days 14 and 21; this effect was considered to be related to D&C Yellow No. 11 exposure. 2-YEAR STUDY: Groups of 60 male and 60 female F(1) rats were given 0, 500, 1,700, or 5,000 ppm D&C Yellow No. 11 in feed for 105 (males) or 106 (females) weeks after weaning (day 28); 6 to 10 rats per group were evaluated at 12 months. These exposure concentrations resulted in average daily doses of approximately 25, 85, or 250 mg D&C Yellow No. 11/kg body weight to males and 25, 100, or 280 mg/kg to females. Survival, Body Weights, Feed Consumption, and Clinical Findings: Survival of males given 1,700 or 5,000 ppm was significantly less than that of the controls, and survival of 1,700 ppm females was significantly greater than that of the controls. Mean body weights of 1,700 and 5,000 ppm males and females were generally lower than those of the controls throughout the study. Feed consumption by exposed groups was similar to that by the controls. Chemical-related clinical findings included yellow discoloration of the entire body in all exposed males and females from day 1 and head swelling and edema in 1,700 and 5,000 ppm males. One 1,700 ppm and five 5,000 ppm males were moribund and were killed between weeks 49 and 81; these deaths were attributed to extensive edema. Hematology: A few minimal hematology changes occurred in male rats at the 12-month interim evaluation. There was evidence of minimal anemia in exposed males; this anemia was characterized by decreased hematocrit values, hemoglobin concentrations, and erythrocyte counts. The minimal anemia was characterized as normocytic, normochromic, and nonresponsive. There were no biologically or statistically significant differences in hematology parameters between control and exposed females. Pathology Findings: Absolute and relative liver weights of all exposed groups of md relative liver weights of all exposed groups of males and females were significantly greater than those of the controls at 12 months. At 2 years, the incidences of hepatocellular adenoma in 5,000 ppm males and of hepatocellular adenoma or carcinoma (combined) in 5,000 ppm females were significantly greater than those in the controls. At 12 months, the incidences of clear cell foci in 1,700 and 5,000 ppm females were significantly greater than that in the controls. At 2 years, the incidences of mixed cell foci in exposed males and of clear cell foci in exposed males (except 500 ppm) and females were significantly greater than those in the controls. Incidences of cytologic alterations (basophilia and granularity) of hepatocytes, and pigmentation in bile duct epithelium, hepatocytes, and Kupffer cells in exposed males and females were greater than those in the controls at both 12 months and 2 years. Renal tubule adenomas were observed in two 5,000 ppm males, and one renal tubule carcinoma was observed in a 1,700 ppm male. During an extended evaluation, renal tubule adenomas were observed in two additional 5,000 ppm males, four 1,700 ppm males, and two 500 ppm males. Renal tubule hyperplasia was observed in exposed groups of males but not in controls, and the incidences in 1,700 ppm males from both standard and extended evaluations were significantly greater than those in the controls. Necrosis and regeneration of the renal tubule epithelium were observed in all control and exposed male rats and in most female rats at 12 months and 2 years. The severity of nephropathy in exposed males and females was significantly greater than that in the controls. In exposed males and 1,700 ppm females at 2 years, the incidences of hyperplasia of the transitional epithelium in the kidney, which commonly accompanies advanced nephropathy, were greater than those of the controls, and the severity of this lesion in exposed males and females was greater than that in the controls. The incidences of renal tubule pigmentation in all exposed groups of males and females at 12 months and 2 years were significantly greater than those in the controls. Squamous cell carcinomas of the tongue were observed in one 500 ppm male at 12 months and one 5,000 ppm female at 2 years, and one squamous cell carcinoma of the oral mucosa was observed in each group of exposed males and in one 5,000 ppm female at 2 years. At 2 years, squamous cell papillomas were observed in the oral cavity (oral mucosa or tongue) of one control, one 500 ppm, two 1,700 ppm, and four 5,000 ppm males; this lesion was also observed in one control and one 500 ppm female. GENETIC TOXICOLOGY: Results of mutagenicity tests with D&amp;C Yellow No. 11 in Salmonella typhimurium were equivocal in one study, based on responses observed in strain TA100 with induced rat liver S9, and weakly positive in a second study, based on responses observed in strains TA98 and TA100 with induced rat or hamster liver S9. D&amp;C Yellow No. 11 induced sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells, with and without S9. No increase in the frequency of micronucleated normochromatic erythrocytes was observed in peripheral blood samples from male and female B6C3F(1) mice administered D&amp;C Yellow No. 11 in feed for 13 weeks. CONCLUSIONS: Under the conditions of this perinatal exposure followed by a 2-year dosed feed study, there was some evidence of carcinogenic activity of D&amp;C Yellow No. 11 in male F344/N rats based on increased incidences of hepatocellular adenoma, renal tubule neoplasms, and squamous cell neoplasms of the oral cavity. There was some evidence of carcinogenic activity in female F344/N rats based on increased inci dences of hepatocellular neoplasms. Incidences of uncommon squamous cell carcinoma of the oral cavity in females may have been related to chemical treatment. Exposure of rats to D&amp;C Yellow No. 11 in feed for 2 years resulted in increased incidences of nonneoplastic liver lesions including clear cell foci, increased basophilia and granularity in the cytoplasm of hepatocytes, and bile duct, hepatocyte, and Kupffer cell pigmentation in males and females and mixed cell foci in males. In the kidney, there were increased incidences of renal tubule pigmentation and transitional epithelial hyperplasia in males and females and renal tubule hyperplasia in males. The severity of nephropathy was increased in exposed males and females. Synonyms: 2-(2-Quinolinyl)-1H-indene-1,3-(2H)-dione; 2-(2-quinolyl)-1,3-indandione Trade names: Arlosol Yellow S, Chinoline Yellow D (soluble in spirits), Chinoline Yellow ZSS, C.I. 47000, C.I. Solvent Yellow 33, Nitro Fast Yellow SL, Oil Yellow SIS, Petrol Yellow C, Quinoline Yellow A Spirit Soluble, Quinoline Yellow Base, Quinoline Yellow Spirit Soluble, Quinoline Yellow SS, Solvent Yellow 33, Waxoline Yellow T	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
It will be seen at once that the mean values obtained for calcium are higher than most of those recorded in the literature, and that the values for inorganic phosphorus are perhaps lower. It is well to bear in mind, however, that the significance that may be attached to any series of determinations of calcium and inorganic phosphorus in the blood of animals depends largely upon the conditions under which the determinations are made. As is well known, there are many factors that may affect the values obtained, including inherent differences in the animal material and the method of analysis used as well as the particular procedure employed in carrying out a given method. When all other conditions are uniform, irregularities in the handling of the blood after it is drawn will give rise to surprisingly large differences in the results for both calcium and inorganic phosphorus, as permitting blood to stand tends to decrease calcium values and to increase those for inorganic phosphorus. It seems desirable, therefore, to emphasize the fact that the results recorded above are to be viewed as results obtained under certain definitely prescribed conditions which differ in several important respects from those governing determinations made by other workers in this field. Moreover, it is to be noted that the conditions varied to some extent with each of the 4 groups of animals comprising this series. For example, there was a small but definite age difference. The animals of Groups I and II were older and more mature than those of Groups III and IV at the beginning of the experiments, and this initial difference was increased by the extension of the experiments on Groups I and II over a longer period of time, so that the observations made on these animals not only included data for a more advanced age, but represented a mean age considerably above that of the observations made on the animals of Groups III and IV. There was a similar difference of experimental conditions between Groups III and IV, while the observations on Group II differed from those on Group I in that no blood analyses were made on the animals of Group II for 2 months after they were placed under observation. These particular features of the experiments are mentioned because an examination of the text-figures will show that a line of cleavage between Groups I and II on the one hand, and III and IV on the other, is traceable through all of the distribution curves and to some extent in the tabulated results. With the combined values as the axis of distribution, Groups I and II invariably hang together, or swing to one side, while Groups III and IV swing to the other. Moreover, the extreme positions are usually represented by Groups II and IV. Whether these peculiarities of the results are in reality attributable to the conditions mentioned or to some other cause, such as the length of cage life (2), or the particular period covered by the observations, the suggested relation is sufficient to indicate the extent to which even slight differences in experimental conditions may affect the results obtained for blood calcium and inorganic phosphorus. The values obtained for calcium may be regarded as showing a fairly close agreement (Tables I and II and Text-fig. 1). The extreme difference between the means for the 4 groups of animals is only 0.5 mg. or approximately 3.00 per cent of the mean for the combined groups. Still, the small absolute difference between the means for Groups I and IV is nearly 6 times its probable error and, hence, cannot be disregarded. The most important feature of these results is, however, the range of normal variation. The distribution curves (Text-fig. 1) show a remarkably close agreement in the frequency with which values of a given magnitude occurred and an unusually symmetrical distribution of all values. The coefficients of variation are comparatively small (7.09 to 8.9 per cent), but values anywhere between 14.0 and 16.0 mg. of calcium per 100 cc. of serum occurred with great frequency, while figures as low as 13.5 or as high as 17.5 mg. (Table II) were by no means rare; and the extreme limits of observation indicate a potential difference in the calcium content of the blood of normal rabbits of as much as 100 per cent. Inorganic phosphorus was found to be subject to much wider variation than calcium (Tables III and IV and Text-fig. 2). The coefficient of variation is approximately twice that for calcium (17.29 and 8.01 respectively), while the group means for phosphorus show a difference of 0.85 mg. per 100 cc. of serum. This difference is small in absolute value, but is nearly 20.0 per cent of the mean for all groups and is 15 times its probable error. It is safe to assume, therefore, that the values obtained indicate an actual difference in the inorganic phosphorus in the blood of the several groups of animals. This conclusion is borne out by the distribution frequencies (Table IV and Text-fig. 2) which show that the values obtained for Groups I and II lie at a distinctly lower level than those for Groups III and IV; the difference between modal classes is, in fact, of the same order as that shown by the means. The limits of probable variation as determined by the standard deviation of the combined results are 3.73 and 5.29 mg. per 100 cc. of serum, but one-third of all values lie outside of these limits, while the extreme limits of normal are sufficiently wide to include values that may differ by as much as 200.0 or even 300.0 per cent. From the values obtained for calcium and inorganic phosphorus, the relation existing between the two substances may be measured in a number of ways. The ratio of the calcium to the phosphorus and the product of the amounts of the two substances have received the greatest attention. In addition to these values, we have computed values for the sum and for the ratio of the product to the sum, and also for the sum of the calcium-phophorus ratio and the product-sum ratio. The value for the sum of the calcium and inorganic phosphorus in the serum is determined largely by the calcium, but as it is also affected by the phosphorus, one might expect that the constancy of the value as compared with that of calcium would be diminished unless the variations in the two substances were so related as to neutralize each other. As is well known, there is an apparent tendency in this direction and in these experiments it was found that on the whole the values for the sum showed less variation (coefficients 6.42 and 8.01 per cent) and were more uniformly distributed than those for calcium (Tables V and VI and Text-fig. 3). It is true that differences between groups were distinctly greater than in the case of calcium, but the agreement is sufficiently close to give evidence of a tendency to the maintenance of an inverse relation between serum calcium and inorganic phosphorus. Values for the product of calcium and inorganic phosphorus emphasize the phosphorus factor rather than the calcium, reversing the conditions that obtain in the case of the sum. A consideration of the product values given in Tables VII and VIII and Text-fig. 4 show that, while the order of variation is essentially the same as that of inorganic phosphorus (coefficients 17.09 and 17.29 per cent respectively), the distribution of values is more uniform. This may be attributable to the occurrence of coordinate variations in calcium and inorganic phosphorus. The situation presented by the values obtained for the ratio of calcium to inorganic phosphorus is somewhat surprising in that the ratio between the two substances proves to be less constant than the absolute amounts of either substance (Tables IX and X and Text-fig. 5). There are considerable differences between the standard values for individual groups of animals, and the distribution frequencies are inclined to be irregular. Moreover, all groups show a large standard deviation and correspondingly high coefficients of variation, but combining the results for the 4 groups of animals gives a fairly uniform and symmetrical distribution, a striking feature of which is the high frequency with which values occur over the entire range of standard variation, that is, from ratios of 2.85 to 4.29. It thus appears that, despite the evidence of a tendency to the observance of an inverse relation between the calcium and inorganic phosphorus in the blood, the ratio of one substance to the other is by no means constant. By using the product and the sum as a basis of expressing the relation between calcium and inorganic phosphorus, the form of the relation is ???	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Capsicum-derived ingredients function as skin-conditioning agents--miscellaneous, external analgesics, flavoring agents, or fragrance components in cosmetics. These ingredients are used in 19 cosmetic products at concentrations as high as 5%. Cosmetic-grade material may be extracted using hexane, ethanol, or vegetable oil and contain the full range of phytocompounds that are found in the Capsicum annuum or Capsicum frutescens plant (aka red chiles), including Capsaicin. Aflatoxin and N-nitroso compounds (N-nitrosodimethylamine and N-nitrosopyrrolidine) have been detected as contaminants. The ultraviolet (UV) absorption spectrum for Capsicum Annuum Fruit Extract indicates a small peak at approximately 275 nm, and a gradual increase in absorbance, beginning at approximately 400 nm. Capsicum and paprika are generally recognized as safe by the U.S. Food and Drug Administration for use in food. Hexane, chloroform, and ethyl acetate extracts of Capsicum Frutescens Fruit at 200 mg/kg resulted in death of all mice. In a short-term inhalation toxicity study using rats, no difference was found between vehicle control and a 7% Capsicum Oleoresin solution. In a 4-week feeding study, red chilli (Capsicum annuum) in the diet at concentrations up to 10% was relatively nontoxic in groups of male mice. In an 8-week feeding study using rats, intestinal exfoliation, cytoplasmic fatty vacuolation and centrilobular necrosis of hepatocytes, and aggregation of lymphocytes in the portal areas were seen at 10% Capsicum Frutescens Fruit, but not 2%. Rats fed 0.5 g/kg day-1 crude Capsicum Fruit Extract for 60 days exhibited no significant gross pathology at necropsy, but slight hyperemia of the liver and reddening of the gastric mucosa were observed. Weanling rats fed basal diets supplemented with whole red pepper at concentrations up to 5.0% for up to 8 weeks had no pathology of the large intestines, livers, and kidneys, but destruction of the taste buds and keratinization and erosion of the gastrointestinal (GI) tract were noted in groups fed 0.5% to 5.0% red pepper. The results of 9-and 12-month extension of this study showed normal large intestines and kidneys. In rabbits fed Capsicum Annuum Powder at 5 mg/kg day-1 in the diet daily for 12 months damage to the liver and spleen was noted. A rabbit skin irritation test of Capsicum Annuum Fruit Extract at concentrations ranging from 0.1% to 1.0% produced no irritation, but Capsicum Frutescens Fruit Extract induced concentration-dependent (at 25 to 500 microg/ml) cytotoxicity in a human buccal mucosa fibroblast cell line. An ethanol extract of red chili was mutagenic in Salmonella typhimurium TA98, but not in TA100, or in Escherichia coli. Other genotoxicity assays gave a similar pattern of mixed results. Adenocarcinoma of the abdomen was observed in 7/20 mice fed 100 mg red chilies per day for 12 months; no tumors were seen in control animals. Neoplastic changes in the liver and intestinal tumors were observed in rats fed red chili powder at 80 mg/kg day-1 for 30 days, intestinal and colon tumors were seen in rats fed red chili powder and 1,2-dimethyl hydrazine, but no tumors were observed in controls. In another study in rats, however, red chile pepper in the diet at the same dose decreased the number of tumors seen with 1,2-dimethylhydrazine. Other feeding studies evaluated the effect of red chili peppers on the incidence of stomach tumors produced by N-methyl-N'-nitro-N-nitrosoguanidine, finding that red pepper had a promoting effect. Capsicum Frutescens Fruit Extract promoted the carcinogenic effect of methyl(acetoxymethyl)nitrosamine (carcinogen) or benzene hexachloride (hepatocarcinogen) in inbred male and female Balb/c mice dosed orally (tongue application). Clinical findings include symptoms of cough, sneezing, and runny nose in chili factory workers. Human respiratory responses to Capsicum Oleoresin spray include burning of the throat, wheezing, dry cough, shortness of breath, gagging, gasping, inability to breathe or speak, and, rarely, cyanosis, apnea, and respiratory arrest. A trade name mixture containing 1% to 5% Capsicum Frutescens Fruit Extract induced very slight erythema in 1 of 10 volunteers patch tested for 48 h. Capsicum Frutescens Fruit Extract at 0.025% in a repeated-insult patch test using 103 subjects resulted in no clinically meaningful irritation or allergic contact dermatitis. One epidemiological study indicated that chili pepper consumption may be a strong risk factor for gastric cancer in populations with high intakes of chili pepper; however, other studies did not find this association. Capsaicin functions as an external analgesic, a fragrance ingredient, and as a skin-conditioning agent--miscellaneous in cosmetic products, but is not in current use. Capsaicin is not generally recognized as safe and effective by the U.S. Food and Drug Administration for fever blister and cold sore treatment, but is considered to be safe and effective as an external analgesic counterirritant. Ingested Capsaicin is rapidly absorbed from the stomach and small intestine in animal studies. Subcutaneous injection of Capsaicin in rats resulted in a rise in the blood concentration, reaching a maximum at 5 h; the highest tissue concentrations were in the kidney and lowest in the liver. In vitro percutaneous absorption of Capsaicin has been demonstrated in human, rat, mouse, rabbit, and pig skin. Enhancement of the skin permeation of naproxen (nonsteroidal anti-inflammatory agent) in the presence of Capsaicin has also been demonstrated. Pharmacological and physiological studies demonstrated that Capsaicin, which contains a vanillyl moiety, produces its sensory effects by activating a Ca2 +-permeable ion channel on sensory neurons. Capsaicin is a known activator of vanilloid receptor 1. Capsaicin-induced stimulation of prostaglandin biosynthesis has been shown using bull seminal vesicles and rheumatoid arthritis synoviocytes. Capsaicin inhibits protein synthesis in Vero kidney cells and human neuroblastoma SHSY-5Y cells in vitro, and inhibits growth of E. coli, Pseudomonas solanacearum, and Bacillus subtilis bacterial cultures, but not Saccharomyces cerevisiae. Oral LD50 values as low as 161.2 mg/kg (rats) and 118.8 mg/kg (mice) have been reported for Capsaicin in acute oral toxicity studies, with hemorrhage of the gastric fundus observed in some of the animals that died. Intravenous, intraperitoneal, and subcutaneous LD50 values were lower. In subchronic oral toxicity studies using mice, Capsaicin produced statistically significant differences in the growth rate and liver/body weight increases. Capsaicin is an ocular irritant in mice, rats, and rabbits. Dose-related edema was observed in animals receiving Capsaicin injections into the hindpaw (rats) or application to the ear (mice). In guinea pigs, dinitrochlorobenzene contact dermatitis was enhanced in the presence of Capsaicin, injected subcutaneously, whereas dermal application inhibited sensitization in mice. Immune system effects have been observed in neonatal rats injected subcutaneously with Capsaicin. Capsaicin produced mixed results in S. typhimurium micronucleus and sister-chromatid exchange genotoxicity assays. Positive results for Capsaicin were reported in DNA damage assays. Carcinogenic, cocarcinogenic, anticarcinogenic, antitumorigenic, tumor promotion, and anti-tumor promotion effects of Capsaicin have been reported in animal studies. Except for a significant reduction in crown-rump length in day 18 rats injected subcutaneously with Capsaicin (50 mg/kg) on gestation days 14, 16, 18, or 20, no reproductive or developmental toxicity was noted. In pregnant mice dosed subcutaneously with Capsaicin, depletion of substance P in the spinal cord and peripheral nerves of pregnant females and fetuses was noted. In clinical tests, nerve degeneration of intracutaneous nerve fibers and a decrease in pain sensation induced by heat and mechanical stimuli were evident in subjects injected intradermally with Capsaicin. An increase in mean inspiratory flow was reported for eight normal subjects who inhaled nebulized 10(-7) M Capsaicin. The results of provocative and predictive tests involving human subjects indicated that Capsaicin is a skin irritant. Overall, studies suggested that these ingredients can be irritating at low concentrations. Although the genotoxicity, carcinogenicity, and tumor promotion potential of Capsaicin have been demonstrated, so have opposite effects. Skin irritation and other tumor-promoting effects of Capsaicin appear to be mediated through interaction with the same vanilloid receptor. Given this mechanism of action and the observation that many tumor promoters are irritating to the skin, the Panel considered it likely that a potent tumor promoter may also be a moderate to severe skin irritant. Thus, a limitation on Capsaicin content that would significantly reduce its skin irritation potential is expected to, in effect, lessen any concerns relating to tumor promotion potential. Because Capsaicin enhanced the penetration of an anti-inflammatory agent through human skin, the Panel recommends that care should be exercised in using ingredients that contain Capsaicin in cosmetic products. The Panel advised industry that the total polychlorinated biphenyl (PCB)/pesticide contamination should be limited to not more than 40 ppm, with not more than 10 ppm for any specific residue, and agreed on the following limitations for other impurities: arsenic (3 mg/kg max), heavy metals (0.002% max), and lead (5 mg/kg max). Industry was also advised that aflatoxin should not be present in these ingredients (the Panel adopted < or =15 ppb as corresponding to "negative" aflatoxin content), and that ingredients derived from Capsicum annuum and Capsicum Frutescens Plant species should not be used in products where N-nitroso compounds may be formed. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry's newly released Diabetes Strategy.After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,DIABETES STRATEGY EVIDENCE PLATFORM: Summary of Evidence-Based AnalysesContinuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based AnalysisBehavioural Interventions for Type 2 Diabetes: An Evidence-Based AnalysisBARIATRIC SURGERY FOR PEOPLE WITH DIABETES AND MORBID OBESITY: An Evidence-Based SummaryCommunity-Based Care for the Management of Type 2 Diabetes: An Evidence-Based AnalysisHome Telemonitoring for Type 2 Diabetes: An Evidence-Based AnalysisApplication of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario The objective of this analysis is to review the efficacy of continuous subcutaneous insulin infusion (CSII) pumps as compared to multiple daily injections (MDI) for the type 1 and type 2 adult diabetics. Insulin therapy is an integral component of the treatment of many individuals with diabetes. Type 1, or juvenile-onset diabetes, is a life-long disorder that commonly manifests in children and adolescents, but onset can occur at any age. It represents about 10% of the total diabetes population and involves immune-mediated destruction of insulin producing cells in the pancreas. The loss of these cells results in a decrease in insulin production, which in turn necessitates exogenous insulin therapy. Type 2, or 'maturity-onset' diabetes represents about 90% of the total diabetes population and is marked by a resistance to insulin or insufficient insulin secretion. The risk of developing type 2 diabetes increases with age, obesity, and lack of physical activity. The condition tends to develop gradually and may remain undiagnosed for many years. Approximately 30% of patients with type 2 diabetes eventually require insulin therapy. CSII PUMPS: In conventional therapy programs for diabetes, insulin is injected once or twice a day in some combination of short- and long-acting insulin preparations. Some patients require intensive therapy regimes known as multiple daily injection (MDI) programs, in which insulin is injected three or more times a day. It's a time consuming process and usually requires an injection of slow acting basal insulin in the morning or evening and frequent doses of short-acting insulin prior to eating. The most common form of slower acting insulin used is neutral protamine gagedorn (NPH), which reaches peak activity 3 to 5 hours after injection. There are some concerns surrounding the use of NPH at night-time as, if injected immediately before bed, nocturnal hypoglycemia may occur. To combat nocturnal hypoglycemia and other issues related to absorption, alternative insulins have been developed, such as the slow-acting insulin glargine. Glargine has no peak action time and instead acts consistently over a twenty-four hour period, helping reduce the frequency of hypoglycemic episodes. Alternatively, intensive therapy regimes can be administered by continuous insulin infusion (CSII) pumps. These devices attempt to closely mimic the behaviour of the pancreas, continuously providing a basal level insulin to the body with additional boluses at meal times. Modern CSII pumps are comprised of a small battery-driven pump that is designed to administer insulin subcutaneously through the abdominal wall via butterfly needle. The insulin dose is adjusted in response to measured capillary glucose values in a fashion similar to MDI and is thus often seen as a preferred method to multiple injection therapy. There are, however, still risks associated with the use of CSII pumps. Despite the increased use of CSII pumps, there is uncertainty around their effectiveness as compared to MDI for improving glycemic control. PART A: TYPE 1 DIABETIC ADULTS (#ENTITYSTARTX02265;19 YEARS) An evidence-based analysis on the efficacy of CSII pumps compared to MDI was carried out on both type 1 and type 2 adult diabetic populations. Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 1 diabetes?Are CSII pumps more effective than MDI for improving additional outcomes related to diabetes such as quality of life (QoL)? Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, EMBASE, CINAHLAdults (≥ 19 years)Type 1 diabetesStudy evaluates CSII vs. MDIPublished between January 1, 2002 - March 24, 2009Patient currently on intensive insulin therapy Studies with <20 patientsStudies <5 weeks in durationCSII applied only at night time and not 24 hours/dayMixed group of diabetes patients (children, adults, type 1, type 2)Pregnancy studies The primary outcomes of interest were glycosylated hemoglobin (HbA1c) levels, mean daily blood glucose, glucose variability, and frequency of hypoglycaemic events. Other outcomes of interest were insulin requirements, adverse events, and quality of life. The literature search strategy employed keywords and subject headings to capture the concepts of: 1) insulin pumps, and 2) type 1 diabetes. The search was run on July 6, 2008 in the following databases: Ovid MEDLINE (1996 to June Week 4 2008), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2008 Week 26), OVID CINAHL (1982 to June Week 4 2008) the Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. A search update was run on March 24, 2009 and studies published prior to 2002 were also examined for inclusion into the review. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 2002 and March 24, 2009. Abstracts were reviewed, and studies meeting the inclusion criteria outlined above were obtained. Reference lists were also checked for relevant studies. The database search identified 519 relevant citations published between 1996 and March 24, 2009. Of the 519 abstracts reviewed, four RCTs and one abstract met the inclusion criteria outlined above. While efficacy outcomes were reported in each of the trials, a meta-analysis was not possible due to missing data around standard deviations of change values as well as missing data for the first period of the crossover arm of the trial. Meta-analysis was not possible on other outcomes (quality of life, insulin requirements, frequency of hypoglycemia) due to differences in reporting. HBA1C: In studies where no baseline data was reported, the final values were used. Two studies (Hanaire-Broutin et al. 2000, Hoogma et al. 2005) reported a slight reduction in HbA1c of 0.35% and 0.22% respectively for CSII pumps in comparison to MDI. A slightly larger reduction in HbA1c of 0.84% was reported by DeVries et al.; however, this study was the only study to include patients with poor glycemic control marked by higher baseline HbA1c levels. One study (Bruttomesso et al. 2008) showed no difference between CSII pumps and MDI on Hba1c levels and was the only study using insulin glargine (consistent with results of parallel RCT in abstract by Bolli 2004). While there is statistically significant reduction in HbA1c in three of four trials, there is no evidence to suggest these results are clinically significant. MEAN BLOOD GLUCOSE: Three of four studies reported a statistically significant reduction in the mean daily blood glucose for patients using CSII pump, though these results were not clinically significant. One study (DeVries et al. 2002) did not report study data on mean blood glucose but noted that the differences were not statistically significant. There is difficulty with interpreting study findings as blood glucose was measured differently across studies. Three of four studies used a glucose diary, while one study used a memory meter. In addition, frequency of self monitoring of blood glucose (SMBG) varied from four to nine times per day. Measurements used to determine differences in mean daily blood glucose between the CSII pump group and MDI group at clinic visits were collected at varying time points. Two studies use measurements from the last day prior to the final visit (Hoogma et al. 2005, DeVries et al. 2002), while one study used measurements taken during the last 30 days and another study used measurements taken during the 14 days prior to the final visit of each treatment period. GLUCOSE VARIABILITY: All four studies showed a statistically significant reduction in glucose variability for patients using CSII pumps compared to those using MDI, though one, Bruttomesso et al. 2008, only showed a significant reduction at the morning time point. Brutomesso et al. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The objective of the MAS evidence review was to conduct a systematic review of the available evidence on the safety, effectiveness, durability and cost-effectiveness of endovascular radiofrequency ablation (RFA) for the treatment of primary symptomatic varicose veins. The Ontario Health Technology Advisory Committee (OHTAC) met on August 26th, 2010 to review the safety, effectiveness, durability, and cost-effectiveness of RFA for the treatment of primary symptomatic varicose veins based on an evidence-based review by the Medical Advisory Secretariat (MAS). CLINICAL CONDITION: Varicose veins (VV) are tortuous, twisted, or elongated veins. This can be due to existing (inherited) valve dysfunction or decreased vein elasticity (primary venous reflux) or valve damage from prior thrombotic events (secondary venous reflux). The end result is pooling of blood in the veins, increased venous pressure and subsequent vein enlargement. As a result of high venous pressure, branch vessels balloon out leading to varicosities (varicose veins). SYMPTOMS TYPICALLY AFFECT THE LOWER EXTREMITIES AND INCLUDE (BUT ARE NOT LIMITED TO): aching, swelling, throbbing, night cramps, restless legs, leg fatigue, itching and burning. Left untreated, venous reflux tends to be progressive, often leading to chronic venous insufficiency (CVI). A number of complications are associated with untreated venous reflux: including superficial thrombophlebitis as well as variceal rupture and haemorrhage. CVI often results in chronic skin changes referred to as stasis dermatitis. Stasis dermatitis is comprised of a spectrum of cutaneous abnormalities including edema, hyperpigmentation, eczema, lipodermatosclerosis and stasis ulceration. Ulceration represents the disease end point for severe CVI. CVI is associated with a reduced quality of life particularly in relation to pain, physical function and mobility. In severe cases, VV with ulcers, QOL has been rated to be as bad or worse as other chronic diseases such as back pain and arthritis. Lower limb VV is a very common disease affecting adults - estimated to be the 7th most common reason for physician referral in the US. There is a very strong familial predisposition to VV. The risk in offspring is 90% if both parents affected, 20% when neither affected and 45% (25% boys, 62% girls) if one parent affected. The prevalence of VV worldwide ranges from 5% to 15% among men and 3% to 29% among women varying by the age, gender and ethnicity of the study population, survey methods and disease definition and measurement. The annual incidence of VV estimated from the Framingham Study was reported to be 2.6% among women and 1.9% among men and did not vary within the age range (40-89 years) studied. Approximately 1% of the adult population has a stasis ulcer of venous origin at any one time with 4% at risk. The majority of leg ulcer patients are elderly with simple superficial vein reflux. Stasis ulcers are often lengthy medical problems and can last for several years and, despite effective compression therapy and multilayer bandaging are associated with high recurrence rates. Recent trials involving surgical treatment of superficial vein reflux have resulted in healing and significantly reduced recurrence rates. ENDOVASCULAR RADIOFREQUENCY ABLATION FOR VARICOSE VEINS: RFA is an image-guided minimally invasive treatment alternative to surgical stripping of superficial venous reflux. RFA does not require an operating room or general anaesthesia and has been performed in an outpatient setting by a variety of medical specialties including surgeons and interventional radiologists. Rather than surgically removing the vein, RFA works by destroying or ablating the refluxing vein segment using thermal energy delivered through a radiofrequency catheter. Prior to performing RFA, color-flow Doppler ultrasonography is used to confirm and map all areas of venous reflux to devise a safe and effective treatment plan. The RFA procedure involves the introduction of a guide wire into the target vein under ultrasound guidance followed by the insertion of an introducer sheath through which the RFA catheter is advanced. Once satisfactory positioning has been confirmed with ultrasound, a tumescent anaesthetic solution is injected into the soft tissue surrounding the target vein along its entire length. This serves to anaesthetize the vein, insulate the heat from damaging adjacent structures, including nerves and skin and compresses the vein increasing optimal contact of the vessel wall with the electrodes or expanded prongs of the RF device. The RF generator is then activated and the catheter is slowly pulled along the length of the vein. At the end of the procedure, hemostasis is then achieved by applying pressure to the vein entry point. Adequate and proper compression stockings and bandages are applied after the procedure to reduce the risk of venous thromboembolism and to reduce postoperative bruising and tenderness. Patients are encouraged to walk immediately after the procedure. Follow-up protocols vary, with most patients returning 1 to 3 weeks later for an initial follow-up visit. At this point, the initial clinical result is assessed and occlusion of the treated vessels is confirmed with ultrasound. Patients often have a second follow-up visit 1 to 3 months following RFA at which time clinical evaluation and ultrasound are repeated. If required, additional procedures such as phlebectomy or sclerotherapy may be performed during the RFA procedure or at any follow-up visits. The Closure System® radiofrequency generator for endovascular thermal ablation of varicose veins was approved by Health Canada as a class 3 device in March 2005, registered under medical device license 67865. The RFA intravascular catheter was approved by Health Canada in November 2007 for the ClosureFast catheter, registered under medical device license 16574. The Closure System® also has regulatory approvals in Australia, Europe (CE Mark) and the United States (FDA clearance). In Ontario, RFA is not an insured service and is currently being introduced in private clinics. Literature Search The MAS evidence-based review was performed to support public financing decisions. The literature search was performed on March 9th, 2010 using standard bibliographic databases for studies published up until March, 2010. English language full-reports and human studies Original reports with defined study methodologyReports including standardized measurements on outcome events such as technical success, safety, effectiveness, durability, quality of life or patient satisfaction Reports involving RFA for varicose veins (great or small saphenous veins)Randomized controlled trials (RCTs), systematic reviews and meta-analysesCohort and controlled clinical studies involving ≥ 1 month ultrasound imaging follow-up Non systematic reviews, letters, comments and editorials Reports not involving outcome events such as safety, effectiveness, durability, or patient satisfaction following an intervention with RFAReports not involving interventions with RFA for varicose veinsPilot studies or studies with small samples (< 50 subjects) THE MAS EVIDENCE SEARCH ON THE SAFETY AND EFFECTIVENESS OF ENDOVASCULAR RFA ABLATION OF VV IDENTIFIED THE FOLLOWING EVIDENCE: three HTAs, nine systematic reviews, eight randomized controlled trials (five comparing RFA to surgery and three comparing RFA to ELT), five controlled clinical trials and fourteen cohort case series (four were multicenter registry studies). The majority (12⁄14) of the cohort studies (3,664) evaluating RFA for VV involved treatment with first generation RFA catheters and the great saphenous vein (GSV) was the target vessel in all studies. Major adverse events were uncommonly reported and the overall pooled major adverse event rate extracted from the cohort studies was 2.9% (105⁄3,664). Imaging defined treatment effectiveness of vein closure rates were variable ranging from 68% to 96% at post-operative follow-up. Vein ablation rate at 6-month follow-up was reported in four studies with rates close to 90%. Only one study reported vein closure rates at 2 years but only for a minority of the eligible cases. The two studies reporting on RFA ablation with the more efficient second generation catheters involved better follow-up and reported higher ablation rates close to 100% at 6-month follow-up with no major adverse events. A large prospective registry trial that recruited over 1,000 patients at thirty-four largely European centers reported on treatment success in six overlapping reports on selected patient subgroups at various follow-up points up to 5 year. However, the follow-up for eligible recruited patients at all time points was low resulting in inadequate estimates of longer term treatment efficacy. The overall level of evidence of randomized trials comparing RFA with surgical ligation and vein stripping (n = 5) was graded as low to moderate. In all trials RFA ablation was performed with first generation catheters in the setting of the operating theatre under general anaesthesia, usually without tumescent anaesthesia. Procedure times were significantly longer after RFA than surgery. Recovery after treatment was significantly quicker after RFA both with return to usual activity and return to work with on average a one week less of work loss. Major adverse events occurring after surgery were higher [(1.8% (n=4) vs. 0.4% (n = 1) than after RFA but not significantly. Treatment effectiveness measured by imaging defined vein absence or vein closure was comparable in the two treatment groups. Significant improvements in vein symptoms and quality of life over baseline were reported for both treatment groups. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
It will be well to restate the main problem at this point and to examine how far the accumulated data can help to elucidate it. The problem is this: Why are old mice generally resistant to all forms of peripheral inoculation of vesicular stomatitis virus when intracerebral injection is equally fatal for mice of all ages? The results of experiments in which the presence of virus was demonstrated by animal passage suggested that the reason can perhaps be found in (a) the different mechanisms of virus progression after intracerebral and peripheral injection, and (b) the development with age of localized barriers capable of halting the spread of virus (1, 2). The present study sought histological evidence for the nature of virus progression and for the changes observed in the older animals. The results clearly demonstrate that after intracerebral injection virus spreads along an open system, the lesions being distributed almost entirely in contiguity with the ventricles and their extensions, while after peripheral inoculations the evidence points to progression of the virus in a closed system of neurons and their processes, at least in the stage preceding neuronal necrosis, the distribution of lesions depending upon the central connections of the primary neurons connected with the inoculated site. Thus, in young mice, nasal instillation of the virus was followed by necrosis of a long chain of neurons, starting with those in the olfactory mucosa and progressing through specific zones of the olfactory pathway, pursuing the same order in which the various regions are known to have their major connections with one another. It is important to note that after nasal instillation the apparent lesions were present where the cell bodies of the neurons are situated, and not along the tracts connecting one group of neurons with another, which accounts for the lack of contiguity between the affected zones and the normal appearing, intervening areas. The assumption that the primary progression of the virus in this case occurs in a closed system is based on the absence of lesions in unrelated areas contiguous to those which are necrotic and to the tracts which connect one affected zone with another. Additional evidence for the assumption that the initial dissemination of peripherally injected virus is in a closed system is found in the decussating optic nerve pathway primarily pursued by the intraocularly injected virus. The progression of the virus along this decussating pathway was indicated in the experimental data obtained on mice 21 days or older, while in younger animals the spread of virus was so rapid and diffuse that the pathways along which it might have occurred remained obscure (2). In the present study, in which 15 day old mice were used, the lesions in the retinal neurons and the constant involvement of only the contralateral superior colliculus left little doubt that the primary spread of the virus, even in these very young animals, must have occurred within the retinal neuron processes (axons) which decussate in the optic chiasm (in the mouse, as in the rat, very few of these go to the homolateral side) and synapse chiefly with the neurons of the contralateral superior colliculus and also, apparently to a lesser extent, with those of the contralateral external geniculate body, where lesions were also demonstrated. Virus spreading in the optic nerve along the perineural subarachnoid space would be found at the base of the brain at the optic chiasm; virus extending along the interstitial spaces in the optic nerve should involve not only the nuclei of both sides of the optic pathway but also non-optic structures, such as the medial geniculate bodies, posterior colliculi, etc., by means of the commissures of von Gudden and of Meynert, whose fibers course through the chiasm. The highly specific localization observed in the present study is best accounted for by progression along the suggested closed pathway. Hurst (10) observed that poliomyelitis virus, after injection into the left sciatic nerve, may, after invading the lumbar cord, be found first in the contralateral motor cortex or thalamus and he suggested that this was evidence of progression along a decussating pathway and in favor of the axonal hypothesis of virus spread. It was not shown, however, that this particular localization was specifically related to the introduction of virus in the left sciatic nerve, or that it could be reversed by inoculating the sciatic nerve of the opposite side. The hypothesis proposed by Hurst, however, finds support in the present instance for (a) the superior colliculi never showed lesions after intracerebral, intranasal, or intramuscular inoculations, and (b) necrosis was produced in either the right or the left superior colliculus, depending on whether the virus was injected into the left or right eyes. The localization of lesions after injection of virus into the muscles of one leg indicated that in the young the invasion occurred along the local peripheral nerves, especially the motor fibers (neurons destroyed in the lumbar cord with those in the spinal ganglia intact), after a primary attack on the muscle itself. The only other lesions found at a late stage were in the reticular substance of the medulla, the olfactory portions of the brain appearing entirely normal. In this respect the mechanism of progression of intramuscularly injected vesicular stomatitis virus differs from that of eastern equine encephalomyelitis and pseudorabies viruses similarly injected into mice of the same age and breed: the former (E.E.E.) invades the central nervous system in the majority of instances, by being eliminated on the nasal mucosa and then along the olfactory pathways (18), while the latter appears to employ chiefly the local sensory fibers, attacking primarily the neurons in the spinal ganglia (unpublished observations). Because the CNS of old mice remain for the most part susceptible to vesicular stomatitis virus (although definite evidence of resistance to necrosis of the neurons was observed), and because after intracerebral injection the virus has been shown to spread in an open (ventricular) system, it is clear why young and old mice are equally susceptible to inoculation by this route. After peripheral inoculation, however, it has been amply demonstrated by experimental and histological methods that the spread of this virus begins and continues, at least until the cells disintegrate, in a closed system within the neurons and their processes and apparently also across the synapses. The halting of the virus somewhere in the anterior rhinencephalon after nasal instillation in resistant mice (1) would appear to be due to an arrest in an insusceptible neuron or an impenetrable synapse somewhere in the chain, and to the failure of the affected neurons to disintegrate (no lesions were found in the CNS of these mice) and thus to liberate the virus into the open system. After intramuscular injection, on the other hand, the virus encounters a different kind of muscle cell in the old mouse, and its inability to invade the nerves may perhaps be bound up with its demonstrated inability to attack and multiply in these changed muscle cells, although the role of a possible alteration in the terminal nerve endings themselves is not yet clear. After intraocular injection, the virus fails to affect visibly the retinal neurons of resistant old mice and the further invasion of the CNS is inhibited. The resistance of old mice to peripheral inoculations of vesicular stomatitis virus thus appears to be the result of (a) changes produced by age not in the whole animal but in certain specific, isolated structures, and (b) the special mode of progression of peripherally injected virus. It may be of interest to point out two phenomena which may perhaps be related to the one investigated in the present study. Tobacco mosaic virus has been found to produce different types of disease in certain plants of different ages; thus a widespread, systemic necrosis leads to the death of young Nicotiana rustica plants, while in old plants it is possible to produce necrotic foci in many parts of the plant by direct inoculation, although generalization does not occur from an isolated focus as it does in young specimens (19). In other words, age apparently does not change the whole plant, but it does transform something which allows the virus to spread easily from one site to another. MacNider (20) has observed that dogs which survive a severe type of hepatic injury from uranium, repair this injury with a special type of atypical, epithelial cell and become resistant not only to secondary intoxications by uranium but also by chloroform; he has also found that this change in epithelial cell type may be acquired as a product of senility, and that when it develops it imparts to the liver a degree of resistance to chloroform comparable to that induced by a process of repair following a severe hepatic injury from uranium nitrate.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The aim of this review was to assess the effectiveness, safety, and cost of sacral nerve stimulation (SNS) to treat urinary urge incontinence, urgency-frequency, urinary retention, and fecal incontinence. CONDITION AND TARGET POPULATION Urinary urge incontinence, urgency-frequency, urinary retention, and fecal incontinence are prevalent, yet rarely discussed, conditions. They are rarely discussed because patients may be uncomfortable disclosing their symptoms to a health professional or may be unaware that there are treatment options for these conditions. Briefly, urge incontinence is an involuntary loss of urine upon a sudden urge. Urgency-frequency is an uncontrollable urge to void, which results in frequent, small-volume voids. People with urgency-frequency may or may not also experience chronic pelvic pain. Urinary retention refers to the inability to void despite having the urge to void. It can be caused by a hypocontractile detrusor (weak or no bladder muscle contraction) or obstruction due to urethral overactivity. Fecal incontinence is a loss of voluntary bowel control. The prevalence of urge incontinence, urgency-frequency, and urinary retention in the general population is 3.3% to 8.2%, and the prevalence of fecal incontinence is 1.4% to 1.9%. About three-quarters of these people will be successfully treated by behaviour and/or drug therapy. For those who do not respond to these therapies, the options for treatment are management with diapers or pads, or surgery. The surgical procedures are generally quite invasive, permanent, and are associated with complications. Pads and/or diapers are used throughout the course of treatment as different therapies are tried. Patients who respond successfully to treatment may still require pads or diapers, but to a lesser extent. SACRAL NERVE STIMULATION Sacral nerve stimulation is a procedure where a small device attached to an electrode is implanted in the abdomen or buttock to stimulate the sacral nerves in an attempt to manage urinary urge incontinence, urgency-frequency, urinary retention, and fecal incontinence. The device was originally developed to manage urinary urge incontinence; however, it has also been used in patients with urgency-frequency, urinary retention, and fecal incontinence. SNS is intended for patients who are refractory to behaviour, drug, and/or interventional therapy. There are 2 phases in the SNS process: first, patients must undergo a test stimulation phase to determine if they respond to sacral nerve stimulation. If there is a 50% or greater improvement in voiding function, then the patient is considered a candidate for the next phase, implantation. The standard Medical Advisory Secretariat search strategy was used to locate international health technology assessments and English-language journal articles published from 2000 to November 2004. The Medical Advisory Secretariat also conducted Internet searches of Medscape (1) and the manufacturer's website (2) to identify product information and recent reports on trials that were unpublished but that were presented at international conferences. In addition, the Web site Current Controlled Trials (3) was searched for ongoing randomized controlled trials (RCTs) investigating the role of sacral nerve stimulation in the management of voiding conditions. Four health technology assessments were found that reviewed SNS in patients with urge incontinence, urgency-frequency, and/or urinary retention. One assessment was found that reviewed SNS in patients with fecal incontinence. The assessments consistently reported that SNS was an effective technology in managing these voiding conditions in patients who did not respond to drug or behaviour therapy. They also reported that there was a substantial complication profile associated with SNS. Complication rates ranged from 33% to 50%. However, none of the assessments reported that they found any incidences of permanent injury or death associated with the device. The health technology assessments for urge incontinence, urgency-frequency, and urinary retention included (RCTs (level 2) as their primary source of evidence for their conclusions. The assessment of fecal incontinence based its conclusions on evidence from case series (level 4). Because there was level 2 data available for the use of SNS in patients with urinary conditions, the Medical Advisory Secretariat chose to review thoroughly the RCTs included in the assessments and search for publications since the assessments were released. However, for the health technology assessment for fecal incontinence, which contained only level 4 evidence, the Medical Advisory Secretariat searched for studies on SNS and fecal incontinence that were published since that assessment was released. URGE INCONTINENCE: Two RCTs were identified that compared SNS to no treatment in patients with refractory urge incontinence. Both RCTs reported significant improvements (> 50% improvement in voiding function) in the SNS group for number of incontinence episodes per day, number of pads used per day, and severity of incontinence episodes. URGENCY-FREQUENCY (WITH OR WITHOUT CHRONIC PELVIC PAIN): One RCT was identified that compared SNS to no treatment in patients with refractory urgency-frequency. The RCT reported significant improvements in urgency-frequency symptoms in the SNS group (average volume per void, detrusor pressure). In addition to the RCT, 1 retrospective review and 2 prospective case series were identified that measured pelvic pain associated with urgency-frequency in patients who underwent SNS. All 3 studies reported a significant decrease in pain at median follow-up. URINARY RETENTION: One RCT was identified that compared SNS to no treatment in patients with refractory urinary retention. The RCT reported significant improvements in urinary retention in the SNS group compared to the control group for number of catheterizations required and number of voids per day. In addition to this RCT, 1 case series was also identified investigating SNS in women with urinary retention. This study also found that there were significant improvements in urinary retention after the women had received the SNS implants. FECAL INCONTINENCE: Three case series were identified that investigated the role of SNS in patients with fecal incontinence. All 3 reported significant improvements in fecal incontinence symptoms (number of incontinent episodes per week) after the patients received the SNS implants. LONG-TERM FOLLOW-UP: None of the studies identified followed patients until the point of battery failure. Of the 6 studies identified describing the long-term follow-up of patients with SNS, follow-up periods ranged from 1.5 years to over 5 years. None of the long-term follow-up studies included patients with fecal incontinence. All of the studies reported that most of the patients who had SNS had at least a 50% improvement in voiding function (range 58%-77%). These studies also reported the number of patients who had their device explanted in the follow-up period. The rates of explantation ranged from 12% to 21%. SAFETY, COMPLICATIONS, AND QUALITY OF LIFE: A 33% surgical revision rate was reported in an analysis of the safety of 3 RCTs comparing SNS to no treatment in patients with urge incontinence, urgency-frequency, or urinary retention. The most commonly reported adverse effects were pain at the implant site and lead migration. Despite the high rate of surgical revision, there were no reports of permanent injury or death in any of the studies or health technology assessments identified. Additionally, patients consistently said that they would recommend the procedure to a friend or family member. One health technology assessment and 1 abstract were found that investigated the costing factors pertinent to SNS. The authors of this assessment did their own "indicative analysis" and found that SNS was not more cost-effective than using incontinence supplies. However, the assessment did not account for quality of life. Conversely, the authors of the abstract found that SNS was more cost-effective than incontinence supplies alone; however, they noted that in the first year after SNS, it is much more expensive than only incontinence supplies. This is owing to the cost of the procedure, and the adjustments required to make the device most effective. They also noted the positive effects that SNS had on quality of life. In summary, there is level 2 evidence to support the effectiveness of SNS to treat people with urge incontinence, urgency-frequency, or urinary retention. There is level 4 evidence to support the effectiveness of SNS to treat people with fecal incontinence. To qualify for SNS, people must meet the following criteria: Be refractory to behaviour and/or drug therapyHave had a successful test stimulation before implantation; successful test stimulation is defined by a 50% or greater improvement in voiding function based on the results of a voiding diary. Test stimulation periods range from 3 to 7 days for patients with urinary dysfunctions, and from 2 to 3 weeks for patients with fecal incontinence.Be able to record voiding diary data, so that clinical results of the implantation can be evaluated.Patients with stress incontinence, urinary retention due to obstruction and neurogenic conditions (such as diabetes with peripheral nerve involvement) are ineligible for sacral nerve stimulation. Physicians will need to learn how to use the InterStim System for Urinary Control. Requirements for training include these: Physicians must be experienced in the diagnosis and treatment of lower urinary tract disorders and should be trained in the implantation and use of the InterStim System for Urinary Control. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
<bObjective:</b To investigate whether adipose-derived stem cells (ASCs) from allogeneic diabetic rats can promote wound healing in diabetic rats or not and the mechanism. <bMethods:</b (1) Fifty-six male Wistar rats aged 12-16 weeks were divided into diabetic group and healthy group according to the random number table (the same grouping method below), with 28 rats in each group. Rats in healthy group were not treated with any treatment. Rats in diabetic group were injected with 10 g/L streptozotocin 60 mg/kg intraperitoneally in one time to establish the diabetic model. Four rats in diabetic group and 4 rats in healthy group were selected according to the random number table, and the adipose tissue in the inguinal region was taken to culture and purify ASCs, so as to obtain healthy rat-derived ASCs (hereinafter referred to as nASCs) and diabetic rat-derived ASCs (hereinafter referred to as dASCs). The third passage of nASCs (<in</i=3) and dASCs (<in</i=3) were taken, and the positive expression rates of cell surface differentiation antigens CD105, CD31, CD34, and CD44 were detected with flow cytometer for defining ASCs purity. (2) The rest 24 rats in healthy group and 24 rats in diabetic group were used to make three round full-thickness skin defect wounds with a diameter of 12 mm on the back of each rat. Immediately after injury, phosphate buffer saline (PBS), nASCs of 2×10(7)/mL, and dASCs of 2×10(7)/mL each in the volume of 0.5 mL were subcutaneously injected into three wounds and their margins of each rat, respectively. On post injury day (PID) 1, 3, 7, and 12, 6 rats in each group were selected according to the random number table to calculate the wound area, and the wound tissue was stained with hematoxylin-eosin to observe the histological morphology of the wound. (3) Human ASCs (hASCs) were subcultured, and the 4th to 7th passage of cells were used for the subsequent experiments. The hASCs were divided into 7 groups, with 12 samples in each group. Cells in blank control group were cultured with mesenchymal stem cell culture medium, and cells in simple advanced glycation end products (AGEs) group, simple protein group, simple high glucose group, simple high osmotic pressure group, AGEs-high glucose combination group, and protein-high osmotic pressure combination group were cultured with mesenchymal stem cell culture medium containing a final mass concentration of 100 mg/L AGEs, 100 mg/L bovine serum albumin (BSA), 28 mmol/L D-glucose, 28 mmol/L mannitol, 100 mg/L AGEs+ 28 mmol/L D-glucose, 100 mg/L BSA+ 28 mmol/L mannitol, respectively. Cell proliferation was detected by cell counting kit 8 at post culture hour (PCH) 2 and on post culture day (PCD) 2, 4 and 6. (4) The hASCs were divided into blank control group, simple AGE group, simple high glucose group, and AGE-high glucose combination group, with 12 samples in each group, which were treated the same as corresponding groups in experiment (3). On PCD 0, 2, 4, and 6, the positive expression rates of cell surface differentiation antigens CD105, CD44, and CD45 were detected by flow cytometer to estimate their homeostasis. (5) The hASCs were divided into AGE-high glucose combination group and protein-high osmotic pressure combination group, with 9 samples in each group, which were treated the same as corresponding groups in experiment (3). On PCD 2, 4, and 6, the expression of intracellular protein was detected by cyanine 3-streptavidin double-antibody sandwich technique. Data were processed with analysis of variance for factorial design, least significant difference test, and Bonferroni correction. <bResults:</b (1) The positive expression rates of CD44 in nASCs and dASCs were both higher than 96%, the positive expression rates of CD31 and CD34 were low, and the positive expression rates of CD105 were about 40%, which basically met the purity requirements. (2) The areas of wounds treated by three methods in rats of healthy group and diabetic group were similar on PID 1 (<iP</i>0.05). In healthy group, compared with (0.682 1±0.078 9), (0.314 3±0.113 7), and (0.064 3±0.002 1) cm(2) of the PBS-treated wounds in rats, the area of nASCs-treated wounds in rats decreased significantly on PID 3, 7, and 12 [(0.464 1±0.092 6), (0.223 9±0.072 7), and (0.034 3±0.012 5) cm(2), <iP</i<0.05], the area of dASCs-treated wounds in rats decreased significantly on PID 3 and 12 [(0.514 1±0.124 1) and (0.043 7±0.032 8) cm(2), <iP</i<0.05] but was not obviously changed on PID 7 [(0.274 2±0.062 5) cm(2), <iP</i>0.05]. Compared with those of the dASCs-treated wounds of rats within the same group, the area of the nASCs-treated wounds of rats in healthy group decreased significantly on PID 3 and 7 (<iP</i<0.05) but was not obviously changed on PID 12 (<iP</i>0.05). In diabetic group, compared with (0.853 5±0.204 8), (0.670 5±0.164 8), and (0.131 4±0.074 4) cm(2) of the PBS-treated wounds in rats, the area of nASCs-treated wounds in rats decreased significantly on PID 3, 7, and 12 [(0.633 4±0.132 5), (0.331 8±0.023 5), and (0.074 2±0.003 8) cm(2), <iP</i<0.05], the area of dASCs-treated wounds in rats decreased significantly on PID 3 [(0.773 6±0.182 2) cm(2), <iP</i<0.05] but was not obviously changed on PID 7 and 12 [(0.510 6±0.192 2) and (0.114 4±0.003 1) cm(2), <iP</i>0.05]. Compared with the dASCs-treated wounds of rats within the same group, the area of the nASCs-treated wounds of rats in diabetic group was not obviously changed on PID 3 and 7 (<iP</i>0.05) but decreased significantly on PID 12 (<iP</i<0.05). There was no obvious difference in histological morphology of the wounds treated with three methods in rats of each group on PID 1. On PID 3, a small amount of microvessels were formed in the wounds treated with nASCs and dASCs of rats in both groups, but microvessel formation was almost undetected in the PBS-treated wounds. On PID 7, more small blood vessels and fibroblasts (Fbs) were observed in the wounds treated with nASCs and dASCs of rats in both groups, but the small blood vessels and Fbs were slightly less in the PBS-treated wounds. On PID 12, the wounds treated with nASCs and dASCs of rats in the two groups were covered by epithelial tissue, the granulation tissue in the PBS-treated wounds of rats in healthy group was not obvious, and the PBS-treated wounds of rats in diabetic group were not completely epithelialized. (3) Compared with those of blank control group, the cell number of hASCs in simple AGEs group decreased significantly on PCD 2, 4, and 6 (<iP</i<0.05), which increased significantly on PCD 2 and 4 in simple high glucose group (<iP</i<0.05), and that in AGEs-high glucose combination group decreased significantly on PCD 4 and 6 (<iP</i<0.05). (4) Compared with that on PCD 4 within the same group, the positive expression rate of CD105 in hASCs decreased significantly in blank control group, simple AGEs group, and AGEs-high glucose combination group on PCD 6 (<iP</i<0.05). The positive expression rate of CD44 was higher than 95%, and that of CD45 was less than 2% in hASCs of each group at each time point. (5) Detection values of 7 proteins were located in the confidence interval. The expression levels of basic fibroblast growth factor and tissue inhibitor of metalloproteinase-1 in hASCs of AGEs-high glucose combination group and protein-high osmotic pressure combination group showed increasing trend with the prolongation of culture time. The expression level of human monocyte chemoattractant protein 1 (MCP-1) in hASCs of AGEs-high glucose combination group showed increasing trend with the prolongation of culture time, while the expression level of growth-regulated oncogene (GRO) on PCD 6 was significantly higher than that on PCD 4 within the same group (<iP</i<0.05); the expression levels of MCP-1 and GRO in hASCs of protein-high osmotic pressure combination group showed decreasing trend with the prolongation of culture time. The expression level of follistatin in hASCs of protein-high osmotic pressure combination group decreased obviously on PCD 4, while that in hASCs of AGEs-high glucose combination group was significantly lower on PCD 6 than that on PCD 4 (<iP</i<0.05). The expression level of vascular endothelial growth factor (VEGF) in hASCs of protein-high osmotic pressure combination group decreased gradually with the prolongation of culture time, while that in hASCs of AGEs-high glucose combination group on PCD 4 decreased significantly as compared with that on PCD 2 (<iP</i<0.05). The expression level of urokinase-type plasminogen activator receptor in hASCs of protein-high osmotic pressure combination group on PCD 6 was significantly higher than that on PCD 4 within the same group (<iP</i<0.05) and that of AGEs-high glucose combination group on PCD 6 (<iP</i<0.05). <bConclusions:</b Both nASCs and dASCs can promote wound healing in rats with simple defect injury, but dASCs have no significant effect on wound healing in rats with diabetes mellitus, which may be related to the inhibition of ASCs proliferation and the influence of high glucose and AGEs intervention on their homeostasis and secretory function.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
1-Trans-delta(9)-tetrahydrocannabinol (THC) was nominated by the National Cancer Institute to the NTP for study because it is the major psychoactive component of marijuana and a widely used Schedule I substance. Male and female F344/N rats and B6C3F1 mice received THC (97% pure) in corn oil by gavage for 13 weeks, 13 weeks with a 9-week recovery period, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood cells. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats received 0, 5, 15, 50, 150, or 500 mg THC/kg body weight in corn oil by gavage, 5 days per week for 13 weeks. Six male and six female rats receiving 500 mg/kg died before the end of the study. The final mean body weights and weight gains of all dosed groups of males and females, except 5 mg/kg females, were significantly lower than those of the controls. Feed consumption by dosed groups was similar to that by controls. Clinical findings observed during the study included lethargy, sensitivity to touch, convulsions, tremors, and aggressiveness. There were no clinical pathology differences considered to be directly related to the administration of THC. The absolute and relative uterus weights of 50, 150, and 500 mg/kg females were significantly lower than those of the controls. Treatment-related multifocal atrophy was observed in the testes of 150 and 500 mg/kg males; uterine and ovarian hypoplasia observed in 150 and 500 mg/kg females was also considered to be related to THC administration. Based on final mean body weights and mortality observed in the 13-week study, doses selected for the 2-year rat study were 12.5, 25, and 50 mg/kg. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice received 0, 5, 15, 50, 150, or 500 mg THC/kg body weight in corn oil by gavage, 5 days per week for 13 weeks. There were no treatment-related deaths. The final mean body weight and weight gain of 500 mg/kg males were significantly lower than those of the controls. Clinical findings included lethargy and aggressiveness, and both male and female mice in all dosed groups were easily startled. There were no absolute or relative organ weight differences, clinical pathology differences, or microscopic changes observed that were considered to be related to the administration of THC. Due to the minimal THC-related effects observed in the 13-week study, doses selected for the 2-year mouse study were 125, 250, and 500 mg/kg. 13-WEEK WITH 9-WEEK RECOVERY STUDY IN RATS: Groups of 10 male and 10 female rats received 0, 5, 15, 50, 150, or 500 mg THC/kg body weight in corn oil by gavage, 5 days per week for 13 weeks, and then were allowed to recover during a 9-week treatment-free period. Five male and eight female 500 mg/kg rats, five male and two female 150 mg/kg rats, and three male and two female 50 mg/kg rats died before the end of the study. During the 13-week dosing period, mean body weight gains of all dosed groups of rats were lower than those of the controls but returned to normal during the recovery period. Final mean body weights of all dosed groups were similar to those of the controls. Clinical findings observed during the recovery period included sensitivity to touch, convulsions, and aggressiveness. The absolute right testis weight of 500 mg/kg males was significantly lower than that of the controls. Treatment-related multifocal atrophy of the testis was observed in 150 and 500 mg/kg males. There were no treatment-related lesions observed in females administered THC. 13-WEEK WITH 9-WEEK RECOVERY STUDY IN MICE: Groups of 10 male and 10 female mice received 0, 5, 15, 50, 150, or 500 mg THC/kg body weight in corn oil by gavage, 5 days per week for 13 weeks, and then were allowed to recover during a 9-week treatment-free period. The final mean body weights of all dosed groups were similar to those of the controls. Clinical findings observed during the study included lethargy and aggressiveness, and both male and female mice in all dosed groups were easily startled. The absolutebsolute and relative uterus weights of 150 and 500 mg/kg female mice were significantly lower than those of the controls, as was the absolute uterus weight of 50 mg/kg females. 2-YEAR STUDY IN RATS: Groups of 62 vehicle control male rats, 60 low-dose male rats, 70 mid- and high-dose male rats, and 60 female rats were administered 0, 12.5, 25, or 50 mg THC/kg body weight in corn oil by gavage for 104 to 105 weeks. Nine or ten animals from each group were evaluated at 15 months. Survival, Body Weights, and Clinical Findings: Survival of all dosed groups was generally significantly greater than that of the controls. Mean body weights of dosed groups of males and females were lower than those of the controls throughout the study. Convulsions and seizures were observed in all dosed groups of male and female rats, usually following dosing or handling. Hematology and Clinical Chemistry: At the 15-month interim evaluation, total leukocyte and lymphocyte counts in all dosed groups of females were greater than those of the controls, and platelet counts in these groups were lower than that of the controls. Levels of follicle stimulating and luteinizing hormones in all dosed groups of males were significantly greater than those of the controls, as was the serum corticosterone level of 25 mg/kg females. Pathology Findings: No increased incidences of neoplasms were considered related to administration of THC. The incidences of mammary gland fibroadenoma and uterine stromal polyps were decreased in dosed groups of females, as were the incidences of pituitary gland adenomas, interstitial cell adenomas of the testis, and pancreatic adenomas in dosed males. 2-YEAR STUDY IN MICE: Groups of 62 vehicle control male mice, 60 low-dose male mice, 61 mid-dose male mice, and 60 high-dose male mice and 60 female mice were administered 0, 125, 250, or 500 mg THC/kg body weight in corn oil by gavage for 104 to 105 weeks (males) or 105 to 106 weeks (females). Survival, Body Weights, and Clinical Findings: Survival of 500 mg/kg males was significantly less than that of the controls; survival of all other groups of males and of all dosed groups of females was similar to that of the controls. Mean body weights of all dosed groups were markedly lower than those of the controls throughout the study. Clinical findings in dosed groups included hyperactivity, convulsions, and seizures which occurred following dosing or handling. Hematology: At the 15-month interim evaluation, total leukocyte and lymphocyte counts in all dosed groups of males were significantly lower than those of the controls. Pathology Findings: Increased incidences of thyroid gland follicular cell adenoma occurred in 125 mg/kg males and females, but the increase was not dose-related. Increased incidences of thyroid gland follicular cell hyperplasia occurred in all dosed groups of males and females. Increased incidences of forestomach hyperplasia and ulcers occurred in all groups of males administered THC. Incidences of hepatocellular adenoma and of hepatocellular adenoma or carcinoma (combined) occurred with a significant negative trend in male and female mice, as did incidences of eosinophilic foci and fatty change in the liver. GENETIC TOXICOLOGY: THC was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535 with or without rat and hamster liver S9 fractions. In cultured Chinese hamster ovary cells, THC induced sister chromatid exchanges at the highest dose tested in the presence of S9; at this dose level, cell cycle delay indicative of toxicity was observed. THC did not induce chromosomal aberrations in cultured Chinese hamster ovary cells with or without S9 metabolic activation enzymes. In vivo, no increase in the frequency of micronucleated erythrocytes was observed in the peripheral blood of male or female mice administered THC by gavage for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of 1-trans-delta(9)-tetrahydrocannabinol in male or female F344/N rats administered 12.5, 25, or 50 mg/kg. There was equivocal evidence of carcinogenic activity of THC in male and female B6C3F1 mice based on the increased incidences of thyroid gland follicular cell adenomas in 125 mg/kg groups. Increased incidences of thyroid gland follicular cell hyperplasia occurred in male and female mice, and increased incidences of hyperplasia and ulcers of the forestomach were observed in male mice. The incidences of mammary gland fibroadenomas and uterine stromal polyps were decreased in dosed groups of female rats, as were the incidences of pancreatic adenomas, pituitary gland adenomas, and interstitial cell adenomas of the testis in dosed male rats and liver neoplasms in dosed mice. These decreases were likely related to lower body weights in dosed animals. Synonyms: 3-Pentyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6h-dibenzo(b,d)pyran-1-ol; delta1-tetrahydrocannabinol; (-)-delta1-3,4-trans- tetrahydrocannabinol; delta(9)-tetrahydrocannabinon; THC; delta1-THC; delta(9)-THC	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
<bObjective:</b To explore the effects and mechanism of <iLactococcus lactis</i (<iL</i. <ilactis</i) thermo-sensitive hydrogel on the wound healing of full-thickness skin defects in diabetic mice. <bMethods:</b (1) According to the volume ratio of bacteria to medium of 1∶100, about 5×10(8) colony forming units/mL (the same concentration below) <iL</i. <ilactis</i was cultured in M17GS liquid medium. The growth conditions were observed at 0 (immediately), 2, 4, 6, 8, 10, and 12 h of culture with a microplate reader. In addition, another colony of the bacteria was taken and cultured under the same condition mentioned above. The culture medium was collected at the same time points as mentioned above, and the supernatant of bacterial culture was isolated. With the supernatant, the pH value was measured with a desktop pH meter, and the concentration of L-lactic acid at 0 (immediately), 2, 4, 8, and 12 h of culture was determined by the L-lactic acid detection and analysis kit (<in</i=3). (2) To prepare a simple thermo-sensitive hydrogel, the poloxamer thermo-sensitive polymer and M17GS liquid medium were mixed thoroughly according to the mass-volume ratio of 0.2 g∶1 mL. <iL</i. <ilactis</i was added to the simple thermo-sensitive hydrogel according to the volume ratio of bacteria to hydrogel of 1∶100, and the <iL</i. <ilactis</i thermo-sensitive hydrogel was prepared after thorough mixing. Afterwards, the morphology of <iL</i. <ilactis</i thermo-sensitive hydrogel was observed after 4 ℃, 37 ℃ incubation and again at 4 ℃ incubation after gelation. The storage modulus and loss modulus of the <iL</i. <ilactis</i thermo-sensitive hydrogel at 10-40 ℃ were measured by rheometer, and the gel forming temperature was observed. After freeze-drying the <iL</i. <ilactis</i thermo-sensitive hydrogel, the surface and the morphological structure of <iL</i. <ilactis</i in the hydrogel were observed by scanning electron microscope. (3) Mouse macrophages Raw264.7 cells were M1-type polarization stimulated by culturing with lipopolysaccharide and interferon γ in the final mass concentration of 100 and 10 ng/mL respectively for 24 h. The cells were divided into blank control group (without other treatment), <iL</i. <ilactis</i thermo-sensitive hydrogel group, and lactic acid group. <iL</i. <ilactis</i thermo-sensitive hydrogel in the volume of 1 mL was added to the cells of <iL</i. <ilactis</i thermo-sensitive hydrogel group, while lactic acid with the final molarity of 30 mmol/L was added to the cells in lactic acid group. After being cultured at 37 ℃ for 24 h, mRNA expressions of the markers arginase 1 and CD206 of M2-type macrophages were detected by real-time fluorescence quantitative reverse transcription polymerase chain reaction (RT-PCR) (<in</i=3), and the immunofluorescence method was used to detect the protein localization and expression of arginase 1 and CD206. (4) Fifteen female BALB/c mice aged 8-10 weeks were induced into diabetic mouse models by the method of streptozotocin combined with high-sugar and high-fat diet, and a full-thickness wound with the diameter of 6 mm was made on the back of each mouse. The mice were divided into blank control group (without other treatment), thermo-sensitive hydrogel alone group, and <iL</i. <ilactis</i thermo-sensitive hydrogel group according to the random number table, with 5 mice in each group. The mice in the hydrogel treatment two groups were dripped with 200 μL corresponding hydrogel to the wound surface immediately after injury, and the hydrogel was replaced every day. After treatment for 0 (immediately), 3, 6, 9, and 12 days in the hydrogel treatment two groups, wound healing was observed, and wound area was measured. After 12 days of treatment, the wound tissue was taken to observe the thickness of granulation tissue by hematoxylin-eosin staining and CD206 and the marker of M1-type macrophages of inducible nitric oxide synthase (iNOS) positive cells by immunofluorescence method. The mice in blank control group were observed at the same time points as mentioned above. (5) Nine female BALB/c mice aged 8-10 weeks were induced into diabetic mouse models by the same method of experiment (4). Then, they were divided into normal skin group (without other treatment), wound alone group, and <iL</i. <ilactis</i thermo-sensitive hydrogel group according to the random number table, with 3 mice in each group. Mice in wound alone group and <iL</i. <ilactis</i thermo-sensitive hydrogel group were prepared with full-thickness skin defect wounds according to the method of experiment (4). Mice in the former group was left untreated after injury, and in the latter group, 200 μL <iL</i. <ilactis</i thermo-sensitive hydrogel was dripped onto the wound surface immediately after injury. After treatment for 1 day in hydrogel treatment group, the wound tissue of mice was taken, and the mRNA expressions of interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), and nuclear factor κB were detected by real-time fluorescence quantitative RT-PCR; after the eyeball blood was collected, the leukocyte count, lymphocyte count, and monocyte count in peripheral blood were measured by an automatic blood cell analyzer, and the serum L-lactic acid concentration was measured by the L-lactic acid detection and analysis kit. At the same time point mentioned above, normal skin tissue was taken from the corresponding parts of mice in normal skin group, wound tissue was taken from mice in wound alone group, and blood was taken from mice of the two groups for corresponding detection. Data were statistically analyzed with one-way analysis of variance, analysis of variance for repeated measurement, Tukey, and Dunnett test. <bResults:</b (1) The growth of <iL</i. <ilactis</i reached the plateau in about 6 h of culture. In the culture supernatant of <iL</i. <ilactis,</i the pH value gradually decreased, reaching the nadir about 4.9 after 8 h of culture, and the L-lactic acid concentration gradually increased, which peaked about 70 mmol/L after 8 h of culture. (2) The <iL</i. <ilactis</i thermo-sensitive hydrogel was a liquid at 4 ℃, and a solid gel at 37 ℃. After gelation, it became a liquid again after incubating at 4 ℃. The gel forming temperature was about 25 ℃. The storage modulus was about 3 000 Pa, and the loss modulus was about 1 000 Pa after gelation. Under the scanning electron microscope, the <iL</i. <ilactis</i thermo-sensitive hydrogel showed a loose three-dimensional porous structure, and the <iL</i. <ilactis</i had an ellipsoidal shape being wrapped inside the hydrogel. (3) After 24 h of culture, compared with those in blank control group, the expression of arginase 1 increased significantly (<iq</i=11.620, 15.250, <iP</i<0.01), the expression of CD206 mRNA increased significantly (<iq</i=16.770, 19.030, <iP</i<0.01), and the expression of CD206 protein located in the cell membrane and arginase 1 protein located in the cytoplasm increased significantly in the macrophages of <iL</i. <ilactis</i thermo-sensitive hydrogel group and lactic acid group. The expressions of arginase 1 and CD206 mRNA in the macrophages between lactic acid group and <iL</i. <ilactis</i thermo-sensitive hydrogel group were similar (<iq</i=3.629, 2.259, <iP</i>0.05). (4) After 3-12 days of treatment, compared with those in blank control group and thermo-sensitive hydrogel alone group, the wound of mice in <iL</i. <ilactis</i thermo-sensitive hydrogel group healed faster, the wound area was significantly reduced, and the inflammation of the wound edge tissue was reduced. After treatment of 3, 6, 9, 12 days, the wound areas of mice in <iL</i. <ilactis</i thermo-sensitive hydrogel group were (25.8±5.9), (21.2±4.6), (16.0±2.4), (8.4±2.4) mm(2) respectively, which were significantly smaller than (31.8±5.3), (28.0±3.4), (22.6±3.7), (17.0±1.0) mm(2) in blank control group (<iq</i=3.506, 3.973, 3.856, 5.025, <iP</i<0.05 or <iP</i<0.01). After treatment of 3 and 6 days, the wound areas of mice in <iL</i. <ilactis</i thermo-sensitive hydrogel group were significantly smaller than those in thermo-sensitive hydrogel alone group (<iq</i=3.739, 3.739, <iP</i<0.05). After 12 days of treatment, compared with those in blank control group and thermo-sensitive hydrogel alone group, the wound granulation tissue of mice in <iL</i. <ilactis</i thermo-sensitive hydrogel group was thicker, with significantly reduced iNOS positive cells and increased CD206 positive cells in wound tissue. (5) After 1 day of treatment, the mRNA expressions of IL-1β, TNF-α, and nuclear factor κB in the wound tissue of mice in wound alone group were significantly higher than those of normal skin tissue of mice in normal skin group (<iq</i=9.253, 4.819, 6.020, <iP</i<0.01) but similar to those in <iL</i. <ilactis</i thermo-sensitive hydrogel group (<iq</i=2.850, 2.735, 2.556, <iP</i>0.05). The peripheral blood leukocyte count, lymphocyte count, and monocyte count of mice in wound alone group were significantly higher than those in normal skin group (<iq</i=3.523, 5.373, 5.279, <iP</i<0.05 or <iP</i<0.01) but similar to those in <iL</i. <ilactis</i thermo-sensitive hydrogel group (<iq</i=0.621, 1.240, 1.293, <iP</i>0.05). The serum L-lactic acid concentration of mice in the three groups remained within the normal range and the overall comparison among them was not statistically significant (<iF</i=4.095, <iP</i>0.05). <bConclusions:</b The <iL</i. <ilactis</i thermo-sensitive hydrogel was safe to use locally on the wounds of diabetic mice with full-thickness skin defects. It can produce and deliver lactic acid in situ, promote the polarization of macrophages from M1 to M2, reshape the wound healing microenvironment, and promote efficient wound healing.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The objective of this analysis was to assess the effectiveness, safety and cost-effectiveness of gastric electrical stimulation (GES) for the treatment of chronic, symptomatic refractory gastroparesis and morbid obesity. GASTROPARESIS - EPIDEMIOLOGY: Gastroparesis (GP) broadly refers to impaired gastric emptying in the absence of obstruction. Clinically, this can range from the incidental detection of delayed gastric emptying in an asymptomatic person to patients with severe nausea, vomiting and malnutrition. Symptoms of GP are nonspecific and may mimic structural disorders such as ulcer disease, partial gastric or small bowel obstruction, gastric cancer, and pancreaticobiliary disorders. Gastroparesis may occur in association with diabetes, gastric surgery (consequence of peptic ulcer surgery and vagotomy) or for unknown reasons (idiopathic gastroparesis). Symptoms include early satiety, nausea, vomiting, abdominal pain and weight loss. The majority of patients with GP are women. The relationship between upper gastrointestinal symptoms and the rate of gastric emptying is considered to be weak. Some patients with markedly delayed gastric emptying are asymptomatic and sometimes, severe symptoms may remit spontaneously. Idiopathic GP may represent the most common form of GP. In one tertiary referral retrospective series, the etiologies in 146 GP patients were 36% idiopathic, 29% diabetic, 13% postgastric surgery, 7.5% Parkinson's disease, 4.8% collagen vascular disorders, 4.1% intestinal pseudoobstruction and 6% miscellaneous causes. The true prevalence of digestive symptoms in patients with diabetes and the relationship of these symptoms to delayed gastric emptying are unknown. Delayed gastric emptying is present in 27% to 58% of patients with type 1 diabetes and 30% with type 2 diabetes. However, highly variable rates of gastric emptying have been reported in type 1 and 2 diabetes, suggesting that development of GP in patients with diabetes is neither universal nor inevitable. In a review of studies examining gastric emptying in patients with diabetes compared to control patients, investigators noted that in many cases the magnitude of the delay in gastric emptying is modest. GP may occur as a complication of a number of different surgical procedures. For example, vagal nerve injury may occur in 4% to 40% of patients who undergo laparoscopic fundoplication for gastroesophageal reflux disease. The prevalence of severe, refractory GP is scantily reported in the literature. Using data from a past study, it has been estimated that the prevalence of severe, symptomatic and refractory GP in the United States population is 0.017%. Assuming an Ontario population of 13 million, this would correspond to approximately 2,000 people in Ontario having severe, symptomatic, refractory GP. The incidence of severe refractory GP estimated by the United States Food and Drug Administration (FDA) is approximately 4,000 per year in the United States. This corresponds to about 150 patients in Ontario. Using expert opinion and FDA data, the incidence of severe refractory GP in Ontario is estimated to be about 20 to 150 per year. To date, there have been no long-term studies confirming the beneficial effects of maintaining euglycemia on GP symptoms. However, it has been suggested that consistent findings of physiologic studies in healthy volunteers and diabetes patients provides an argument to strive for near-normal blood glucose levels in affected diabetes patients. Dietary measures (e.g., low fibre, low fat food), prokinetic drugs (e.g., domperidone, metoclopramide and erythromycin) and antiemetic or antinausea drugs (e.g, phenothiazines, diphenhydramine) are generally effective for symptomatic relief in the majority of patients with GP. For patients with chronic, symptomatic GP who are refractory to drug treatment, surgical options may include jejunostomy tube for feeding, gastrotomy tube for stomach decompression and pyloroplasty for gastric emptying. Few small studies examined the use of botulinum toxin injections into the pyloric sphincter. However, the contribution of excessive pyloric contraction to GP has been insufficiently defined and there have been no controlled studies of this therapy. Treatment with GES is reversible and may be a less invasive option compared to stomach surgery for the treatment of patients with chronic, drug-refractory nausea and vomiting secondary to GP. In theory, GES represents an intermediate step between treatment directed at the underlying pathophysiology, and the treatment of symptoms. It is based on studies of gastric electrical patterns in GP that have identified the presence of a variety of gastric arrhythmias. Similar to a cardiac pacemaker, it was hypothesized that GES could override the abnormal rhythms, stimulate gastric emptying and eliminate symptoms. Obesity is defined as a body mass index (BMI) of at last 30 kg/m(2). Morbid obesity is defined as a BMI of at least 40 kg/m(2) or at least 35 kg/m(2) with comorbid conditions. Comorbid conditions associated with obesity include diabetes, hypertension, dyslipidemias, obstructive sleep apnea, weight-related arthropathies, and stress urinary incontinence. In the United States, the age-adjusted prevalence of extreme obesity (BMI ≥ 40 kg/m(2)) for adults aged 20 years and older has increased significantly in the population, from 2.9% (1988-1994) to 4.7% (1999-2000). An expert estimated that about 160,000 to 180,000 people are morbidly obese in Ontario. Diet, exercise, and behavioural therapy are used to help people lose weight. Bariatric surgery for morbid obesity is considered an intervention of last resort for patients who have attempted first-line forms of medical management. Gastric stimulation has been investigated for the treatment of morbid obesity; the intention being to reduce appetite and induce early satiety possibly due to inhibitory effects on gastric motility and effects on the central nervous system (CNS) and hormones related to satiety and/or appetite. Possible advantages to GES for the treatment of morbid obesity include reversibility of the procedure, less invasiveness than some bariatric procedures, e.g., gastric bypass, and less side effects (e.g., dumping syndrome). Electrical stimulation is delivered via an implanted system that consists of a neurostimulator and 2 leads. The surgical procedure can be performed via either an open or laparoscopic approach. An external programmer used by the physician can deliver instructions to the GES, i.e., adjust the rate and amplitude of stimulation (Figure 1). GES may be turned off by the physician at any time or may be removed. The battery life is approximately 4-5 years For treatment of GP, the GES leads are secured in the muscle of the lower stomach, 10 cm proximal to the pylorus (the opening from the stomach to the intestine), 1 cm apart and connected to an implantable battery-powered neurostimulator which is placed in a small pocket in the abdominal wall For treatment of morbid obesity, GES leads are implanted along the lesser curvature of the stomach where the vagal nerve branches spread, approximately 8 cm proximal to the pylorus. However, the implant positioning of the leads has been variably reported in the literature. The Enterra Therapy System and the Transcend II Implantable Gastric Stimulation System (Medtronic Inc.) are both licensed as class 3 devices by Health Canada (license numbers 60264 and 66948 respectively). The Health Canada indications for use are: ENTERRA THERAPY SYSTEM: "For use in the treatment of chronic intractable (drug-refractory) nausea and vomiting." "For use in weight reduction for obese adults with a body mass index greater than 35."The GES device that is licensed by Health Canada for treatment of GP, produces high-frequency GES. Most clinical studies examining GES for GP have used high-frequency (4 times the intrinsic slow wave frequency, i.e., 12 cycles per minute), low energy, short duration pulses. This type of stimulation does not alter gastric muscular contraction and has no effect on slow wave dysrhythmias. The mechanism of action is unclear but it is hypothesized that high-frequency GES may act on sensory fibers directed to the CNS. The GES device licensed by Health Canada for treatment of morbid obesity produces low-frequency GES, which is close to or just above the normal/native gastric slow wave cycle (approximately 3 cycles/min.). This pacing uses low-frequency, high-energy, long-duration pulses to induce propagated slow waves that replace the spontaneous ones. Low-frequency pacing does not invoke muscular contractions. Most studies examining the use of GES for the treatment of morbid obesity use low-frequency GES. Under normal circumstances, the gastric slow wave propagates distally and determines the frequency and propagation direction of gastric peristalsis. Low-frequency GES aims to produce abnormal gastric slow waves that can induce gastric dysrhythmia, disrupt regular propagation of slow waves, cause hypomotility of the stomach, delay gastric emptying, reduce food intake, prolong satiety, and produce weight loss. In the United States, the Enterra Therapy System is a Humanitarian Use Device (HUD), meaning it is a medical device designated by the FDA for use in the treatment of medical conditions that affect fewer than 4,000 individuals per year. The Enterra Therapy System is indicated for "the treatment of chronic, drug- refractory nausea and vomiting secondary to GP of diabetes or idiopathic etiology" (not postsurgical etiologies). GES for morbid obesity has not been approved by the FDA and is for investigational use only in the United States. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The objective of this systematic review is to synthesize the eligible evidence of patients' experience of engaging and interacting with nurses, in the medical-surgical ward setting.This review will consider the following questions: Communication is a way in which humans make sense of the world around them. Communication takes place as an interactive two-way process or interaction, involving two or more people and can occur by nonverbal, verbal, face-to-face or non-face-to-face methods. Effective communication is described to occur when the sender of a message sends their message in a way that conveys the intent of their message and then is understood by the receiver of the message. As a result of the communication from both the sender and the receiver of the message a shared meaning is created between both parties.Communication can therefore be viewed as a reciprocal process. In the health care literature the terms communication and interaction are used interchangeably.Communication failures between clinicians are the most common primary cause of errors and adverse events in health care. Communication is a significant factor in patient satisfaction and complaints about care. Communication plays an integral role in service quality in all service professions including health care professions.Within healthcare, quality care has been defined by the Institute of Medicine as 'care that is safe, effective, timely, efficient, equitable and patient-centred'. Patient-centered care is defined as 'care that is respectful of and responsive to individual patient preferences, needs and values, and ensuring that patient's values guide all clinical decisions. Patient centered-care encompasses the 'individual experiences of a patient, the clinical service, the organizational and the regulatory levels of health care'. At the individual patient level, patient-centered care is care that is 'provided in a respectful manner, assures open and ongoing sharing of useful information in an ongoing manner and supports and encourages the participation of patients and their families'. Healthcare organizations that are patient-centered engage patients as partners and hold human interactions as a pillar of their service.The deepening evidence base for principles and practice of patient-centered care has resulted in increasing recognition of, and greater focus on, the engagement of patients, and the value and benefit of patient engagement. Contemporary healthcare policy across the globe increasingly supports the engagement of patients as partners in all aspects of their own health care and also in systemic quality improvement. In 2005, the World Health Organization's (WHO) World Alliance for Patient Safety established the Patients for Patient Safety program, to improve patient safety globally in collaboration with patient advocates across the world. As a global initiative, Patients for Patient Safety 'believes that safety will be improved if patients are placed at the center of care and included as full partners'.In 2011 the United States of America Department of Health and Human Services announced its commitment of one billion US dollars of federal funding under The Patient Protection and Affordable Care Act 2010 and launched the Partnership for Patients initiative. The Partnership for Patients public-private consortium, which focuses on patient safety improvements and draws membership from federal government agencies and over 8000 health care providing organizations and individuals, views patients 'as essential partners in improving safety and quality' and 'their participation as active members of their own healthcare team is an essential component of making healthcare safer and reducing readmission'.In Australia, as part of national health care reforms to improve access to care, the efficiency of care and public transparency of the performance and funding of health services, the Australian Health Ministers endorsed the 10 National Safety and Quality Health Service Standards (NSQHSS) in 2011 and the Australian Safety and Quality Goals for Health Care (The Goals) in 2012. The NSQHSS focus on partnerships with health consumers in their own care and treatment and also in health service planning, the design of care and service monitoring and evaluation. Standard 1 - Governance for Safety and Quality, and Standard 2 - Partnering with Consumers, are required to be integrated within all of the other eight Standards.With patient safety and quality being core to the delivery of care the Safety of Care, Appropriateness of Care and Partnering with Consumers goals have been identified as the three areas that will make up the goals over the next five years until 2017. The Australian Commission on Safety and Quality in Health Care, in providing further justification for the focus on these three areas, states:The third priority area of The Goals, Partnering with Consumers, reflects patient-centered care practice by ensuring 'that there are effective partnerships between consumers and healthcare providers and organizations at all levels of healthcare provision, planning and evaluation'. Specifically, 'Consumers and healthcare providers understand each other when communicating about care and treatment and health care organizations are health literate organizations''.As healthcare focuses on providing services that are patient-centered and methods to ensure this occurs, patients' voice and experience of health care provision is increasingly being sought from an organizational quality improvement perspective. Patients are being surveyed on their healthcare experience across interpersonal areas such as being provided the opportunity by their health professional to ask questions, the level of involvement in their own care and whether they were shown courtesy, treated with respect and listened to carefully by their health professional.Surveys of patients' satisfaction with their care are now being superseded by surveys of patient experiences of care. However, current methods used to collect and use information from patients about their care is often retrospective, provides inadequate real time data and is not effective in creating action to produce change at the individual patient level. Methods which focus on including the patient and their information in real-time are considered by many to be crucial to the advancement of improved health outcomes and the reduced costs that are required of health care to be sustainable. One such method is patient-centered communication.The nurse-patient interaction is a core component of nursing science and high quality nursing care. Fleisher et al. contend that 'the main intention of communication and interaction, in the health setting, is to influence the patient's health status or state of well-being'. As a profession, nursing predominately requires communicating with, and relating to, patients at the individual level. In the hospital setting nurses undertake many of their patient related duties in a face-to-face manner with the patient at the bedside and these moments can facilitate effective interaction to occur between the nurse and the patient, which is patient-centered. McCabe et al. state that patient-centered communication as "defined by Langewitz et al. as 'communication that invites and encourages the patient to participate and negotiate in decision-making regarding their own care'.''However, qualitative studies by McCabe and Wellard et al, highlighted that nurses interact with patients only when performing administrative or functional activities and nursing 'practice was predominately task-orientated'. The outcome of these studies are supported by Maurer et al. in their report on the tools and strategies available to support patient and family engagement in the hospital setting. Maurer et al. identified that current strategies 'are not attuned to patient and family member experiences of hospitalization' and that most tools and strategies were 'more reflective of health professional and hospital views and the organization of their work'. The report identified a gap in the initiation of engagement, which is not driven by the patients and families' needs and preferences as they occur but by the 'opportunities that the hospital makes available'.McCabe et al. also argue that nurses' attending behavior, that is their 'accessibility and readiness to listen to patients through the use of non-verbal communication' requires that they have the underpinning elements of 'genuineness, warmth and empathy' all of which are components of patient-centered communication. McCabe et al. observed that 'that nurses do not always communicate in a patient-centered way'.According to Fleischer et al. 'The listening behavior in the way of listening and asking actually is the beginning of the nurse-patient communication relationship' McCabe et al. state that the lack of recognition and support by healthcare organizations of the connection and subsequent importance of patient-centered communication in the provision of high quality care has promulgated a culture averse to patient centered communication and is a significant factor in reducing the value that nurses place on providing patient-centered communication to patients.It is apparent that tensions exist between service quality and patient-centered care principles and practice. The impact of this tension on care and the patient as an individual is reflected in the literature. McCabe et al. claim that the use of non-patient-centered types of communication can negatively affect a patient's sense of well-being and security. Horvey et al. detail patient and family member experiences of not being listened to by their health care providers and describe the resulting consequences to be as severe as the death of the patient during their hospital stay. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The objective of this review is to identify the best available quantitative evidence related to the effectiveness of school-based family asthma educational programs on the quality of life and number of asthma exacerbations of children aged five to18 years with a diagnosis of asthma. Asthma is a serious public health issue globally and nationally. The World Health Organization (WHO) Global Asthma Report 2014 estimates that 334 million people worldwide currently suffer from asthma. In the United States, asthma currently affects about 25 million people. Although asthma can occur at any age, it most often begins early in life, and is the most common non-communicable disease among children. Approximately 14% of the world's children have asthma. In the United States, 7.1 million children have asthma. Globally, the burden of asthma, measured by disability and premature death, is greatest in children approaching adolescence (ages 10-14). Asthma is also a serious economic concern in primary health care worldwide. In the United States, the estimated total cost of asthma to society was US$56 billion in 2007, or US$3259 per person. In 2008 asthma caused 10.5 million missed days from school and 14.2 missed days from work for caregivers. The estimated total cost of loss of productivity resulting from missed school or work days is US$3.8 billion per year, and premature death US$2.1 billion per year. Globally, asthma ranks 14 in terms of disability adjusted life years (DALYs), which are the number of years lost to ill health, disability or death attributed to asthma. According to a 2011 European study, the estimated total cost of asthma was €19.3 billion among people aged 15 to 64 years. A study conducted in the Asia-Pacific region reported that the direct and indirect costs of asthma per person ranged from US$184 in Vietnam to US$1189in Hong Kong in 2000. A Canadian study showed that C$184 loss of productivity during one week was attributed to asthma in 2012. In Australia, AU$655 million was spent on asthma for 2008-09.Asthma is a chronic respiratory disease that affects millions of people of all ethnicities, ages and genders worldwide. The pathophysiology of asthma is multifaceted, and is characterized by restriction of airflow into and out of the lungs, airway inflammation with increased mucus production, and bronchial hyper-reactivity caused by exposure to environmental irritants and chemicals, often referred to as triggers, which in some cases are modifiable. Asthma triggers include respiratory infections, weather changes, stress, excitement, exercise and other physical activities, allergic hypersensitivity reactions, food additives, animal dander, dust mites, cockroaches, outdoor and indoor pollutants, certain medications and cigarette smoke. Asthma is characterized by recurrent, episodic, reversible symptoms often referred to as asthma exacerbations, or asthma attacks. Asthma symptoms include coughing, shortness of breath, chest tightness and wheezing that most frequently occur at night or in the early morning. Asthma symptoms vary in severity and frequency in affected individuals, and can occur several times a day or week. Asthma symptoms may be mild, moderate, or severe, and are classified according to presenting symptoms and quantitative measurements of lung function using a peak expiratory flow meter (PEF), or of forced expiratory volume in one second (FEV1). Asthma symptoms can be so severe that, if left untreated, death can occur.Exacerbations of asthma symptoms often result in school and work absenteeism, activity intolerance and emergency hospital visits for asthma. Nocturnal asthma exacerbations frequently cause sleeplessness, which may result in daytime fatigue. Asthma symptoms can interfere and disrupt activities of daily life, and can have an unfavorable impact on the quality of life for people with the disease, including children and their caregivers. For this review, quality of life represents how well the asthmatic child is able to manage symptoms of the disease and lead a normal healthy life. Caregiver refers to the primary person who takes care of a child with asthma. Family refers to the caregiver and the child.According to the United States Centers for Disease Control and Prevention (CDC), epidemiologists and clinical researchers concur that the burden of asthma is higher among children compared to adults. Asthma prevalence in children varies within and across countries. Asthma disparities also exist along ethnic and racial lines. The International Study of Asthma and Allergies in Childhood (ISAAC) quantified the prevalence of asthma symptoms of children from around the world. In the United States, non-Hispanic Black and Puerto Rican children have higher asthma prevalence compared to Caucasian children. Children from the Ivory Coast, Costa Rica and Wales have higher asthma prevalence compared to children from Kenya, Brazil and England respectively. Indigenous Australians, Aboriginal and Torres Strait Islander Australian children have a higher prevalence of asthma compared to non-Indigenous Australian children. The international prevalence of asthma prompted governments and communities to create initiatives and strategies to address this public health issue.The global burden of asthma led to the development of the Global Initiative for Asthma (GINA). Formed in 1993, in collaboration with theNational Heart, Lung, and Blood Institute, National Institutes of Health, United States of America and the WHO, GINA's goals include working with healthcare providers and public health officials worldwide to reduce asthma prevalence, morbidity and mortality. In an effort to increase public awareness of the global burden of asthma, GINA created World Asthma Day, which is held annually on the first Tuesday in May. The burden of asthma in the United States fostered the creation of the National Asthma Education and Prevention Program (NAEPP). This program is designed to raise awareness about asthma and the major public health concern it poses to society. In addition to conducting asthma prevention activities, NAEPP collaborates with other stakeholders to develop asthma educational programs for minority populations who are disproportionately affected by asthma. The program believes that adequate control of asthma, through modern treatment and educational programs, can be reinforced by the development of partnerships with caregivers, schools and healthcare providers. The NAEPP Expert Panel Report 3, Guidelines for the Diagnosis and Management of Asthma (EPR-3), has a provision that specifies that asthma education programs for children should include their caregivers. Caregivers' involvement is crucial for achieving the goals of asthma management in children, which supports the interest of GINA and NAEPP to include caregivers in school-based asthma education programs for children. The guidelines recommend education for asthma management should occur at all points of care, including schools. According to the EPR-3, schools are ideal locations to facilitate asthma education programs because they provide access to large numbers of children in an environment in which they are accustomed to learning. The long term effects of these approaches are improved healthcare practices, reduced mortality and morbidity, and reduced costs of asthma care.Although there is no cure for asthma, research evidence has demonstrated that asthma symptoms can be well-controlled with the appropriate medications, adherence to treatment, avoidance of asthma triggers, and education about disease management. Research studies that have investigated the effectiveness of school-based asthma education programs that have included caregivers have demonstrated beneficial effects of these programs on the quality of life and disease management of children with asthma, versus no school-based family asthma education programs.A randomized controlled trial (RCT) conducted by Clark et al. that included 835 children and their parents examined the effects of comprehensive school-based asthma education programs on symptoms, grades and school absences, and parents' asthma management practices. The interventions consisted of six components for children, their parents, classmates and school personnel. One of the six components included "Open Airways for Schools" disease management training for children, which also included handouts and homework for the parents. One of the five interventions for the parents included school fairs with asthma care questions and answers sessions to discuss the frequency and type of asthma symptoms of their children. Results of this study demonstrated that 24 months post intervention, children from the intervention groups had better disease management, which included improved control of daytime and nighttime symptoms, and reduced absences from school and work related to asthma exacerbations, compared to the children from the control group.In another study, Bruzzese et al. conducted a pilot RCT that included 24 families. Each family consisted of an asthmatic child and a caregiver. The study examined the effects of a two-month, school-based asthma education program. The interventions consisted of six interactive 75-minute group sessions for students, held once a week for six weeks, and five 90-minute group sessions for caregivers, held once a week. The student sessions were led by a developmental psychologist, and one of the lesson topics included prevention and management of asthma. The group sessions for caregivers were led by a clinical psychologist, and one of the lesson topics included asthma self-management of their children. The interventions resulted in positive short term changes in family relations and an overall improved health status for the children. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The trafficking of falsified and substandard medicinal products is a global socio-economic problem, which poses a serious threat to economy and health of populations of most countries, including the Russian Federation. To identify the main achievements and challenges in the fight against trafficking of falsified and substandard medicinal products in the Russian Federation, to formulate possible solutions to these problems. The study of criminal cases and statistical information about the level of crime in the Russian Federation; legal analysis of regulatory legal acts in the sphere of criminal law and turnover of medicinal products; review of scientific and practical publications. The problem of trafficking of falsified and substandard medicinal products in the Russian Federation was publicly discussed in the late 1990s - early 2000-ies, first in the media and special editions, later this phenomenon was the subject of extensive discussions at international conferences, in public authorities and public circles. However, the most significant results in tackling this problem were achieved only in the last 5 years.Thus, in 2010, the Russian Federation first joined the annual international police operation under the code name Pangaea, held since 2008 on the initiative of Interpol and the Medicines and Healthcare products Regulatory Agency of the World Health Organization (MHRA WHO). From year to year, the special operation Pangea unites the efforts of many countries from different continents and aims to eliminate transnational criminal groups operating through a global network the Internet. In 2010, as a result of large-scale international inspections 1 200 Internet sites were revealed, through which the fake medicines were spread and 10,000 boxes of medicines were seized, making more than a million falsified tablets in the amount of 2.6 million USA dollars. In 2011, in a special operation Pangea IV was attended by 165 different organizations from 81 countries, including 72 customs, 30 regulators, 26 police and representatives of Interpol from 37 countries. Closed 13 495 illegal websites, seized about 8,000 packages of fake medicines, containing about 2.5 million doses. In 2015, the special operation Pangea VIII was held on the territory of 115 member States of Interpol. In the Russian Federation this operation was carried out jointly by the Ministry of internal Affairs, Federal customs service, the Federal Service on Surveillance in Healthcare of Russian Federation, the Federal Drug Control Service of the Russian Federation and their regional subdivisions. As a result of this operation 34 criminal cases were initiated in our country in connection with hard drugs, falsified and substandard medicinal products and biologically active additives under the guise of high-performance drugs. Special attention during the operation was given to uncontrolled Internet sale of medicinal products and biologically active additives at a price, which was significantly higher than the actual costs, under the guise of highly effective means of treatment for various diseases. In General, in the Russian Federation 448 administrative offences were identified, which resulted in withdrawal of more than 268 thousand units of medicines from illegal circulation, worth over 9 million rubles; 40 thousand falsified and substandard preparations Contex and Durex for personal contraception were withdrawn. The mobile laboratory has conducted screening program of quality in respect of 294 samples of medicines. It identified 20 parties of dubious authenticity. A message about 264 Internet sites which sell medicines in violation of applicable Russian legislation was sent to the coordinating headquarters of the General Secretariat of Interpol. An official statement with Internet service providers on cessation of activities at these sites was issued [1].On 26-28 October 2011, Moscow hosted an international high-level conference on counterfeiting of medicinal products, which was attended by more than 750 professionals in the field of law and pharmacy from different countries, including USA, China, countries of the European Council and the Commonwealth of Independent States. At the end of the conference the Convention on the counterfeiting of medicinal products and similar crimes involving threats to public health, was signed, which was called Medicrime [2]. The Convention was signed by representatives of Austria, Germany, Israel, Iceland, Italy, Cyprus, Portugal, Russian Federation, Finland, France, Ukraine, Switzerland. The Medicrime Convention is the first legal agreement in the field of criminal law aimed at criminalizing the trafficking of falsified and substandard medicinal products, as well as aimed at providing legal support for the investigation of these crimes at the international level. The positive side of the Convention of the Council of Europe Medicrime is that it is open for signature not only by member States of the Council of Europe and the European Union, but also by States that are not members of the Council of Europe, but participated in the elaboration of a Convention or have observer status with the Council of Europe. In addition, the Convention is open for signature by any other state at the invitation of the Committee of Ministers of the Council of Europe. The Convention introduces the responsibility for the production, storage and distribution of falsified medicinal products, active substances, excipients, components, materials and supplies; the use of falsified documents related to the trafficking of medicinal products (Articles 5, 6, 7). This legal act regulates the cooperation between the health authorities, customs, police and other competent authorities at international and national level (Articles 17, 21, 22).One of the results of the legal implementation of the rules of the Convention Medicrime in the Russian legislation was the adoption of the Federal law of the Russian Federation dated 31.12.2014 No. 532-FZ On amendments to certain legislative acts of the Russian Federation on countering the trafficking of falsified, counterfeit, substandard and unregistered medicines, medicinal devices and falsified biologically active additives [3]. The law came into force on 23 January 2015. In accordance with the Federal Law of the Russian Federation Criminal Code is supplemented by three new articles: Article 235.1. Illegal manufacture of medicines and medicinal devices; article 238.1. Circulation of falsified, substandard and unregistered medicines, medicinal devices and trafficking in falsified biologically active additives; article 327.2. Forgery of documents on medicines or medicinal devices or the packaging of medicines or medicinal devices [4].Although there are some deficiencies in the wording of these penal regulations, we believe their introduction in the Criminal Code is a serious step forward by the state to neutralize the trafficking of falsified and substandard medicinal products, and consequently to ensure the safety of the nation's health and economic security of the country. The inclusion of these special articles in the Criminal Code will allow to analyze statistical information on their practical application by the authorities, to investigate crimes, to fully implement the monitoring, prediction and prevention of these socially dangerous acts. It will contribute to the development and implementation of effective management decisions on the identification and investigation of crimes of this type.In recent years, in the framework of the joint preventive measures to combat the circulation of falsified and substandard medicinal products there has been some constructive interaction between law enforcement and regulatory authorities, primarily by the bodies of internal Affairs and units of the Federal Service on Surveillance in Healthcare of Russian Federation. During 2010-2013 researches in the field of Economics, International and Criminal Law, Criminology, Criminalistics, Operatively-search activity, devoted to the development of measures to neutralize trafficking of falsified and substandard medicinal products, were developed as reserved dissertations. The legislation in the sphere of protection of public health and the turnover of medicines was updated.Thus, trafficking of falsified and substandard medicinal products in the Russian Federation at present is not an appeal and not a theory, but there is a real activity of specialists in the field of law and pharmacy, with a certain legal framework, scientific and methodological support.However, this problem is not yet solved. The Indicator of withdrawn from circulation of falsified and substandard drugs remains high. In Russia by the end of 2014, 1 109 batches of substandard, falsified and counterfeit medicines were detected and withdrawn from circulation. The volume of state quality control of medicines coming into circulation accounted for 16,3% [5]. A serious danger is the increased level of falsification of pharmaceutical substances, 80% of which is imported to the Russian Federation on indirect contracts from China and India without proper control at customs posts.The study of criminal cases and statistics about the trafficking of falsified and substandard medicinal products in the Russian Federation leads to the conclusion that this crime is of a latent character. Every year about 50 crimes are detected, for only 30-35 of them criminal cases are initiated, and only 15-20 of the investigated criminal cases are submitted to court. This indicates serious problems in proving the guilt of the perpetrators of these crimes and bringing them to justice. The fight against this crime requires long and reliable operational development of criminal groups, qualified investigation and trial. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Canada has among the highest rates of childhood-onset IBD in the world. Over 7000 children and youth under 18 years old are living with IBD in Canada, and 600 to 650 children under 16 years old are diagnosed annually. While the peak age of onset of IBD is highest in the second and third decades of life, over the past two decades incidence has risen most rapidly in children under 5 years old. The treatment of children with IBD presents important challenges including therapeutic choices, risk of adverse events to medications, psychosocial impact on the child and family, increased cost of health care and the implications of the transition from pediatric to adult care. Despite the unique circumstances faced by children and their families, there is a lack of research to help understand the causes of the rising incidence and the best therapies for children with IBD. Scientific evidence-and specifically clinical trials of pharmaceuticals-are too often extrapolated from adult research. Health care providers must strive to understand the unique impact of childhood-onset IBD on patients and families, while researchers must expand work to address the important needs of this growing patient population. In 2018, there are over 7000 children and youth under 18 years old living with IBD in Canada, and 600 to 650 young children (under 16 years) diagnosed every year.The number of children in Canada living with IBD is growing rapidly, increasing 50% in the first decade of the 21st century.Inflammatory bowel disease is still rare in children younger than 5 years of age, but it is occurring in such young children more often than in the past.Children with IBD are different from adults. For example, delayed growth, extent of disease and difficulties encountered during adolescence are all unique to the pediatric experience.We must consider the psychosocial well-being of both children and their families, given that caring for a child with IBD can affect the global functioning of families.Treatment approaches in children sometimes differ from those in adults. However, to date, all effective therapies in adults have also been effective in children. There is great need for clinical trials of new therapies in children so that they have equal access to emerging treatments and optimal pediatric dosing can be established. Rates of new diagnoses in children under 16 years old were increasing most rapidly in Ontario (increased 5.8% per year) and Quebec (increased 2.8% per year).Nova Scotia has the highest rate of pediatric IBD, with lower rates in Quebec and Ontario. However, even Ontario and Quebec have higher rates of pediatric IBD than most countries in the world.Inflammatory bowel disease is caused by the interaction between genes, environmental risk factors, the microbiome and the immune system. Since children experience shorter exposures and possibly fewer environmental risk factors, the interaction between these risk factors and genes may be stronger with childhood-onset IBD.The microbiome is mostly established in early childhood and is affected by a number of factors such as environment, diet, pregnancy/delivery factors and antibiotic use. Changing the microbiome to a healthier state may prevent the disease and may also be a novel therapeutic target to treat active inflammation in children with IBD.Children with IBD are different from adults. They are more likely to have extensive involvement of their intestines, especially in ulcerative colitis, and are at risk for growth impairment, osteoporosis, and psychosocial difficulties affecting their families.Children with IBD may incur more direct health costs for treatment of their IBD compared with adults. However, this is not universally true for all children because those who are very young at diagnosis (2 to 6 years old) may have milder disease or respond better to medications. This may result in decreased use of the health system, fewer hospitalizations and less risk of surgery than older children and adolescents.The choice of treatments for children with IBD may be different from that of adults. It is important to consider pediatric-specific disease considerations. Delayed growth, deficient bone development, psychosocial well-being of the child and family, disease extent, disease severity and risk of poor outcomes during transition from pediatric to adult health care are all important considerations when choosing the best treatment for children and adolescents.While the medications used are similar in children and adults with IBD, research to assess the effectiveness and safety of these medications in children (especially very young children) is sparse.Children with IBD may be more responsive to treatment than adults because they are more likely to have inflammatory (rather than stricturing) disease. Therefore, treating the inflammation earlier in the course of disease may prevent long-term complications such as strictures, obstruction, need for surgery and need for hospitalization.Some medications used in IBD have unique or more pronounced risks in children compared with adults. For example, chronic prednisone use is associated with growth impairment and stunting in children. Anti-TNF biologics are the only medications proven to improve growth in children with Crohn's disease and should be considered early in the course of disease in patients with severe IBD or those with marked growth impairment at the time of diagnosis.Some medications are used differently, depending on the sex of the patient. For example, azathioprine (with or without biologics) is associated with hepatosplenic T cell lymphoma (and other forms of lymphoma) in adolescent and young adult males more often than females. Methotrexate is associated with birth defects in the growing fetus and therefore should be avoided in adolescent and adult women of child-bearing age who are not using two or more forms of birth control.A small group of children, typically presenting in the first two years of life, have single-gene mutations that cause an IBD-like bowel disease and also immune system dysfunction. These patients may not respond to traditional IBD medications and may require therapies such as bone marrow transplant. Canada is leading research efforts to investigate, diagnose and treat this small group of very vulnerable children.Inflammatory bowel disease (especially when it is active) can affect school attendance, social interactions, concentration and learning. Schools should be aware of the implications of IBD and make allowances for these factors in children with active inflammation and symptoms to optimize their chances of academic and social success. We have limited knowledge on what causes IBD in children and why rates are rising most rapidly in young children. We must better understand the interaction between genes, the environment, the immune system and the microbiome in order to better prevent and treat the disease.Treatment for infants with IBD-like illnesses and single-gene mutations is limited. Future research should work towards identifying these children and learning how best to treat them.There are few clinical trials for biologics in children, and most exclude very young children. Support for such trials is important to understand whether the treatments work, how they should optimally be given and whether they are safe for young children with IBD.Considering the effectiveness of dietary therapies for children with Crohn's disease (exclusive enteral nutrition), we should work to understand how diet affects intestinal inflammation and the microbiome in order to better use dietary therapies to treat IBD.Health services researchers, health care providers and policy-makers should work together to understand why variation in the access to treatment and medical care of children with IBD exists. We must work together to improve the quality of care provided to these children and ensure they have the highest quality of care.Psychosocial implications of IBD in children and their families are of importance to long-term and overall well-being. Children with a chronic, incurable disease are at risk for mental illness associated with their disease. We should design interventions to improve the psychosocial status, mental health and quality of life of children with IBD and their families.While nonlive immunizations are safe for children with IBD, we must understand how to improve their effectiveness in children who are immunosuppressed. While the peak onset of IBD occurs in the second or third decades of life, the frequency of new diagnoses in younger children is rising rapidly. In Canada, the fastest growing group of newly diagnosed people with IBD are children aged under 5 years (termed 'very early onset [VEO] IBD). These young children have not been included in clinical trials of new medications, resulting in a lack of scientific evidence of safety and effectiveness of treatments in this group, and clinical experience has shown that they do not respond to usual medications used for the majority of children with IBD. Providing children with IBD with high-quality care and social support also poses other challenges to care providers, families and the health system. This section will focus on the unique challenges facing Canadian children with IBD. A complete overview of the objectives, working committees and methodology of creating the report can be found in the supplemental file, Technical Document.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Styrene-acrylonitrile trimer (SAN Trimer) is a mixture of isomers formed by the condensation of two moles of acrylonitrile and one mole of styrene and has a molecular weight of 210. The mixture is composed of two structural forms: 4-cyano-1,2,3,4-tetrahydro-a-methyl-1-naphthaleneacetonitrile (THNA, CAS No. 57964-39-3) and 4-cyano-1,2,3,4-tetrahydro-1-naphthalenepropionitrile (THNP, CAS No. 57964-40-6). The THNA form consists of four stereoisomers. [Structure:see text]. The THNP form consists of two stereoisomers. [Structure:see text]. SAN Trimer is a by-product of the production of acrylonitrile styrene plastics and is created in specific manufacturing processes for polymers of acrylonitrile and styrene. In June 1998, due to community concerns about the toxicity of SAN Trimer, it was nominated to the NTP for carcinogenicity testing by a member of Congress. Male and female F344/N rats were exposed to SAN Trimer in feed in perinatal and postnatal studies for 7 weeks, 18 weeks, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium and Escherichia coli, and in rat reticulocytes, leukocytes, liver cells, and brain cells. In vivo comet and micronucleus assays were performed in the juvenile rats. 7-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 250, 500, 1,000, 2,000, or 4,000 ppm SAN Trimer (equivalent to average daily doses of approximately 50, 90, 175, 270, or 410 mg SAN Trimer/kg body weight to males and 45, 90, 185, 295, or 430 mg/kg to females) for 2 weeks postweaning; the dams of these rats were fed the same concentrations of SAN Trimer from gestation day 7 until the pups were weaned. One 4,000 ppm male rat died 3 days after weaning; all other rats that started the postweaning phase survived to the end of the study. Mean body weights of 1,000, 2,000, and 4,000 ppm males and 2,000 and 4,000 ppm females were significantly less than those of the controls; weaning mean body weights were reduced in 4,000 ppm males and females and in 2,000 ppm females. Feed consumption by 2,000 and 4,000 ppm males and females was less than that by the control groups. Thinness in 4,000 ppm male rats was the only clinical finding related to SAN Trimer exposure. Nonneoplastic lesions were observed in the brain, thymus, spleen, liver, kidney, and reproductive organs of males and females and were considered due to overt toxicity. 18-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets of 0, 100, 200, 400, 800, or 1,600 ppm SAN Trimer (equivalent to average daily doses of 10, 20, 40, 80, or 150 mg/kg to males and females) for 3 months postweaning; the dams of these rats were fed the same concentrations from gestation day 7 until the pups were weaned. All rats survived to the end of the study. Mean body weights of 1,600 ppm males and females exposed to 200 ppm or greater were significantly less than those of the controls. At termination, brown staining of the urogenital fur was observed in females exposed to 200 ppm or greater. The liver weights of all exposed groups of males and the spleen weights of 800 and 1,600 ppm males and 1,600 ppm females were significantly greater than those of the controls. There were no significant differences in sperm parameters of male rats or the estrous cyclicity of female rats administered 400, 800, or 1,600 ppm in the diet when compared to the control groups. No exposure-related histopathologic lesions were observed. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female core study rats were fed diets of 0, 400, 800, or 1,600 ppm SAN Trimer (equivalent to average daily doses of approximately 20, 40, or 75 mg/kg to males and 20, 40, or 85 mg/kg to females) for 2 years. Special study groups of 20 males and 20 females were fed the same exposure concentrations and were evaluated at 27, 52, and 78 weeks for hematology and clinical chemistry or at 26, 51, and 77 weeks for urinalysis. The dams of core and special study rats were fed the same concentrations from gestation day 7 until the pups were weaned. Mean body weights of 1,600 ppm males were less than 90% of the controls after week 1; mean body weights of 800 and 1,600 ppm females were less than 90% of the controls after weeks 41 and 13, respectively. Feed consumption by exposed groups of males and females was generally similar to that by the control groups. Brown staining of the urogenital fur was observed in all exposed groups, and the number of animals affected increased with increasing exposure concentration. Rare neoplasms were present in the central nervous system of male and female rats. In the original evaluation, the 800 and 1,600 ppm groups of male rats each had one astrocytoma and one granular cell tumor in the brain. Also in the brain, one 400 ppm female had a granular cell tumor and one control, one 400 ppm, and one 800 ppm female had a mixed cell glioma. In the spinal cord, one astrocytoma was noted in a 1,600 ppm male in the original evaluation. In the expanded review of the spinal cord, one granular cell tumor was found in a 400 ppm male and one meningioma was found in an 800 ppm female. There were statistically significant increases in the incidence of spinal nerve root degeneration in 1,600 ppm males and the incidences of sciatic nerve degeneration in 800 and 1,600 ppm females. More importantly, there were increases in the severities of both nerve lesions in males and in the severity of spinal nerve root degeneration in females. The incidences of bone marrow hyperplasia were significantly increased in 1,600 ppm males and females and 800 ppm females. Incidences of bone marrow granulomatous inflammation were increased in 1,600 ppm males and 800 and 1,600 ppm females, and the increase in the 800 ppm females was significant. Because this lesion is very rare and did not occur in control animals, it should be considered biologically significant. In the liver, the incidence of eosinophilic focus was significantly increased in 1,600 ppm males and the incidences of mixed cell focus were significantly increased in 400 and 1,600 ppm males. Incidences of mixed cell focus were increased in the liver of all exposed groups of females, and the increase was significant in the 1,600 ppm group. The incidence of transitional epithelial hyperplasia of the urinary bladder in 1,600 ppm females was significantly greater than that in the controls. There were significant decreases in the incidences of pituitary gland pars distalis adenoma in 1,600 ppm males and females, and the incidences in both sexes occurred with negative trends. The incidences of mammary gland fibroadenoma occurred in females with a negative trend, and the incidences in 800 and 1,600 ppm females were significantly less than that in the control group. The incidences of mononuclear cell leukemia in all exposed groups of males and females were significantly less than those in the controls. SAN Trimer (Batch 3) was not mutagenic in Salmonella typhimurium strains TA98 or TA100 or in Escherichia coli strain WP2 uvrA/pKM101 in tests conducted with and without exogenous metabolic activation. In vivo, however, results of a comet assay indicated significantly increased levels of DNA damage in brain cells of male and female juvenile rats following administration of SAN Trimer (Batch 3) by oral gavage. Dose-related increases in DNA damage in liver cells of these rats were also observed, but the increases were smaller than those observed in brain cells and were judged to be equivocal in both males and females. Indications of DNA damage following exposure to SAN Trimer were also seen in leukocytes of male and female rats. Increases in male rats were significant, but in females, observed levels of DNA damage did not correlate with dose. Therefore, the results were judged to be positive in males and equivocal in females. In addition to the positive comet assay results, significant increases in the frequencies of micronucleated reticulocytes were observed in peripheral blood of male and female juvenile rats dosed with SAN Trimer. Under the conditions of this 2-year feed study preceded by perinatal exposure, there was no evidence of carcinogenic activity of SAN Trimer in male and female F344/N rats given feed containing 400, 800, or 1,600 ppm SAN Trimer. Exposure to SAN Trimer resulted in increased incidences and/or severities of peripheral nerve degeneration in male and female F344/N rats, increased incidences of nonneoplastic lesions of the bone marrow and liver in male and female F344/N rats, and of nonneoplastic urinary bladder lesions in female F344/N rats. The incidences of pituitary gland adenoma and mononuclear cell leukemia in male and female F344/N rats and mammary gland fibroadenoma in female F344/N rats were decreased.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
This health technology policy assessment will answer the following questions: When should in-room air cleaners be used?How effective are in-room air cleaners?Are in-room air cleaners that use combined HEPA and UVGI air cleaning technology more effective than those that use HEPA filtration alone?What is the Plasmacluster ion air purifier in the pandemic influenza preparation plan?The experience of severe acute respiratory syndrome (SARS) locally, nationally, and internationally underscored the importance of administrative, environmental, and personal protective infection control measures in health care facilities. In the aftermath of the SARS crisis, there was a need for a clearer understanding of Ontario's capacity to manage suspected or confirmed cases of airborne infectious diseases. In so doing, the Walker Commission thought that more attention should be paid to the potential use of new technologies such as in-room air cleaning units. It recommended that the Medical Advisory Secretariat of the Ontario Ministry of Health and Long-Term Care evaluate the appropriate use and effectiveness of such new technologies. Accordingly, the Ontario Health Technology Advisory Committee asked the Medical Advisory Secretariat to review the literature on the effectiveness and utility of in-room air cleaners that use high-efficiency particle air (HEPA) filters and ultraviolet germicidal irradiation (UVGI) air cleaning technology. Additionally, the Ontario Health Technology Advisory Committee prioritized a request from the ministry's Emergency Management Unit to investigate the possible role of the Plasmacluster ion air purifier manufactured by Sharp Electronics Corporation, in the pandemic influenza preparation plan. Airborne transmission of infectious diseases depends in part on the concentration of breathable infectious pathogens (germs) in room air. Infection control is achieved by a combination of administrative, engineering, and personal protection methods. Engineering methods that are usually carried out by the building's heating, ventilation, and air conditioning (HVAC) system function to prevent the spread of airborne infectious pathogens by diluting (dilution ventilation) and removing (exhaust ventilation) contaminated air from a room, controlling the direction of airflow and the air flow patterns in a building. However, general wear and tear over time may compromise the HVAC system's effectiveness to maintain adequate indoor air quality. Likewise, economic issues may curtail the completion of necessary renovations to increase its effectiveness. Therefore, when exposure to airborne infectious pathogens is a risk, the use of an in-room air cleaner to reduce the concentration of airborne pathogens and prevent the spread of airborne infectious diseases has been proposed as an alternative to renovating a HVAC system. Airborne transmission is the spread of infectious pathogens over large distances through the air. Infectious pathogens, which may include fungi, bacteria, and viruses, vary in size and can be dispersed into the air in drops of moisture after coughing or sneezing. Small drops of moisture carrying infectious pathogens are called droplet nuclei. Droplet nuclei are about 1 to 5μm in diameter. This small size in part allows them to remain suspended in the air for several hours and be carried by air currents over considerable distances. Large drops of moisture carrying infectious pathogens are called droplets. Droplets being larger than droplet nuclei, travel shorter distances (about 1 metre) before rapidly falling out of the air to the ground. Because droplet nuclei remain airborne for longer periods than do droplets, they are more amenable to engineering infection control methods than are droplets. Droplet nuclei are responsible for the airborne transmission of infectious diseases such as tuberculosis, chicken pox (varicella), measles (rubeola), and dessiminated herpes zoster, whereas close contact is required for the direct transmission of infectious diseases transmitted by droplets, such as influenza (the flu) and SARS. In-room air cleaners are supplied as portable or fixed devices. Fixed devices can be attached to either a wall or ceiling and are preferred over portable units because they have a greater degree of reliability (if installed properly) for achieving adequate room air mixing and airflow patterns, which are important for optimal effectiveness. Through a method of air recirculation, an in-room air cleaner can be used to increase room ventilation rates and if used to exhaust air out of the room it can create a negative-pressure room for airborne infection isolation (AII) when the building's HVAC system cannot do so. A negative-pressure room is one where clean air flows into the room but contaminated air does not flow out of it. Contaminated room air is pulled into the in-room air cleaner and cleaned by passing through a series of filters, which remove the airborne infectious pathogens. The cleaned air is either recirculated into the room or exhausted outside the building. By filtering contaminated room air and then recirculating the cleaned air into the room, an in-room air cleaner can improve the room's ventilation. By exhausting the filtered air to the outside the unit can create a negative-pressure room. There are many types of in-room air cleaners. They vary widely in the airflow rates through the unit, the type of air cleaning technology used, and the technical design. Crucial to maximizing the efficiency of any in-room air cleaner is its strategic placement and set-up within a room, which should be done in consultation with ventilation engineers, infection control experts, and/or industrial hygienists. A poorly positioned air cleaner may disrupt airflow patterns within the room and through the air cleaner, thereby compromising its air cleaning efficiency. The effectiveness of an in-room air cleaner to remove airborne pathogens from room air depends on several factors, including the airflow rate through the unit's filter and the airflow patterns in the room. Tested under a variety of conditions, in-room air cleaners, including portable or ceiling mounted units with either a HEPA or a non-HEPA filter, portable units with UVGI lights only, or ceiling mounted units with combined HEPA filtration and UVGI lights, have been estimated to be between 30% and 90%, 99% and 12% and 80% effective, respectively. However, and although their effectiveness is variable, the United States Centers for Disease Control and Prevention has acknowledged in-room air cleaners as alternative technology for increasing room ventilation when this cannot be achieved by the building's HVAC system with preference given to fixed recirculating systems over portable ones. Importantly, the use of an in-room air cleaner does not preclude either the need for health care workers and visitors to use personal protective equipment (N95 mask or equivalent) when entering AII rooms or health care facilities from meeting current regulatory requirements for airflow rates (ventilation rates) in buildings and airflow differentials for effective negative-pressure rooms. The Plasmacluster ion technology, developed in 2000, is an air purification technology. Its manufacturer, Sharp Electronics Corporation, says that it can disable airborne microorganisms through the generation of both positive and negative ions. (1) The functional unit is the hydroxyl, which is a molecule comprised of one oxygen molecule and one hydrogen atom. Plasmacluster ion air purifier uses a multilayer filter system composed of a prefilter, a carbon filter, an antibacterial filter, and a HEPA filter, combined with an ion generator to purify the air. The ion generator uses an alternating plasma discharge to split water molecules into positively and negatively charged ions. When these ions are emitted into the air, they are surrounded by water molecules and form cluster ions which are attracted to airborne particles. The cluster ion surrounds the airborne particle, and the positive and negative ions react to form hydroxyls. These hydroxyls steal the airborne particle's hydrogen atom, which creates a hole in the particle's outer protein membrane, thereby rendering it inactive. Because influenza is primarily acquired by large droplets and direct and indirect contact with an infectious person, any in-room air cleaner will have little benefit in controlling and preventing its spread. Therefore, there is no role for the Plasmacluster ion air purifier or any other in-room air cleaner in the control of the spread of influenza. Accordingly, for purposes of this review, the Medical Advisory Secretariat presents no further analysis of the Plasmacluster. The objective of the systematic review was to determine the effectiveness of in-room air cleaners with built in UVGI lights and HEPA filtration compared with those using HEPA filtration only. The Medical Advisory Secretariat searched the databases of MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, INAHATA (International Network of Agencies for Health Technology Assessment), Biosis Previews, Bacteriology Abstracts, Web of Science, Dissertation Abstracts, and NIOSHTIC 2. A meta-analysis was conducted if adequate data was available from 2 or more studies and where statistical and clinical heterogeneity among studies was not an issue. Otherwise, a qualitative review was completed. The GRADE system was used to summarize the quality of the body of evidence comprised of 1 or more studies. There were no existing health technology assessments on air cleaning technology located during the literature review. The literature search yielded 59 citations of which none were retained. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
This review was conducted to assess the effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the treatment of major depressive disorder (MDD). rTMS is a noninvasive way to stimulate nerve cells in areas of the brain. During rTMS, an electrical current passes through a wire coil placed over the scalp. The current induces a magnetic field that produces an electrical field in the brain that then causes nerve cells to depolarize, resulting in the stimulation or disruption of brain activity. Researchers have investigated rTMS as an option to treat MDD, as an add-on to drug therapy, and, in particular, as an alternative to electroconvulsive therapy (ECT) for patients with treatment-resistant depression. The advantages of rTMS over ECT for patients with severe refractory depression are that general anesthesia is not needed, it is an outpatient procedure, it requires less energy, the simulation is specific and targeted, and convulsion is not required. The advantages of rTMS as an add-on treatment to drug therapy may include hastening of the clinical response when used with antidepressant drugs. The Medical Advisory Secretariat used its standard search strategy to locate international health technology assessments and English-language journal articles published from January 1996 to March 2004. Some early meta-analyses suggested rTMS might be effective for the treatment of MDD (for treatment-resistant MDD and as an add-on treatment to drug therapy for patients not specifically defined as treatment resistant). There were, however, several crucial methodological limitations in the included studies that were not critically assessed. These are discussed below. Recent meta-analyses (including 2 international health technology assessments) have done evidence-based critical analyses of studies that have assessed rTMS for MDD. The 2 most recent health technology assessments (from the Oxford Cochrane Collaboration and the Norwegian Centre for Health Technology Assessment) concluded that there is no evidence that rTMS is effective for the treatment of MDD, either as compared with a placebo for patients with treatment-resistant or nontreatment-resistant MDD, or as an alternative to ECT for patients with treatment-resistant MDD. This mainly due to the poor quality of the studies. The major methodological limitations were identified in older meta-analyses, recent health technology assessments, and the most recently published trials (Level 2-4 evidence) on the effectiveness of rTMS for MDD are discussed below. Small sample size was a limitation acknowledged by many of the authors. There was also a lack of a priori sample size calculation or justification. Biased randomization may have been a problem. Generally, the published reports lacked detailed information on the method of allocation concealment used. This is important because it is impossible to determine if there was a possible influence (direct or indirect) in the allocation of the patients to different treatment groups. The trials were single blind, evaluated by external blinded assessors, rather than double blind. Double blinding is more robust, because neither the participants nor the investigators know which participants are receiving the active treatment and which are getting a placebo. Those administering rTMS, however, cannot be blinded to whether they are administering the active treatment or a placebo. There was patient variability among the studies. In some studies, the authors said that patients were "medication resistant," but the definitions of resistant, if provided, were inconsistent or unclear. For example, some described "medication resistant" as failing at least one trial of drugs during the current depressive episode. Furthermore, it was unclear if the term "medication resistant" referred to antidepressants only or to combinations of antidepressants and other drug augmentation strategies (such as neuroleptics, benzodiazepine, carbamazepine, and lithium). Also variable was the type of depression (i.e., unipolar and/or bipolar), if patients were inpatients or outpatients, if they had psychotic symptoms or no psychotic symptoms, and the chronicity of depression. Dropouts or withdrawals were a concern. Some studies reported that patients dropped out, but provided no further details. Intent-to-treat analysis was not done in any of the trials. This is important, because ignoring patients who drop out of a trial can bias the results, usually in favour of the treatment. This is because patients who withdraw from trials are less likely to have had the treatment, more likely to have missed their interim checkups, and more likely to have experienced adverse effects when taking the treatment, compared with patients who do not withdraw. (1) Measurement of treatment outcomes using scales or inventories makes interpreting results and drawing conclusions difficult. The most common scale, the Hamilton Depression Rating Scale (HDRS) is based on a semistructured interview. Some authors (2) reported that rating scales based on semistructured interviews are more susceptible to observation bias than are self-administered questionnaires such as the Beck Depression Inventory (BDI). Martin et al. (3) argued that the lack of consistency in effect as determined by the 2 scales (a positive result after 2 weeks of treatment as measured by the HDRS and a negative result for the BDI) makes definitive conclusions about the nature of the change in mood of patients impossible. It was suggested that because of difficulties interpreting results from psychometric scales, (4) and the subjective or unstable character of MDD, other, more objective, outcome measures such as readmission to hospital, time to hospital discharge, time to adjunctive treatment, and time off work should be used to assess rTMS for the treatment of depression. A placebo effect could have influenced the results. Many studies reported response rates for patients who received placebo treatment. For example, Klein et al. (5) reported a control group response rate as high as 25%. Patients receiving placebo rTMS may receive a small dose of magnetic energy that may alter their depression. Short-term studies were the most common. Patients received rTMS treatment for 1 to 2 weeks. Most studies followed-up patients for 2 to 4 weeks post-treatment. Dannon et al. (6) followed-up patients who responded to a course of ECT or rTMS for up to 6 months; however, the assessment procedure was not blinded, the medication regimen during follow-up was not controlled, and initial baseline data for the patient groups were not reported. The long-term effectiveness of rTMS for the treatment of depression is unknown, as is the long-term use, if any, of maintenance therapy. The cost-effectiveness of rTMS for the treatment of depression is also unknown. A lack of long-term studies makes cost-effectiveness analysis difficult. The complexity of possible combinations for administering rTMS makes comparing like with like difficult. Wasserman and Lisanby (7) have said that the method for precisely targeting the stimulation in this area is unreliable. It is unknown if the left dorsolateral prefrontal cortex is the optimal location for treatment. Further, differences in rTMS administration include number of trains per session, duration of each train, and motor threshold. Clinical versus statistical significance. Several meta-analyses and studies have found that the degree of therapeutic change associated with rTMS across studies is relatively modest; that is, results may be statistically, but not necessarily clinically, significant. (8-11). Conventionally, a 50% reduction in the HDRS scores is commonly accepted as a clinically important reduction in depression. Although some studies have observed a statistically significant reduction in the depression rating, many have not shows the clinically significant reduction of 50% on the HDRS. (11-13) Therefore, few patients in these studies would meet the standard criteria for response. (9) Clinical/methodological diversity and statistical heterogeneity. In the Norwegian health technology assessment, Aarre et al. (14) said that a formal meta-analysis was not feasible because the designs of the studies varied too much, particularly in how rTMS was administered and in the characteristics of the patients. They noted that the quality of the study designs was poor. The 12 studies that comprised the assessment had small samples, and highly variable inclusion criteria and study designs. The patients' previous histories, diagnoses, treatment histories, and treatment settings were often insufficiently characterized. Furthermore, many studies reported that patients had treatment-resistant MDD, yet did not listclear criteria for the designation. Without this information, Aarre and colleagues suggested that the interpretation of the results is difficult and the generalizability of results is questionable. They concluded that rTMS cannot be recommended as a standard treatment for depression: "More, larger and more carefully designed studies are needed to demonstrate convincingly a clinically relevant effect of rTMS." In the Cochrane Collaboration systematic review, Martin et al. (3;15) said that the complexity of possible combinations for administering rTMS makes comparison of like versus like difficult. A statistical test for heterogeneity (chi-square test) examines if the observed treatment effects are more different from each other than one would expect due to random error (or chance) alone. (16) However, this statistical test must be interpreted with caution because it has low power in the (common) situation of a meta-analysis when the trials have small sample sizes or are few. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Biological treatment of wastewater basically reduces the pollutant concentration through microbial coagulation and removal of non-settleable organic colloidal solids. Organic matter is biologically stabilized so that no further oxygen demand is exerted by it. The biological treatment requires contact of the biomass with the substrate. Various advances and improvements in anaerobic reactors to achieve variations in contact time and method of contact have resulted in development of in suspended growth systems, attached growth or fixed film systems or combinations thereof. Although anaerobic systems for waste treatment have been used since late 19th century, they were considered to have limited treatment efficiencies and were too slow to serve the needs of a quickly expanding wastewater volume, especially in industrialized and densely populated areas. At present aerobic treatment is the most commonly used process to reduce the organic pollution level of both domestic and industrial wastewaters. Aerobic techniques, such as activated sludge process, trickling filters, oxidation ponds and aerated lagoons, with more or less intense mixing devices, have been successfully installed for domestic wastewater as well as industrial wastewater treatment. Anaerobic digestion systems have undergone modifications in the last two decades, mainly as a result of the energy crisis. Major developments have been made with regard to anaerobic metabolism, physiological interactions among different microbial species, effects of toxic compounds and biomass accumulation. Recent developments however, have demonstrated that anaerobic processes might be an economically attractive alternative for the treatment of different types of industrial wastewaters and in (semi-) tropical areas also for domestic wastewaters. The anaerobic degradation of complex, particulate organic matter has been described as a multistep process of series and parallel reactions. It involves the decomposition of organic and inorganic matter in the absence of molecular oxygen. Complex polymeric materials such as polysaccharides, proteins, and lipids (fat and grease) are first hydrolyzed to soluble products by extracellular enzymes, secreted by microorganisms, so as to facilitate their transport or diffusion across the cell membrane. These relatively simple, soluble compounds are fermented or anaerobically oxidized, further to short-chain fatty acids, alcohols, carbon dioxide, hydrogen, and ammonia. The short-chain fatty acids (other than acetate) are converted to acetate, hydrogen gas, and carbon dioxide. Methanogenesis finally occurs from the reduction of carbon dioxide and acetate by hydrogen. The initial stage of anaerobic degradation, i.e. acid fermentation is essentially a constant BOD stage because the organic molecules are only rearranged. The first stage does not stabilize the organics in the waste. However this step is essential for the initiation of second stage methane fermentation as it converts the organic material to a form, usable by the methane producing bacteria. The second reaction is initiated when anaerobic methane forming bacteria act upon the short chain organic acids produced in the 1st stage. Here these acids undergo methane fermentation with carbon dioxide acting as hydrogen acceptor and getting reduced to methane. The methane formed, being insoluble in water, escapes from the system and can be tapped and used as an energy source. The production and subsequent escape of methane causes the stabilization of the organic material. The methane-producing bacteria consist of several different groups. Each group has the ability to ferment only specific compounds. Therefore, the bacterial consortia in a methane producing system should include a number of different groups. When the rate of bacterial growth is considered, then the retention time of the solids becomes important parameter. The acid fermentation stage is faster as compared to the methane fermentation stage. This means that a sudden increase in the easily degradable organics will result in increased acid production with subsequent accumulation of acids. This inhibits the methanogenesis step. Acclimatization of the microorganisms to a substrate has been reported to take more than five weeks. Sufficiently acclimated bacteria have shown greater stability towards stress-inducing events such as hydraulic overloads, fluctuations in temperature, fluctuations in volatile acid and ammonia concentrations etc. Several environmental factors can affect anaerobic digestion, by altering the parameters such as specific growth rate, decay rate, gas production, substrate utilization, start-up and response to changes in input. It has long been recognized that an anaerobic process is in many ways ideal for wastewater treatment and has following merits: A high degree of waste stabilization A low production of excess A low nutrient requirements No oxygen requirement Production of methane gas Anaerobic microorganisms, especially methanogens have a slow growth rate. At lower HRTs, the possibility of washout of biomass is more prominent. This makes it difficult to maintain the effective number of useful microorganisms in the system. To maintain the population of anaerobes, large reactor volumes or higher HRTs are required. This may ultimately provide longer SRTs upto 20 days for high rate systems. Thus, provision of larger reactor volumes or higher HRTs ultimately lead to higher capital cost. Among notable disadvantages, it has low synthesis/reaction rate hence long start up periods and difficulty in recovery from upset conditions. Special attention is, therefore, warranted towards, controlling the factors that affect process adversely; important among them being environmental factors such as temperature, pH and concentration of toxic substances. The conventional anaerobic treatment process consists of a reactor containing waste and biological solids (bacteria) responsible for the digestion process. Concentrated waste (usually sewage sludge) can be added continuously or periodically (semi-batch operation), where it is mixed with the contents of the reactor. Theoretically, the conventional digester is operated as a once-through, completely mixed, reactor. In this particular mode of operation the hydraulic retention time (HRT) is equal to the solids retention time (SRT). Basically, the required process efficiency is related to the sludge retention time (SRT), and hence longer SRT provided, results in satisfactory population (by reproduction) for further waste stabilization. By reducing the hydraulic retention time (HRT) in the conventional mode reactor, the quantity of biological solids within the reactor is also decreased as the solids escape with the effluent. The limiting HRT is reached when the bacteria are removed from the reactor faster than they can grow. Methanogenic bacteria are slow growers and are considered the rate-limiting component in the anaerobic digestion process. The first anaerobic process developed, which separated the SRT from the HRT was the anaerobic contact process. In 1963, Young and McCarty (1968) began work, which eventually led to the development of the anaerobic upflow filter (AF) process. The anaerobic filter represented a significant advance in anaerobic waste treatment, since the filter can trap and maintain a high concentration of biological solids. By trapping these solids, long SRT's could be obtained at large waste flows, necessary to anaerobically treat low strength wastes at nominal temperatures economically. Another anaerobic process which relies on the development of biomass on the surfaces of a media is an expanded bed upflow reactor. The primary concept of the process consists of passing wastewater up through a bed of inert sand sized particles at sufficient velocities to fluidize and partially expand the sand bed. One of the more interesting new processes is the upflow anaerobic sludge blanket process (UASB), which was developed by Lettinga and his co-workers in Holland in the early 1970's. The key to the process was the discovery that anaerobic sludge inherently has superior flocculation and settling characteristics, provided the physical and chemical conditions for sludge flocculation are favorable. When these conditions are met, a high solids retention time (at high HRT loadings) can be achieved, with separation of the gas from the sludge solids. The UASB reactor is one of the reactor types with high loading capacity. It differs from other processes by the simplicity of its design. UASB process is a combination of physical & biological processes. The main feature of physical process is separation of solids and gases from the liquid and that of biological process is degradation of decomposable organic matter under anaerobic conditions. No separate settler with sludge return pump is required, as in the anaerobic contact process. There is no loss of reactor volume through filter or carrier material, as in the case with the anaerobic filter and fixed film reactor types, and there is no need for high rate effluent recirculation and concomitant pumping energy, as in the case with fluidized bed reactor. Anaerobic sludge inherently possesses good settling properties, provided the sludge is not exposed to heavy mechanical agitation. For this reason mechanical mixing is generally omitted in UASB-reactors. At high organic loading rates, the biogas production guarantees sufficient contact between substrate and biomass. Regarding the dynamic behaviour of the water phase UASB reactor approaches the completely mixed reactor. For achieving the required sufficient contact between sludge and wastewater, the UASB-system relies on the agitation brought about by the natural gas production and on an even feed inlet distribution at the bottom of the reactor. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The purpose of this empirical study is to analyze modalities of announcing the end of attempts at in vitro ferti-lization to women who, for various reasons, were not able to have a child after several trials. What are the problems physicians face when, in the course of their work, they make these announcements? How do they give (or not give) support to these women who have placed so much hope in this technique? These are some of the questions that led the authors to conduct this empirical study within the framework of a clinical and qualitative approach to work psychology. Within this framework, work is conceptualised as a complex activity that involves the subject, both bodily and through his various modes of socialisation. The field of clinical and quali-tative approach to work psychology situations focuses on different ways of expressing distress related to contradictory work demands, as the activity is being performed; it also focuses on those creative processes used by the subject to cope with those internal and external conflicts that hinder task performance. A review of the literature and preliminary observations led us to postulate that the problems physicians are faced with when they announce the end of attempts at in vitro fertilisation (IVF) are linked to several conflicts between work values (that are specific to the medical world) and the recognition of work failure: termination of attempts at IVF. The popu-lation that participated in this research project belongs to a network of private practitioners who work with the in-house team of a Parisian clinic. But the group is not uniform and some physicians perform IVFs more frequently than others. Our qualitative study involved 10 semi-directive interviews of approximately 1 1/2 hours each, which were recorded and transcribed. Initial instructions focused on a concrete description of situations of abandonment of attempts at IVF, in terms of their preparation, development, and the way they are experienced . Interviews therefore centred on specific and limited practitioner activity. Each transcription was submitted to a Qualitative Analysis of Discourse, followed by a comparative analysis of the 10 transcriptions. We propose an original method of Qualitative Analysis of Discourse, to be applied to semi-structured clinical interviews. This method seeks to analyse the structure of the resulting egocentric monologue in research si-tuations of semi-directive interviewing. The method of Quali-tative Analysis of Discourse involves three steps, but only the first two were applied in this work: a) identification of sequences of discourse; b) analysis of relationships between statements; c) stylistic analysis of figures of speech. Our first set of analyses showed that seve-ral markers increase in physicians' discourse when they describe difficult and/or conflict-laden consultation situations: logical connectors, impersonal pronouns, reported discourse, anti-cipations regarding the interviewer's judgement. The logical balance of the discourse therefore appears threatened when pro-blems inherent in the work demands involved in ending IVF attempts are mentioned. As a whole, these markers underscore the importance of the implicit dimension of discourse (inferences, presuppositions, hints, allusions, etc.), thus reflecting complex speech that attempts to negotiate between subjective positions and shared cultural values. A comparative analysis of the markers identified in the 10 interviews revealed four areas, each involving nervous tension poles, that are suggestive of cognitive-emotional dissonance in the task to be performed. Some factors increase professional distress while others temper it. They act upon the work situation itself on the one hand, and on the working relationship between physician and patient on the other. 1. Areas of tension relating to the task to be performed. The first area contrasts individual with collective decision-making. The independent status which characterises private medical practice increases self-esteem in cases of success but weakens it when IVF attempts fail. In addition, it goes against collective involvement in the work situation, yet such involvement may act as a strong moderating factor for the experience of distress. The second area contrasts work that is well done with recognition by peers. Indeed, in the hierarchy of medical values, recognition by peers that work has been well performed is anchored in successful healing (in the broad sense of the term), whereas in situations of abandonment of IVF attempts, ending the attempt is considered by everyone to be a failure, even if it has been well conducted . The third area opposes objective medical practice to a necessarily subjective medical involvement. The scientific and ideal values which characterise medicine reflect its objective and scientific orientation, but IVF situations are a reminder that medicine is not an exact science and that it can make mistakes. There are numerous special individual cases which reduce certainty that a decision to terminate IVF is well-founded. The fourth area distinguishes between work that is considered to be well done and work considered to be well conducted . Personal estimation of work that is well done is based on the impression that the maximum feasible has been done . But in IVF situations, constant uncertainty leads to professional over-involvement (examinations, verifications, changes of protocols). Work that is poorly done is work that does not cure or that brings no relief. As a result, work that consists in ending IVF attempts, even if it is well conducted , remains a subjective failure for everyone since it does not bring a cure (pregnancy). 2. Areas of tension in the physician-patient relationship. The first area contrasts women's irrational desire with possible support from their husbands, when the time has come to announce the end of the attempts. But this voice/presence of husbands is consi-dered desirable and important only when attempts have failed, so that husbands are not encouraged to participate in the protocols except to help restrain their wives' over reactions . The second area opposes respect for the patient role with demands made by women. Lack of respect for the patient role, by making demands or by refusing to follow advice, particularly when IVF attempts are abandoned, crystallises all the resentment experienced by physicians in difficult work situations. Two cognitive-emotional worlds, more or less tuned to one another over the course of the IVF, start to clash and lose all mutual understanding: the medical world and the patient's subjective world. The third area results from the second one. It contrasts a listening physician with a powerful one. Physicians are very concerned that their relationship with their patients be one of partnership. But this (idealised) equilibrium is abruptly disrupted by the end of the attempts, inasmuch as it is the physician who has the power to stop these attempts and who decides to do so. The unveiling of this reality of a power relationship becomes a source of suffering and contradicts expressed surface values. The fourth area contrasts an attitude of ongoing patient support based on a belief in success with an attitude of patient support based on the prediction of a possible failure. Indeed, for a patient to be supported in a way physicians would consider right and adequate , the abandonment of IVF attempts should be anticipated in advance so that the physician can prepare both himself and the patients for the high risk of failure. But physicians insist on the fact that medical work can only succeed if they believe in it . As a result, the more energy the physician puts into launching the initial phase of IVF, the greater the feeling of self-accomplishment during the first phase of IVF; but conversely, the weaker the efficacy of the process of seeing the patient through the end of the attempts, the stronger the fee-ling of subjective distress at work will be. Overall, it is a para-doxical work situation for physicians to have to anticipate the interruption of IVF attempts and to have to prepare for seeing the patient through this abandonment. This situation creates conflicts of representations and values within their very practice and generates distress at work. It is worth noting that some moderating factors could alleviate their sense of suffering and contribute to improving their work experience: a) the deve-lopment of a protocol for seeing patients through the end of IVF attempts, which would make abandonment part of a job well done for physicians; b) regular participation by the spouse in these protocols; c) making all decisions to end IVF attempts a collective process, in order to avoid placing exclusive responsibility on the treating physician. The limitations of this study are inherent both in the qualitative nature of the data that involve a small number of physicians, and in the specificity of this population that works within a poorly structured network. On the other hand, our method of Qualitative Analysis of Discourse can be applied to all types of discourse obtained in research situations, provided the discourse is produced through semi-directive or non-directive interviews.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
To conduct an assessment on endovascular repair of descending thoracic aortic aneurysm (TAA). Aneurysm is the most common condition of the thoracic aorta requiring surgery. Aortic aneurysm is defined as a localized dilatation of the aorta. Most aneurysms of the thoracic aorta are asymptomatic and incidentally discovered. However, TAA tends to enlarge progressively and compress surrounding structures causing symptoms such as chest or back pain, dysphagia (difficulty swallowing), dyspnea (shortness of breath), cough, stridor (a harsh, high-pitched breath sound), and hoarseness. Significant aortic regurgitation causes symptoms of congestive heart failure. Embolization of the thrombus to the distal arterial circulation may occur and cause related symptoms. The aneurysm may eventually rupture and create a life-threatening condition. The overall incidence rate of TAA is about 10 per 100,000 person-years. The descending aorta is involved in about 30% to 40% of these cases. The prognosis of large untreated TAAs is poor, with a 3-year survival rate as low as 25%. Intervention is strongly recommended for any symptomatic TAA or any TAA that exceeds twice the diameter of a normal aorta or is 6 cm or larger. Open surgical treatment of TAA involves left thoracotomy and aortic graft replacement. Surgical treatment has been found to improve survival when compared with medical therapy. However, despite dramatic advances in surgical techniques for performing such complex operations, operative mortality from centres of excellence are between 8% and 20% for elective cases, and up to 50% in patients requiring emergency operations. In addition, survivors of open surgical repair of TAAs may suffer from severe complications. Postoperative or postprocedural complications of descending TAA repair include paraplegia, myocardial infarction, stroke, respiratory failure, renal failure, and intestinal ischemia. Endovascular aortic aneurysm repair (EVAR) using a stent graft, a procedure called endovascular stent-graft (ESG) placement, is a new alternative to the traditional surgical approach. It is less invasive, and initial results from several studies suggest that it may reduce mortality and morbidity associated with the repair of descending TAAs. The goal in endovascular repair is to exclude the aneurysm from the systemic circulation and prevent it from rupturing, which is life-threatening. The endovascular placement of a stent graft eliminates the systemic pressure acting on the weakened wall of the aneurysm that may lead to the rupture. However, ESG placement has some specific complications, including endovascular leak (endoleak), graft migration, stent fracture, and mechanical damage to the access artery and aortic wall. The Talent stent graft (manufactured by Medtronic Inc., Minneapolis, MN) is licensed in Canada for the treatment of patients with TAA (Class 4; licence 36552). The design of this device has evolved since its clinical introduction. The current version has a more flexible delivery catheter than did the original system. The prosthesis is composed of nitinol stents between thin layers of polyester graft material. Each stent is secured with oversewn sutures to prevent migration. Objectives To compare the effectiveness and cost-effectiveness of ESG placement in the treatment of TAAs with a conventional surgical approachTo summarize the safety profile and effectiveness of ESG placement in the treatment of descending TAAsMeasures of Effectiveness Primary Outcome Mortality rates (30-day and longer term)Secondary Outcomes Technical success rate of introducing a stent graft and exclusion of the aneurysm sac from systemic circulationRate of reintervention (through surgical or endovascular approach)Measures of Safety Complications were categorized into 2 classes: Those specific to the ESG procedure, including rates of aneurysm rupture, endoleak, graft migration, stent fracture, and kinking; andThose due to the intervention, either surgical or endovascular. These include paraplegia, stroke, cardiovascular events, respiratory failure, real insufficiency, and intestinal ischemia.Inclusion Criteria Studies comparing the clinical outcomes of ESG treatment with surgical approachesStudies reporting on the safety and effectiveness of the ESG procedure for the treatment of descending TAAsExclusion Criteria Studies investigating the clinical effectiveness of ESG placement for other conditions such as aortic dissection, aortic ulcer, and traumatic injuries of the thoracic aortaStudies investigating the aneurysms of the ascending and the arch of the aortaStudies using custom-made graftsLiterature Search The Medical Advisory Secretariat searched The International Network of Agencies for Health Technology Assessment and the Cochrane Database of Systematic Reviews for health technology assessments. It also searched MEDLINE, EMBASE, Medline In-Process & Other Non-Indexed Citations, and Cochrane CENTRAL from January 1, 2000 to July 11, 2005 for studies on ESG procedures. The search was limited to English-language articles and human studies. One health technology assessment from the United Kingdom was identified. This systematic review included all pathologies of the thoracic aorta; therefore, it did not match the inclusion criteria. The search yielded 435 citations; of these, 9 studies met inclusion criteria. Mortality The results of a comparative study found that in-hospital mortality was not significantly different between ESG placement and surgery patients (2 [4.8%] for ESG vs. 6 [11.3%] for surgery).Pooled data from case series with a mean follow-up ranging from 12 to 38 months showed a 30-day mortality and late mortality rate of 3.9% and 5.5%, respectively. These rates are lower than are those reported in the literature for surgical repair of TAA.Case series showed that the most common cause of early death in patients undergoing endovascular repair is aortic rupture, and the most common causes of late death are cardiac events and aortoesophageal or aortobronchial fistula.Technical Success Rate Technical success rates reported by case series are 55% to 100% (100% and 94.4% in 2 studies with all elective cases, 89% in a study with 5% emergent cases, and 55% in a study with 42% emergent cases).Surgical Reintervention In the comparative study, 3 (7.1%) patients in the ESG group and 14 (26.5%) patients in the surgery group required surgical reintervention. In the ESG group, the reasons for surgical intervention were postoperative bleeding at the access site, paraplegia, and type 1 endoleak. In the surgical group, the reasons for surgery were duodenal perforation, persistent thoracic duct leakage, false aneurysm, and 11 cases of postoperative bleeding.Pooled data from case series show that 9 (2.6%) patients required surgical intervention. The reasons for surgical intervention were endoleak (3 cases), aneurysm enlargement and suspected infection (1 case), aortic dissection (1 case), pseudoaneurysm of common femoral artery (1 case), evacuation of hematoma (1 case), graft migration (1 case), and injury to the access site (1 case).Endovascular Revision In the comparative study, 3 (7.1%) patients required endovascular revision due to persistent endoleak.Pooled data from case series show that 19 (5.3%) patients required endovascular revision due to persistent endoleak.Graft Migration Two case series reported graft migration. In one study, 3 proximal and 4 component migrations were noted at 2-year follow-up (total of 5%). Another study reported 1 (3.7%) case of graft migration. Overall, the incidence of graft migration was 2.6%.Aortic Rupture In the comparative study, aortic rupture due to bare stent occurred in 1 case (2%). The pooled incidence of aortic rupture or dissection reported by case series was 1.4%.Postprocedural Complications In the comparative study, there were no statistically significant differences between the ESG and surgery groups in postprocedural complications, except for pneumonia. The rate of pneumonia was 9% for those who received an ESG and 28% for those who had surgery (P = .02). There were no cases of paraplegia in either group. The rate of other complications for ESG and surgery including stroke, cardiac, respiratory, and intestinal ischemia were all 5.1% for ESG placement and 10% for surgery. The rate for mild renal failure was 16% in the ESG group and 30% in the surgery group. The rate for severe renal failure was 11% for ESG placement and 10% for surgery.POOLED DATA FROM CASE SERIES SHOW THE FOLLOWING POSTPROCEDURAL COMPLICATION RATES IN THE ESG PLACEMENT GROUP: paraplegia (2.2%), stroke (3.9%), cardiac (2.9%), respiratory (8.7%), renal failure (2.8%), and intestinal ischemia (1%).Time-Related Outcomes The results of the comparative study show statistically significant differences between the ESG and surgery group for mean operative time (ESG, 2.7 hours; surgery, 5 hours), mean duration of intensive care unit stay (ESG, 11 days; surgery, 14 days), and mean length of hospital stay (ESG, 10 days; surgery, 30 days).The mean duration of intensive care unit stay and hospital stay derived from case series is 1.6 and 7.8 days, respectively. ONTARIO-BASED ECONOMIC ANALYSIS: In Ontario, the annual treatment figures for fiscal year 2004 include 17 cases of descending TAA repair procedures (source: Provincial Health Planning Database). Fourteen of these have been identified as "not ruptured" with a mean hospital length of stay of 9.23 days, and 3 cases have been identified as "ruptured," with a mean hospital length of stay of 28 days. However, because one Canadian Classification of Health Interventions code was used for both procedures, it is not possible to determine how many were repaired with an EVAR procedure or with an open surgical procedure. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
This collaborative study, based on data collected by the network of Italian Cancer Registries (AIRTUM), describes the burden of rare cancers in Italy. Estimated number of new rare cancer cases yearly diagnosed (incidence), proportion of patients alive after diagnosis (survival), and estimated number of people still alive after a new cancer diagnosis (prevalence) are provided for about 200 different cancer entities. Data herein presented were provided by AIRTUM population- based cancer registries (CRs), covering nowadays 52% of the Italian population. This monograph uses the AIRTUM database (January 2015), which includes all malignant cancer cases diagnosed between 1976 and 2010. All cases are coded according to the International Classification of Diseases for Oncology (ICD-O-3). Data underwent standard quality checks (described in the AIRTUM data management protocol) and were checked against rare-cancer specific quality indicators proposed and published by RARECARE and HAEMACARE (www.rarecarenet.eu; www.haemacare.eu). The definition and list of rare cancers proposed by the RARECAREnet "Information Network on Rare Cancers" project were adopted: rare cancers are entities (defined as a combination of topographical and morphological codes of the ICD-O-3) having an incidence rate of less than 6 per 100,000 per year in the European population. This monograph presents 198 rare cancers grouped in 14 major groups. Crude incidence rates were estimated as the number of all new cancers occurring in 2000-2010 divided by the overall population at risk, for males and females (also for gender-specific tumours).The proportion of rare cancers out of the total cancers (rare and common) by site was also calculated. Incidence rates by sex and age are reported. The expected number of new cases in 2015 in Italy was estimated assuming the incidence in Italy to be the same as in the AIRTUM area. One- and 5-year relative survival estimates of cases aged 0-99 years diagnosed between 2000 and 2008 in the AIRTUM database, and followed up to 31 December 2009, were calculated using complete cohort survival analysis. To estimate the observed prevalence in Italy, incidence and follow-up data from 11 CRs for the period 1992-2006 were used, with a prevalence index date of 1 January 2007. Observed prevalence in the general population was disentangled by time prior to the reference date (≤2 years, 2-5 years, ≤15 years). To calculate the complete prevalence proportion at 1 January 2007 in Italy, the 15-year observed prevalence was corrected by the completeness index, in order to account for those cancer survivors diagnosed before the cancer registry activity started. The completeness index by cancer and age was obtained by means of statistical regression models, using incidence and survival data available in the European RARECAREnet data. In total, 339,403 tumours were included in the incidence analysis. The annual incidence rate (IR) of all 198 rare cancers in the period 2000-2010 was 147 per 100,000 per year, corresponding to about 89,000 new diagnoses in Italy each year, accounting for 25% of all cancer. Five cancers, rare at European level, were not rare in Italy because their IR was higher than 6 per 100,000; these tumours were: diffuse large B-cell lymphoma and squamous cell carcinoma of larynx (whose IRs in Italy were 7 per 100,000), multiple myeloma (IR: 8 per 100,000), hepatocellular carcinoma (IR: 9 per 100,000) and carcinoma of thyroid gland (IR: 14 per 100,000). Among the remaining 193 rare cancers, more than two thirds (No. 139) had an annual IR <0.5 per 100,000, accounting for about 7,100 new cancers cases; for 25 cancer types, the IR ranged between 0.5 and 1 per 100,000, accounting for about 10,000 new diagnoses; while for 29 cancer types the IR was between 1 and 6 per 100,000, accounting for about 41,000 new cancer cases. Among all rare cancers diagnosed in Italy, 7% were rare haematological diseases (IR: 41 per 100,000), 18% were solid rare cancers. Among the latter, the rare epithelial tumours of the digestive system were the most common (23%, IR: 26 per 100,000), followed by epithelial tumours of head and neck (17%, IR: 19) and rare cancers of the female genital system (17%, IR: 17), endocrine tumours (13% including thyroid carcinomas and less than 1% with an IR of 0.4 excluding thyroid carcinomas), sarcomas (8%, IR: 9 per 100,000), central nervous system tumours and rare epithelial tumours of the thoracic cavity (5%with an IR equal to 6 and 5 per 100,000, respectively). The remaining (rare male genital tumours, IR: 4 per 100,000; tumours of eye, IR: 0.7 per 100,000; neuroendocrine tumours, IR: 4 per 100,000; embryonal tumours, IR: 0.4 per 100,000; rare skin tumours and malignant melanoma of mucosae, IR: 0.8 per 100,000) each constituted <4% of all solid rare cancers. Patients with rare cancers were on average younger than those with common cancers. Essentially, all childhood cancers were rare, while after age 40 years, the common cancers (breast, prostate, colon, rectum, and lung) became increasingly more frequent. For 254,821 rare cancers diagnosed in 2000-2008, 5-year RS was on average 55%, lower than the corresponding figures for patients with common cancers (68%). RS was lower for rare cancers than for common cancers at 1 year and continued to diverge up to 3 years, while the gap remained constant from 3 to 5 years after diagnosis. For rare and common cancers, survival decreased with increasing age. Five-year RS was similar and high for both rare and common cancers up to 54 years; it decreased with age, especially after 54 years, with the elderly (75+ years) having a 37% and 20% lower survival than those aged 55-64 years for rare and common cancers, respectively. We estimated that about 900,000 people were alive in Italy with a previous diagnosis of a rare cancer in 2010 (prevalence). The highest prevalence was observed for rare haematological diseases (278 per 100,000) and rare tumours of the female genital system (265 per 100,000). Very low prevalence (<10 prt 100,000) was observed for rare epithelial skin cancers, for rare epithelial tumours of the digestive system and rare epithelial tumours of the thoracic cavity. One in four cancers cases diagnosed in Italy is a rare cancer, in agreement with estimates of 24% calculated in Europe overall. In Italy, the group of all rare cancers combined, include 5 cancer types with an IR>6 per 100,000 in Italy, in particular thyroid cancer (IR: 14 per 100,000).The exclusion of thyroid carcinoma from rare cancers reduces the proportion of them in Italy in 2010 to 22%. Differences in incidence across population can be due to the different distribution of risk factors (whether environmental, lifestyle, occupational, or genetic), heterogeneous diagnostic intensity activity, as well as different diagnostic capacity; moreover heterogeneity in accuracy of registration may determine some minor differences in the account of rare cancers. Rare cancers had worse prognosis than common cancers at 1, 3, and 5 years from diagnosis. Differences between rare and common cancers were small 1 year after diagnosis, but survival for rare cancers declined more markedly thereafter, consistent with the idea that treatments for rare cancers are less effective than those for common cancers. However, differences in stage at diagnosis could not be excluded, as 1- and 3-year RS for rare cancers was lower than the corresponding figures for common cancers. Moreover, rare cancers include many cancer entities with a bad prognosis (5-year RS <50%): cancer of head and neck, oesophagus, small intestine, ovary, brain, biliary tract, liver, pleura, multiple myeloma, acute myeloid and lymphatic leukaemia; in contrast, most common cancer cases are breast, prostate, and colorectal cancers, which have a good prognosis. The high prevalence observed for rare haematological diseases and rare tumours of the female genital system is due to their high incidence (the majority of haematological diseases are rare and gynaecological cancers added up to fairly high incidence rates) and relatively good prognosis. The low prevalence of rare epithelial tumours of the digestive system was due to the low survival rates of the majority of tumours included in this group (oesophagus, stomach, small intestine, pancreas, and liver), regardless of the high incidence rate of rare epithelial cancers of these sites. This AIRTUM study confirms that rare cancers are a major public health problem in Italy and provides quantitative estimations, for the first time in Italy, to a problem long known to exist. This monograph provides detailed epidemiologic indicators for almost 200 rare cancers, the majority of which (72%) are very rare (IR<0.5 per 100,000). These data are of major interest for different stakeholders. Health care planners can find useful information herein to properly plan and think of how to reorganise health care services. Researchers now have numbers to design clinical trials considering alternative study designs and statistical approaches. Population-based cancer registries with good quality data are the best source of information to describe the rare cancer burden in a population.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. 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N-Methylolacrylamide is a cross-linking agent used in adhesives, binders for paper, crease-resistant textiles, resins, latex film, and sizing agents. Toxicology and carcinogenesis studies were conducted by administering N-methylolacrylamide (98% pure) in water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 16 days, 13 weeks, or 2 years. In vitro genetic toxicology studies were conducted in Salmonella typhimurium and Chinese hamster ovary (CHO) cells; an in vivo bone marrow micronucleus test was performed with B6C3F1 mice. Neurobehavioral assays were performed during the 13-week studies. Sixteen-Day Studies: The doses of N-methylolacrylamide used ranged from 25 to 400 mg/kg. All rats that received 400 mg/kg died within 4 days, and 3/5 male rats that received 200 mg/kg also died before the end of the studies. Compound-related clinical signs seen with 200 mg/kg included ataxia, muscle tremors, and hyperirritability. Ataxia after dosing was observed from day 7 to the end of the studies for rats that received 100 mg/kg. The final mean body weight of male rats that received 100 or 200 mg/kg was 10% or 27% lower than that of the vehicle controls. The final mean body weight of female rats that received 200 mg/kg was 20% lower than that of the vehicle controls. Compound-related lesions in rats included hyperplasia of the bronchiolar and tracheal epithelium, dysplasia of the nasal and tracheal epithelium, centrilobular hepatocellular necrosis, lymphoid depletion of the spleen, and myelin degeneration of the lumbar ventral spinal nerve. All 5 male and 4/5 female mice that received 400 mg/kg N-methylolacrylamide died on the second day of the 16-day studies. The surviving female mouse in the 400 mg/kg group and the male and female mice in the 200 mg/kg groups were ataxic after they were dosed, starting on day 2. Weight changes were inconsistent among dose groups. Bronchial epithelial hyperplasia (mild) appeared to be dose related in males and females. Sinusoidal congestion of the liver and vacuolar degeneration of myocardial fibers were seen in males and females given 400 mg/kg. Thirteen-Week Studies: The doses of N-methylolacrylamide used ranged from 12.5 to 200 mg/kg. All rats that received 100 or 200 mg/kg died before the end of the studies. Rats that received 100 or 200 mg/kg had hind limb ataxia, which progressed to hind limb paralysis. Rats that received 50 mg/kg had hind limb ataxia beginning at week 8, which progressed to hind limb paresis by week 11. The final mean body weight of rats that received 25 or 50 mg/kg was 8% or 16% lower than that of the vehicle controls for males and 6% or 10% lower for females. In neurobehavioral assessments, decreased forelimb and hind limb grip strength was seen at doses as low as 25 mg/kg for female rats and at doses as low as 12.5 mg/kg for male rats. A decreased startle response was seen for females at doses as low as 25 mg/kg. The landing foot spread was significantly increased for male and female rats that received 50 mg/kg. Axon filament and myelin sheath degeneration of the brain stem, spinal cord, and/or peripheral nerves was seen in rats at increased incidences at 25 mg/kg and higher doses. Inflammation and/or hemorrhage and edema of the urinary bladder mucosa were seen with doses of 25 mg/kg or more in a few rats that had distended bladders at gross examination. All mice that received 200 mg/kg N-methylolacrylamide died before the end of the studies. Final mean body weights of dosed and vehicle control mice were similar. A decreased relative testis weight was observed for mice that received 12.5 mg/kg or more. The relative kidney weights for male mice receiving 50 or 100 mg/kg were greater than that for vehicle controls. Neurobehavioral studies indicated decreased forelimb grip strength in male and female mice at doses as low as 25 mg/kg. An exaggerated startle response was seen for female mice given 100 mg/kg. A reduction in rotarod performance was seen for male and female mice receiving 100 mg/kg and for male mice receiving 25 mg/kg. Hepatocellular necrosis anmale mice receiving 25 mg/kg. Hepatocellular necrosis and thymic lymphocytic necrosis were compound-related effects in mice given 200 mg/kg N-methylolacrylamide. Hemorrhage, necrosis, and mineralization of the zona reticularis of the adrenal gland were present in 3/10 female mice given 200 mg/kg, and cytoplasmic vacuolization of the adrenal cortex was seen with lower doses. Based on the results of these short-term studies, 2-year studies were conducted by administering 0, 6, or 12 mg/kg N-methylolacrylamide in water by gavage, 5 days per week for 103 weeks, to groups of 50 rats of each sex. Groups of 50 mice of each sex were administered 0, 25, or 50 mg/kg on the same schedule. Body Weight and Survival in the Two-Year Studies: Mean body weights of dosed rats were within 6&percnt; of those of vehicle controls throughout most of the studies. Mean body weights of dosed mice were as much as 25&percnt; greater than those of vehicle controls for females and as much as 13&percnt; greater for males. The survival of female rats given 25 mg/kg per day was lower than that of vehicle controls after day 550, but survival of female rats given 50 mg/kg per day was not different from that of vehicle controls (vehicle control, 35/50; low dose, 22/50; high dose, 33/50). No differences in survival were observed between any other groups of rats or mice of either sex (male rats: 28/50; 22/50; 27/50; male mice: 30/50; 20/50; 21/50; female mice: 41/50; 35/50; 33/50). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: In rats, no biologically important nonneoplastic or neoplastic lesions were attributed to administration of N-methylolacrylamide. Higher doses might have increased the sensitivity of the studies to determine the presence or absence of a carcinogenic response. In mice, the incidences of adenomas of the Harderian gland were increased in males given either dose of N-methylolacrylamide and in females given the top dose (male: vehicle control, 1/48; low dose, 14/49; high dose, 29/50; female: 5/47; 8/45; 20/48). The incidences of carcinomas of the Harderian gland were not significantly increased by N-methylolacrylamide administration (male: 1/48; 0/49; 2/50; female: 0/47; 3/45; 2/48). The incidences of hepatocellular adenomas were increased in male and female mice given 50 mg/kg N-methylolacrylamide (male: 8/50; 4/50; 19/50; female: 3/50; 4/50; 17/49). The incidences of hepatocellular carcinomas were also marginally increased in dosed male mice (male: 6/50; 13/50; 12/50; female: 3/50; 3/50; 2/49). Hepatocellular adenomas and carcinomas (combined) occurred with positive trends, and the incidences in male and female mice receiving 50 mg/kg were increased compared with those in the vehicle controls (male: 12/50; 17/50; 26/50; female: 6/50; 7/50; 17/49). Chronic inflammation and alveolar epithelial hyperplasia of the lung were observed at increased incidences in mice given N-methylolacrylamide. Sentinel mice were seropositive for Sendai virus at 18 months. The incidences of alveolar/bronchiolar adenomas (3/49; 6/50; 11/50) and carcinomas (2/49; 4/50; 10/50) were increased in male mice given 50 mg/kg. Alveolar/bronchiolar adenomas or carcinomas (combined) occurred with a positive trend in male mice (5/49; 10/50; 18/50). The incidence of alveolar/bronchiolar adenomas or carcinomas (combined) was increased in female mice given the top dose of 50 mg/kg (6/50; 8/50; 13/49). Ovarian atrophy was observed at increased incidences in female mice receiving N-methylolacrylamide (3/50; 39/45; 38/47). The incidences of benign granulosa cell tumors were also increased in the dosed groups (0/50; 5/45; 5/47). The incidence of adenomas of the pars distalis in high dose female mice was significantly lower than that in vehicle controls (13/49; 5/14; 4/43). Genetic Toxicology: N-Methylolacrylamide was not mutagenic in S. typhimurium strains TA97, TA98, TA100, or TA1535 when tested with or without exogenous metabolic activation. N-Methylolacrylamide induced both sister chromatid exchanges (SCEs) and chromosomal aberrations in CHO cells with and without metabolic activation. No increase in micronucleated polychromatic erythrocytes (PCEs) was observed in the bone marrow of B6C3F1 mice after intraperitoneal injection of N-methylolacrylamide. Conclusions: Under the conditions of these 2-year studies, there was no evidence of carcinogenic activity of N-methylolacrylamide for male or female F344/N rats receiving doses of 6 or 12 mg/kg per day by aqueous gavage. There was clear evidence of carcinogenic activity of N-methylolacrylamide for male B6C3F1 mice, based on increased incidences of neoplasms of the Harderian gland, liver, and lung. There was clear evidence of carcinogenic activity of N-methylolacrylamide for female B6C3F1 mice, based on increased incidences of neoplasms of the Harderian gland, liver, lung, and ovary. In rats, because no biologically important toxic effects were attributed to N-methylolacrylamide administration, somewhat higher doses could have been used to increase the sensitivity of these studies for determining the presence or absence of a carcinogenic response. In female mice, ovarian atrophy was compound related. Synonyms: N-(hydroxymethyl)acrylamide; N-(hydroxymethyl)-2-propenamide; N-methanolacrylamide; monomethylolacrylamide	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
In the present monograph, the taxonomy of the species of the genus Maladera Mulsant Rey, 1871 from China is revised. We recorded 224 valid species for China, including 152 species new to science: Maladera allonitens Ahrens, Fabrizi Liu, sp. n., M. anhuiensis Ahrens, Fabrizi Liu, sp. n., M. apicalis Ahrens, Fabrizi Liu, sp. n., M. aptera Ahrens, Fabrizi Liu, sp. n., M. baii Ahrens, Fabrizi Liu, sp. n., M. baishaoensis Ahrens, Fabrizi Liu, sp. n., M. bansongchana Ahrens, Fabrizi Liu, sp. n., M. baoxingensis Ahrens, Fabrizi Liu, sp. n., M. bawanglingana Ahrens, Fabrizi Liu, sp. n., M. bawanglingensis Ahrens, Fabrizi Liu, sp. n., M. beibengensis Ahrens, Fabrizi Liu, sp. n., M. beidouensis Ahrens, Fabrizi Liu, sp. n., M. bikouensis Ahrens, Fabrizi Liu, sp. n., M. breviclava Ahrens, Fabrizi Liu, sp. n., M. bubengensis Ahrens, Fabrizi Liu, sp. n., M. businskyorum Ahrens, Fabrizi Liu, sp. n., M. chenzhouana Ahrens, Fabrizi Liu, sp. n., M. constellata Ahrens, Fabrizi Liu, sp. n., M. crenatotibialis Ahrens, Fabrizi Liu, sp. n., M. crenolatipes Ahrens, Fabrizi Liu, sp. n., M. daanensis Ahrens, Fabrizi Liu, sp. n., M. dadongshanica Ahrens, Fabrizi Liu, sp. n., M. dahongshanica Ahrens, Fabrizi Liu, sp. n., M. dajuensis Ahrens, Fabrizi Liu, sp. n., M. danfengensis Ahrens, Fabrizi Liu, sp. n., M. dayaoshanica Ahrens, Fabrizi Liu, sp. n., M. diaolinensis Ahrens, Fabrizi Liu, sp. n., M. emeifengensis Ahrens, Fabrizi Liu, sp. n., M. enigma Ahrens, Fabrizi Liu, sp. n., M. erlangshanica Ahrens, Fabrizi Liu, sp. n., M. eshanensis Ahrens, Fabrizi Liu, sp. n., M. excisilabrata Ahrens, Fabrizi Liu, sp. n., M. fangana Ahrens, Fabrizi Liu, sp. n., M. fangchengensis Ahrens, Fabrizi Liu, sp. n., M. fencli Ahrens, Fabrizi Liu, sp. n., M. fengyangshanica Ahrens, Fabrizi Liu, sp. n., M. fereobscurata Ahrens, Fabrizi Liu, sp. n., M. filigraniforceps Ahrens, Fabrizi Liu, sp. n., M. flavipennis Ahrens, Fabrizi Liu, sp. n., M. fuanensis Ahrens, Fabrizi Liu, sp. n., M. guangdongana Ahrens, Fabrizi Liu, sp. n., M. guangzhaishanica Ahrens, Fabrizi Liu, sp. n., M. guanxianensis Ahrens, Fabrizi Liu, sp. n., M. guanxiensis Ahrens, Fabrizi Liu, sp. n., M. guomenshanensis Ahrens, Fabrizi Liu, sp. n., M. guomenshanica Ahrens, Fabrizi Liu, sp. n., M. gusakovi Ahrens, Fabrizi Liu, sp. n., M. haba Ahrens, Fabrizi Liu, sp. n., M. habashanensis Ahrens, Fabrizi Liu, sp. n., M. hajeki Ahrens, Fabrizi Liu, sp. n., M. hansmalickyi Ahrens, Fabrizi Liu, sp. n., M. hongyuanensis Ahrens, Fabrizi Liu, sp. n., M. houzhenziensis Ahrens, Fabrizi Liu, sp. n., M. hsui Ahrens, Fabrizi Liu, sp. n., M. huanianensis Ahrens, Fabrizi Liu, sp. n., M. hubeiensis Ahrens, Fabrizi Liu, sp. n., M. hui Ahrens, Fabrizi Liu, sp. n., M. hunanensis Ahrens, Fabrizi Liu, sp. n., M. hunuguensis Ahrens, Fabrizi Liu, sp. n., M. hutiaoensis Ahrens, Fabrizi Liu, sp. n., M. jaroslavi Ahrens, Fabrizi Liu, sp. n., M. jatuai Ahrens, Fabrizi Liu, sp. n., M. jiangi Ahrens, Fabrizi Liu, sp. n., M. jingdongensis Ahrens, Fabrizi Liu, sp. n., M. jinggangshanica Ahrens, Fabrizi Liu, sp. n., M. jinghongensis Ahrens, Fabrizi Liu, sp. n., M. jiucailingensis Ahrens, Fabrizi Liu, sp. n., M. jizuana Ahrens, Fabrizi Liu, sp. n., M. juntongi Ahrens, Fabrizi Liu, sp. n., M. juxianensis Ahrens, Fabrizi Liu, sp. n., M. kalawensis Ahrens, Fabrizi Liu, sp. n., M. kryschanowskii Ahrens, Fabrizi Liu, sp. n., M. kubeceki Ahrens, Fabrizi Liu, sp. n., M. laocaiensis Ahrens, Fabrizi Liu, sp. n., M. lianxianensis Ahrens, Fabrizi Liu, sp. n., M. liaochengensis Ahrens, Fabrizi Liu, sp. n., M. liwenzhui Ahrens, Fabrizi Liu, sp. n., M. longruiensis Ahrens, Fabrizi Liu, sp. n., M. luoxiangensis Ahrens, Fabrizi Liu, sp. n., M. lushanensis Ahrens, Fabrizi Liu, sp. n., M. lushuiensis Ahrens, Fabrizi Liu, sp. n., M. maguanensis Ahrens, Fabrizi Liu, sp. n., M. maoershana Ahrens, Fabrizi Liu, sp. n., M. mupingensis Ahrens, Fabrizi Liu, sp. n., M. nabanensis Ahrens, Fabrizi Liu, sp. n., M. nanlingensis Ahrens, Fabrizi Liu, sp. n., M. nanpingensis Ahrens, Fabrizi Liu, sp. n., M. ninglangensis Ahrens, Fabrizi Liu, sp. n., M. panyuensis Ahrens, Fabrizi Liu, sp. n., M. parabrunnescens Ahrens, Fabrizi Liu, sp. n., M. paradetersa Ahrens, Fabrizi Liu, sp. n., M. paranitens Ahrens, Fabrizi Liu, sp. n., M. paraserripes Ahrens, Fabrizi Liu, sp. n., M. parobscurata Ahrens, Fabrizi Liu, sp. n., M. peregoi Ahrens, Fabrizi Liu, sp. n., M. pieli Ahrens, Fabrizi Liu, sp. n., M. pingchuanensis Ahrens, Fabrizi Liu, sp. n., M. pseudoconsularis Ahrens, Fabrizi Liu, sp. n., M. pseudoegregia Ahrens, Fabrizi Liu, sp. n., M. pseudoexima Ahrens, Fabrizi Liu, sp. n., M. pseudofuscipes Ahrens, Fabrizi Liu, sp. n., M. pseudonitens Ahrens, Fabrizi Liu, sp. n., M. pseudosenta Ahrens, Fabrizi Liu, sp. n., M. pui Ahrens, Fabrizi Liu, sp. n., M. putaodiensis Ahrens, Fabrizi Liu, sp. n., M. qianqingtangensis Ahrens, Fabrizi Liu, sp. n., M. queinneci Ahrens, Fabrizi Liu, sp. n., M. riberai Ahrens, Fabrizi Liu, sp. n., M. robustula Ahrens, Fabrizi Liu, sp. n., M. rubriventris Ahrens, Fabrizi Liu, sp. n., M. rufonitida Ahrens, Fabrizi Liu, sp. n., M. rufopaca Ahrens, Fabrizi Liu, sp. n., M. sanqingshanica Ahrens, Fabrizi Liu, sp. n., M. serratiforceps Ahrens, Fabrizi Liu, sp. n., M. shaluishanica Ahrens, Fabrizi Liu, sp. n., M. shangraoensis Ahrens, Fabrizi Liu, sp. n., M. shaowuensis Ahrens, Fabrizi Liu, sp. n., M. shenglongi Ahrens, Fabrizi Liu, sp. n., M. shengqiaoae Ahrens, Fabrizi Liu, sp. n., M. shiniushanensis Ahrens, Fabrizi Liu, sp. n., M. shiruguanensis Ahrens, Fabrizi Liu, sp. n., M. shiwandashanensis Ahrens, Fabrizi Liu, sp. n., M. shoumanensis Ahrens, Fabrizi Liu, sp. n., M. sinobiloba Ahrens, Fabrizi Liu, sp. n., M. snizeki Ahrens, Fabrizi Liu, sp. n., M. songi Ahrens, Fabrizi Liu, sp. n., M. taiyangheensis Ahrens, Fabrizi Liu, sp. n., M. tengchongensis Ahrens, Fabrizi Liu, sp. n., M. tiachiensis Ahrens, Fabrizi Liu, sp. n., M. tiammushanica Ahrens, Fabrizi Liu, sp. n., M. tiani Ahrens, Fabrizi Liu, sp. n., M. tianzushanica Ahrens, Fabrizi Liu, sp. n., M. tongzhongensis Ahrens, Fabrizi Liu, sp. n., M. trifidiforceps Ahrens, Fabrizi Liu, sp. n., M. uncipenis Ahrens, Fabrizi Liu, sp. n., M. wandingana Ahrens, Fabrizi Liu, sp. n., M. weni Ahrens, Fabrizi Liu, sp. n., M. wipfleri Ahrens, Fabrizi Liu, sp. n., M. wulaoshanica Ahrens, Fabrizi Liu, sp. n., M. wuliangshanensis Ahrens, Fabrizi Liu, sp. n., M. wupingensis Ahrens, Fabrizi Liu, sp. n., M. xingkei Ahrens, Fabrizi Liu, sp. n., M. xingkeyangi Ahrens, Fabrizi Liu, sp. n., M. xinqiaoensis Ahrens, Fabrizi Liu, sp. n., M. xuezhongi Ahrens, Fabrizi Liu, sp. n., M. yakouensis Ahrens, Fabrizi Liu, sp. n., M. yangi Ahrens, Fabrizi Liu, sp. n., M. yibini Ahrens, Fabrizi Liu, sp. n., M. yipinglangensis Ahrens, Fabrizi Liu, sp. n., M. yongrenensis Ahrens, Fabrizi Liu, sp. n., M. yunnanica Ahrens, Fabrizi Liu, sp. n., M. zhejiangensis Ahrens, Fabrizi Liu, sp. n. The work also resulted in nine new combinations and 17 new synonyms: Maladera (subgenus Omaladera Reitter, 1896) (= Cephaloserica Brenske, 1900, syn. n.; = Coronoserica Brenske, 1902, syn. n.); Maladera formosae (Brenske, 1898) (= Autoserica castanea Arrow, 1913, syn. n.; = Serica korgei Petrovitz, 1967, syn. n.); Maladera motschulskyi (Brenske, 1897) (= Autoserica furcillata Brenske, 1897, syn. n.; Serica schoenfeldti Murayama, 1937, syn. n.); Maladera pallida (Burmeister, 1855) comb. n. (= Maladera ludipennis Miyake, Yamaguchi Aoki 2002, syn. n.); Maladera renardi (Ballion, 1870) (= Serica delicta Brenske, 1897, syn. n.); Maladera secreta (Brenske, 1897) (= Autoserica cruralis Frey, 1972, syn. n.); Maladera verticalis (Fairmaire, 1888) (= Autoserica hiekei Frey, 1972, syn. n.); Maladera futschauana (Brenske, 1897) (= Autoserica atavana Brenske, 1902, syn. n.; = Autoserica montivaga Moser, 1915, syn. n.); Maladera aureola (Murayama, 1938) (= Maladera liotibia Nomura, 1974, syn. n.); Maladera brunnescens (Frey, 1972) comb. n., Maladera exima (Arrow, 1946) comb. n., Maladera gansuensis (Miyake Yamaya, 2001) comb. n., Maladera nigrobrunnea (Moser, 1926) comb. n., Maladera orientalis (Motschulsky, 1858) (= Serica salebrosa Brenske, 1897, syn. n.; =Autoserica davidis Brenske, 1898, syn. n.; = Serica mirabilis Brenske, 1894, syn. n.), Maladera punctulata (Frey, 1972) comb. n., Maladera rotunda (Arrow, 1946) comb. n., Maladera serripes (Moser, 1915) comb. n., Maladera senta (Brenske, 1897) (= Autoserica subspinosa Brenske, 1898, syn n.); Maladera spissigrada (Brenske, 1897) (= Serica nakayamai Murayama, 1938, syn. n.); Maladera tibialis (Brenske, 1898) comb. n. The lectotypes of the following species were designated: Autoserica furcillata Brenske, 1897, A. cariniceps Moser, 1915, A. diversipes Moser, 1915, A. flammea Brenske, 1898, A. fuscipes Moser, 1915, A. gibbiventris Brenske, 1897, A. hongkongica Brenske, 1898, A. obscurata Moser, 1915, A. piceola Moser, 1915, Serica delicta Brenske, 1897, S. exigua Brenske, 1894, S. nigrobrunnea Moser, 1926, S. orientalis Motschulsky, 1858, S. pallida Burmeister, 1855, S. salebrosa Brenske, 1897, and S. sibirica Brenske, 1897. Keys to the subgenera and species groups of Maladera, as well as a key to the species within each species-group are provided. Furthermore, we provide maps of the species distribution, as well as illustrations of the habitus and male genitalia.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. 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Nitrofurazone is a synthetic furan derivative, active against a broad spectrum of bacteria, which has been widely used in veterinary and human medicine. Toxicology and carcinogenesis studies were conducted by feeding diets containing nitrofurazone (99% pure) to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Fourteen-Day and Thirteen-Week Studies: Groups of five males and five females of each species were fed diets containing 0, 630, 1,250, 2,500, 5,000, or 10,000 ppm for 14 consecutive days. Early deaths occurred in all groups of rats receiving 5,000 or 10,000 ppm nitrofurazone. The surviving rats in the lower two dose groups gained weight, but weight gain was decreased as the dose of nitrofurazone was increased. Feed consumption by rats of each sex was decreased at all doses above 630 ppm. In all dosed groups, clinical signs of toxicity included rough hair coats and lethargy. At doses of 2,500 ppm and above, rats of each sex exhibited intermittent episodes of seizures and lethargy. All mice that received 2,500, 5,000, or 10,000 ppm nitrofurazone and 3/5 males that received 1,250 ppm died before the end of the 14-day studies; the surviving dosed mice (except females at 630 ppm) lost weight. A dose-related decrease in feed consumption was observed at all doses above 630 ppm. Clinical signs included rough hair coats and convulsive seizures. In the 13-week studies, groups of 10 rats of each sex were given diets containing 0, 150, 310, 620, 1,250, or 2,500 ppm nitrofurazone. No deaths were observed and all animals gained weight, but the magnitude of weight gain was dose dependent with decrements in final mean body weight for the highest dose group reaching 55% in males and 36% in females. Other evidence of chemically related toxicity included convulsive seizures, osteoporosis, degenerative arthropathy, and gonadal hypoplasia in both sexes at the two highest doses. Groups of 10 mice of each sex were given diets containing 0, 70, 150, 310, 620, or 1,250 ppm nitrofurazone for 13 weeks. Early deaths were observed in the two highest dose groups of each sex. The final mean body weights of male and female mice in the 1,250-ppm groups were about 20% lower than those of the controls; weight gains of the other dosed mice were comparable to those of the controls. Stimulus-induced convulsive seizures were observed for all mice in the two highest dose groups. Testicular hypoplasia was observed in the two highest dose groups of male mice. Body Weight and Survival in the Two-Year Studies: Dietary concentrations for the 2-year studies were 0, 310, or 620 ppm for rats and 0, 150, or 310 ppm for mice (50 animals per dose group). Mean body weights of high dose male rats were lower than those of the controls after week 39; mean body weights of low dose male rats and of the controls were comparable throughout the study. Final mean body weights of low and high dose female rats were 9% and 21% lower than those of the controls. Dosed rats consumed less feed than did the controls. The average amount of nitrofurazone consumed per day was approximately 11-12 or 24-26 mg/kg by low or high dose male and female rats. The survival of the high dose group of male rats was lower than that of the controls after week 92 (final survival-- male: control, 33/50; low dose, 30/50; high dose, 20/50; female: 28/50; 37/50; 31/50). Mean body weights of dosed mice were similar to or somewhat greater than those of controls throughout most of the studies. The average daily feed consumption by dosed mice was similar to that of controls. The average amount of nitrofurazone consumed per day was approximately 14-16 or 29-33 mg/kg for low or high dose male and female mice. The survival of the high dose group of male mice was lower than that of the controls after week 88 (final survival-- male: 39/50; 31/50; 27/50; female: 39/50; 40/50; 35/50). In mice of each sex, nitrofurazone administration induced stimulus-sensitive convulsive seizures beginning at week 4 or 5 for high dose mice and week 24 for low dose female mice. These seizures were low dose female mice. These seizures were observed primarily in the first year of the study. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Degenerative changes involving the vertebral and femoro-tibial (knee) joints were observed at increased incidences in dosed rats. The degenerative changes primarily affected the articular cartilage and were similar to those seen in the 13-week studies. Degeneration of the sternal synchondroses was increased in high dose female rats. The osteoporosis seen in the 13-week studies was not observed in the 2-year studies. Testicular degeneration, characterized by atrophy of the germinal epithelium and aspermatogenesis, was observed at increased incidences in dosed male rats (control, 12/50; low dose, 49/50; high dose, 47/50). Adenomas of the sebaceous glands and trichoepitheliomas or sebaceous adenomas (combined) of the skin were observed in high dose male rats (0/50; 0/50; 5/50). Carcinomas of the preputial gland were increased in dosed male rats (1/50; 8/50; 5/50). The incidences of preputial gland adenomas or carcinomas (combined) in dosed male rats were not statistically greater than that in the controls (9/50; 16/50; 7/50). However, in the low dose group, the incidence is greater than the highest incidence observed in historical untreated control groups (9/50). In addition, hyperplasia of the preputial gland was observed in six low dose male rats in which neither adenomas nor carcinomas occurred. The incidence of mesotheliomas of the tunica vaginalis in low dose male rats was greater than that in the controls (0/50; 7/50; 2/50). Fibroadenomas of the mammary gland occurred at markedly increased incidences in dosed female rats (8/49; 36/50; 36/50). Three adenocarcinomas were also observed (1/49; 0/50; 2/50). Ovarian atrophy (7/47; 44/50; 38/50) and tubular cell hyperplasia of the ovary (1/47; 23/50; 21/50) were observed at markedly increased incidences in dosed female mice. The incidences of benign mixed tumors (0/47; 17/50; 20/50), granulosa cell tumors (1/47; 4/50; 9/50), and granulosa cell tumors or luteomas (combined) (3/47; 6/50; 9/50) of the ovary were increased in exposed female mice. Mononuclear cell leukemia in rats occurred with negative trends (male: 21/50; 23/50; 6/50; female: 15/49; 2/50; 2/50). In female mice, the incidences of adenomas or carcinomas (combined) of the anterior pituitary gland occurred with a negative trend (10/50; 7/50; 2/49). The incidences of testicular interstitial cell tumors were decreased in dosed male rats (45/50; 30/50; 28/50). Genetic Toxicity: Nitrofurazone was mutagenic in Salmonella typhimurium strains TA98 and TA100 both with and without exogenous metabolic activation. The responses in strains TA1535 and TA1537 were more varied: nitrofurazone was mutagenic in strain TA1535 only in the presence of S9 and produced no consistent increase in gene reversions in strain TA1537 with or without S9. In the absence of metabolic activation, nitrofurazone induced forward mutations at the TK+/- locus of mouse L5178Y lymphoma cells; the chemical was not tested with S9. Treatment of cultured Chinese hamster ovary cells with nitrofurazone in the absence of S9 produced a dose-related increase in sister chromatid exchanges and chromosomal aberrations; with S9, sister chromatid exchanges were increased, but no induction of chromosomal aberrations was observed. Audit: The data, documents, and pathology materials from the 2-year studies of nitrofurazone were audited at the NTP Archives. The audit findings show that the conduct of the studies is documented adequately and support the data and results given in this Technical Report. Conclusions: Under the conditions of these 2-year feed studies, there was equivocal evidence of carcinogenic activity of nitrofurazone for male F344/N rats as shown by the occurrence of sebaceous gland adenomas and trichoepitheliomas of the skin, mesotheliomas of the tunica vaginalis, and preputial gland tumors. There was clear evidence of carcinogenic activity of nitrofurazone for female F344/N rats as shown by a markedly increased incidence of fibroadenomas of the mammary gland. There was no evidence of carcinogenic activity for male B6C3F1 mice fed diets containing nitrofurazone at concentrations of 150 or 310 ppm. There was clear evidence of carcinogenic activity of nitrofurazone for female B6C3F1 mice as shown by increased incidences of benign mixed tumors and granulosa cell tumors of the ovary. Administration of nitrofurazone was associated with decreased incidences of mononuclear cell leukemia in male and female rats, testicular interstitial cell tumors in male rats, and pituitary gland neoplasms in female mice. Convulsive seizures in mice of each sex, ovarian atrophy in female mice, testicular degeneration in rats, and degeneration of articular cartilage in rats were all associated with the administration of nitrofurazone. Synonyms: 5-nitro-2-furaldehyde semicarbazone; 2-[(5-nitro-2-furanyl)methylene]hydrazine carboximide Trade Names: Aldomycin; Amifur; Chemfuran; Coxistat; Furacin; Furacinetten; Furaplast; Furazol W; Furesol; Furracoccid; Mammex; Nefco; Nifuzon; Nitrofural; Vabrocid	Given the following content, create a question whose answer can be found within the content. 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Baricitinib is supposed to have a double effect on SARS-CoV2 infection. Firstly, it reduces the inflammatory response through the inhibition of the Januse-Kinase signalling transducer and activator of transcription (JAK-STAT) pathway. Moreover, it reduces the receptor mediated viral endocytosis by AP2-associated protein kinase 1 (AAK1) inhibition. We propose the use of baricinitib to prevent the progression of the respiratory insufficiency in SARS-CoV2 pneumonia in onco-haematological patients. In this phase Ib/II study, the primary objective in the safety cohort is to describe the incidence of severe adverse events associated with baricitinib administration. The primary objective of the randomized phase (baricitinib cohort versus standard of care cohort) is to evaluate the number of patients who did not require mechanical oxygen support since start of therapy until day +14 or discharge (whichever it comes first). The secondary objectives of the study (only randomized phase of the study) are represented by the comparison between the two arms of the study in terms of mortality and toxicity at day+30. Moreover, a description of the immunological related changes between the two arms of the study will be reported. The trial is a phase I/II study with a safety run-in cohort (phase 1) followed by an open label phase II randomized controlled trial with an experimental arm compared to a standard of care arm. The study will be performed at the Institut Català d'Oncologia, a tertiary level oncological referral center in the Catalonia region (Spain). The eligibility criteria are: patients > 18 years affected by oncological diseases; ECOG performance status < 2 (Karnofsky score > 60%); a laboratory confirmed infection with SARS-CoV-2 by means of real -time PCR; radiological signs of low respiratory tract disease; absence of organ dysfunction (a total bilirubin within normal institutional limits, AST/ALT≤2.5 X institutional upper limit of normal, alkaline phosphatase ≤2.5 X institutional upper limit of normal, coagulation within normal institutional limits, creatinine clearance >30 mL/min/1.73 m<sup2</sup for patients with creatinine levels above institutional normal); absence of HIV infection; no active or latent HBV or HCV infection. The exclusion criteria are: patients with oncological diseases who are not candidates to receive any active oncological treatment; hemodynamic instability at time of study enrollment; impossibility to receive oral medication; medical history of recent or active pulmonary embolism or deep venous thrombosis or patients at high-risk of suffering them (surgical intervention, immobilization); multi organ failure, rapid worsening of respiratory function with requirement of fraction of inspired oxygen (FiO<sub2</sub) > 50% or high-flow nasal cannula before initiation of study treatment; uncontrolled intercurrent illness (ongoing or severe active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements); allergy to one or more of study treatments; pregnant or breastfeeding women; positive pregnancy test in a pre-dose examination. Patients should have the ability to understand, and the willingness to sign, a written informed consent document; the willingness to accept randomization to any assigned treatment arm; and must agree not to enroll in another study of an investigational agent prior to completion of Day +28 of study. An electronic Case Report Form in the Research Electronic Data Capture (REDCap) platform will be used to collect the data of the trial. Removal from the study will apply in case of unacceptable adverse event(s), development of an intercurrent illness, condition or procedural complication, which could interfere with the patient's continued participation and voluntary patient withdrawal from study treatment (all patients are free to withdraw from participation in this study at any time, for any reasons, specified or unspecified, and without prejudice). Treatment will be administered on an inpatient basis. We will compare the experimental treatment with baricitinib plus the institutional standard of care compared with the standard of care alone. During the phase I, we will define the dose-limiting toxicity of baricitinib and the dose to be used in the phase 2 part of the study. The starting baricitinib dose will be an oral tablet 4 mg-once daily which can be reduced to 2 mg depending on the observed toxicity. The minimum duration of therapy will be 5 days and it can be extended to 7 days. The standard of care will include the following therapies. Antibiotics will be individualized based on clinical suspicion, including the management of febrile neutropenia. Prophylaxis of thromboembolic disease will be administered to all participants. Remdesivir administration will be considered only in patients with severe pneumonia (SatO<sub2</sub <94%) with less than 7 days of onset of symptoms and with supplemental oxygen requirements but not using high-flow nasal cannula, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO). In the randomized phase, tocilizumab or interferon will not be allowed in the experimental arm. Tocilizumab can be used in patients in the standard of care arm at the discretion of the investigator. If it is prescribed it will be used according to the following criteria: patients who, according to his baseline clinical condition, would be an ICU tributary, interstitial pneumonia with severe respiratory failure, patients who are not on mechanical ventilation or ECMO and who are still progressing with corticoid treatment or if they are not candidates for corticosteroids. Mild ARDS (PAFI <300 mmHg) with radiological or blood gases deterioration that meets at least one of the following criteria: CRP >100mg/L D-Dimer >1,000μg/L LDH >400U/L Ferritin >700ng/ml Interleukin 6 ≥40ng/L. The use of tocilizumab is not recommended if there are AST/ALT values greater than 10 times the upper limit of normal, neutrophils <500 cells/mm3, sepsis due to other pathogens other than SARS-CoV-2, presence of comorbidity that can lead to a poor prognosis, complicated diverticulitis or intestinal perforation, ongoing skin infection. The dose will be that recommended by the Spanish Medicine Agency in patients ≥75Kg: 600mg dose whereas in patients <75kg: 400mg dose. Exceptionally, a second infusion can be assessed 12 hours after the first in those patients who experience a worsening of laboratory parameters after a first favourable response. The use of corticosteroids will be recommended in patients who have had symptoms for more than 7 days and who meet all the following criteria: need for oxygen support, non-invasive or invasive mechanical ventilation, acute respiratory failure or rapid deterioration of gas exchange, appearance or worsening of bilateral alveolar-interstitial infiltrates at the radiological level. In case of indication, it is recommended: dexamethasone 6mg/d p.o. or iv for 10 days or methylprednisolone 32mg/d orally or 30mg iv for 10 days or prednisone 40mg day p.o. for 10 days. Phase 1 part: to describe the toxicity profile of baricitinib in COVID19 oncological patients during the 5-7 day treatment period and until day +14 or discharge (whichever it comes first). Phase 2 part: to describe the number of patients in the experimental arm that will not require mechanical oxygen support compared to the standard of care arm until day +14 or discharge (whichever it comes first). For the phase 2 of the study, the allocation ratio will be 1:1. Randomization process will be carried out electronically through the REDcap platform ( https://www.project-redcap.org/ ) BLINDING (MASKING): This is an open label study. No blinding will be performed. The first part of the study (safety run-in cohort) will consist in the enrollment of 6 to 12 patients. In this population, we will test the toxicity of the experimental treatment. An incidence of severe adverse events grade 3-4 (graded by Common Terminology Criteria for Adverse Events v.5.0) inferior than 33% will be considered sufficient to follow with the next part of the study. The second part of the study we will perform an interim analysis of efficacy at first 64 assessed patients and a definitive one will analyze 128 assessed patients. Interim and definitive tests will be performed considering in both cases an alpha error of 0.05. We consider for the control arm this rate is expected to be 0.60 and for the experimental arm of 0.80. Considering this data, a superiority test to prove a difference of 0.20 with an overall alpha error of 0.10 and a beta error of 0.2 will be performed. Considering a 5% of dropout rate, it is expected that a total of 136 patients, 68 for each study arm, will be required to complete study accrual. Version 5.0. 14<supth</sup October 2020 Recruitment started on the 16<supth</sup of December 2020. Expected end of recruitment is June 2021. AEMPs: 20-0356 EudraCT: 2020-001789-12, https://www.clinicaltrialsregister.eu/ctr-search/search (Not publically available as Phase I trial) Clinical trials: BARCOVID19, https://www.clinicaltrials.gov/ (In progress) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol."	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
A detailed and correct pretherapeutic evaluation of stage and resectability is mandatory for an optimal treatment strategy and results in patients with cancer of the esophagus, stomach or pancreas (UGIC). Curative surgery should only be attempted in patients with limited extent of their disease, patients with locally advanced disease should be allocated for neo-adjuvant therapy, while the remaining patients should be referred for palliative measures following a quick, lenient and correct pretherapeutic evaluation. This thorough evaluation and subsequent treatment assignment is also valuable in the identification of uniform patient cohorts for new treatment protocols as well as for the continuing comparison of research data. But despite the importance of accurate pretherapeutic assessment being repeatedly emphasized insufficient staging has been - and is still accepted as - leading to high rates of explorative surgery as well as heterogeneous selection of patients for new treatment trials. Based on the results from the authors PhD thesis he concluded that endoscopic ultrasonography (EUS) as a single imaging modality provided detailed information that hitherto had been inaccessible. EUS was considered a significant progress regarding the loco-regional assessment of stage and resectability, but it was also evident that EUS alone was incapable of providing all the necessary information. In addition, there were no evidence regarding the EUS safety profile, patient tolerance of the procedure and no data on the clinical impact of both EUS and EUS guided fine-needle aspiration biopsy (EUS-FNA) in UGIC patients. Therefore, the author chose to conduct additional EUS trials and to test the use of EUS-FNA, laparoscopy (LAP), laparoscopic ultrasonography (LUS) and LUS guided biopsy in order to improve the overall pretherapeutic evaluation and thus the patient selection. The aim of this thesis was to describe the sequential development, testing and clinical results of a new pretherapeutic evaluation strategy based on EUS and LUS. The value of EUS and EUS-FNA in the primary diagnosis of esophageal and gastric cancer was limited, but EUS-FNA was diagnostically relevant in 25% of the patients with pancreatic lesions and malignancy was confirmed in 86% of these patients. Comparison with other studies were difficult since no other trials have specifically focused on the clinical need for EUS-FNA regarding the primary diagnosis and resectability assessment. Stage and resectability assessment: TN staging based on EUS only provided accuracies above 80% for all cancer types when compared with histopathological or intraoperative findings. A similar high overall accuracy of EUS regarding pretherapeutic resectability assessment dropped to a significantly lower value when re-evaulated in a larger study under routine settings. There may be several explanations for this observation, but the move from a protocolled trial to a routine setting and the possibility of using LAP and LUS in the latter material may have influenced the decision and thus the results. The number of patients where EUS-FNA was indicated and performed remained constant over time, indicating adherence to the stringent biopsy criteria also outside a protocolled setup. EUS-FNA demonstrated a small (12%) but significant impact on the staging/resectability assessment and subsequent patient management. There were no differences between the impact in esophageal, gastric and pancreatic cancer, and the EUS-FNA verification of distant lymph nodes metastases was the major contributor to these results. Although EUS could detect and biopsy lesions not seen by CT, these imaging modalities were considered supplementary, but neither of these nor a combination of both was able to perform a complete evaluation of the TNM stage or the resectability. EUS tolerability, complications and patient satisfaction: Minor transient complaints after the EUS procedure was seen in one-third of the patients, but re-admission (0.7%), or contact to the patients GP (6.1%) due to complaints thought to be related to the EUS procedure were seldom. Overall EUS related morbidity and mortality in UGIC patients were 0.61% and 0.07%, respectively, and this was comparable to later series. Two-thirds of the complications in this study occurred in esophageal cancer patients as potential life threatening perforations. The conduction and evaluation of patient satisfaction surveys are complex and with a high risk of bias. Despite the reported pain, anxiety and discomfort more than 90% were prepared to undergo another EUS examination, and a similar proportion of patients were satisfied with the level of information provided before and after the examination. Treatment impact of EUS and the combination of EUS and LUS: The impact of EUS on treatment decisions in UGIC patients seemed lower than would have been expected from the EUS test performance. This observation suggested that the final treatment decision was based on several parameters, but at the same time stressed the importance of stringent EUS statements based on predefined standards. Lack of knowledge regarding advantages and limitations of EUS, situations where EUS was performed by non-surgeons, confusing terminology and conclusions as well as different treatment traditions may have influenced the comparison of data on the clinical impact of EUS. The inter-observer agreement on the treatment of UGIC patients was improved by EUS, and the ability to detect patients with non-resectable disease was the main reason for this among the one-third of all patients where EUS led to a change in the treatment approach. The clinical effect of a wrong EUS conclusion was limited, but EUS false positive resectability assessment may have denied up to 2% of the patients of a potentially curative resection. The combination of EUS and LUS solved the majority of problems related to EUS as a single imaging modality and related to the lack of deep vision during laparoscopy. The combination of EUS and LUS predicted R0 resection in 91% of the patients, thus significantly increasing the overall accuracy when compared to EUS alone. The prediction of R1/R2 resections showed similar results but with wide confidence intervals. Following EUS and LUS the number of futile laparotomies was reduced to 5%, and this figure dropped to 2.4% when patients who needed surgical by-pass were excluded. LUS guided biopsy: After having developed and tested a new system for LUS guided fine-needle aspiration biopsy and true-cut biopsy the author evaluated the need for biopsy using the same stringent indications as for EUS-FNA. LUS guided biopsies were indicated in 12% of the patients with a final malignant diagnosis. The major overall indication was lack of biopsy from the primary tumour. Adequate material was obtained in 95% of the biopsies despite being taken by six different surgeons. The overall combined impact of laparoscopic and LUS guided biopsy in patient management amounted to 27%. Cost-effectiveness of different imaging strategies in the detection of patients with non-resectable disease: In a retrospective design monitoring the costs on a departmental level EUS and LUS - or a combination with either of these - was cost-effective regarding the detection of patients with non-resectable or disseminated disease. The combination of non-invasive methods (e.g. CT and EUS) seemed attractive from an economical view-point, but such a strategy would be associated with futile surgery in 20% of the patients. However, the combination of EUS and LUS almost eliminated futile laparotomies, and at the same time remained cost-effective. Although not reported the data proved resistant to significant changes in both costs and effect, and the sequential use of EUS followed by laparoscopy and LUS seemed to be a cost-effective strategy. Combined pretherapeutic EUS and LUS as predictors of long-term survival: The literature has suggested a correlation between specific pretherapeutic EUS findings and the prognosis in UGIC patients. Based on an improved evaluation by the combination of EUS and LUS it was relevant to relate the pretherapeutic findings of this strategy to the final prognosis, and to do a stratified analysis based on both the stage and the resectability assessment. The combined approach of EUS and LUS provided relevant and significant stratification estimates of the prognosis in all three cancer types whether based on stage or on resectability assessment. EUS and LUS seemed superior to other imaging strategies regarding the identification of patients who may undergo a "true" R0 resection. Thus, EUS and LUS may have a positive impact on the prognosis of R0 resected UGIC patients. With the results from the present thesis the author has defined and tested a new evaluation strategy based on the combination of EUS and LUS. This combination was supplemented by EUS and LUS guided biopsies in those situations, where a malignant biopsy would change the subsequent treatment strategy. The combination of EUS and LUS was lenient, safe and cost-effective and at the same time provided additional, important pretherapeutic information regarding possible treatment options and the prognosis. It may be speculated if the improved patient selection has had a positive impact on the prognosis of the R0 resected patients. The combined strategy may also allow a more homogenous selection of patients for future treatment trials.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. 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Bromate is a drinking water disinfection by-product formed during the ozonation of source water containing bromide. Sodium bromate is also used as an analytical reagent, in the oxidation of sulfur and vat dyes, and for cleaning boilers. As a mixture with sodium bromide, it is used for dissolving gold from its ores. The cosmetic industry uses sodium bromate and potassium bromate as neutralizers or oxidizers in hair wave preparations. Sodium bromate was nominated for toxicity and carcinogenicity studies in transgenic mouse models by the United States Environmental Protection Agency and the National Institute of Environmental Health Sciences. Male and female Tg.AC hemizygous mice received sodium bromate by dermal application for 26 or 39 weeks and by exposure in drinking water for 27 or 43 weeks. Male and female p53 haploinsufficient mice were exposed to sodium bromate (at least 99% pure) in drinking water for 27 or 43 weeks. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. 26- and 39-WEEK DERMAL STUDIES IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice received dermal applications of 0, 64, 128, or 256 mg sodium bromate/kg body weight in ethanol/water, 5 days per week for 26 weeks. Additional groups of 10 male and 10 female Tg.AC hemizygous mice were dermally administered the same doses for 39 weeks. Survival of dosed groups was similar to that of vehicle control groups at 26 and 39 weeks. Mean body weights of 256 mg/kg males were less than those of the vehicle control group in both studies. Mean body weights of all dosed groups of females were less than those of the vehicle controls at 39 weeks. Minimal decreases in hematocrit and hemoglobin concentration values occurred in 128 mg/kg females and 256 mg/kg males and females at 26 weeks. A minimal decrease in erythrocyte count also occurred in 256 mg/kg males. These decreases in erythron were accompanied by a minimal decrease in mean cell hemoglobin and mean cell hemoglobin concentration values, primarily in the females. Reticulocyte counts were significantly increased in 128 mg/kg females and 256 mg/kg males and females. There were no increased incidences of neoplasms in male or female Tg.AC hemizygous mice exposed to sodium bromate dermally. Relative kidney weights were significantly increased in 256 mg/kg males at 26 weeks and in all dosed groups of males at 39 weeks. Absolute testis weights in 256 mg/kg males and absolute kidney weights in 256 mg/kg females were decreased at 39 weeks. Nephropathy occurred in 14 of 15 males receiving 128 and 256 mg/kg at 26 weeks and in all 256 mg/kg females in both studies. In the thyroid gland, the incidences of follicular cell hypertrophy in all dosed groups of males and females, follicular secretory depletion in 128 and 256 mg/kg females, and lymphocytic cellular infiltrate in 256 mg/kg females were significantly increased in both studies. Splenic hematopoietic cell proliferation occurred with a significantly increased incidence in 128 and 256 mg/kg females at 26 weeks. The incidence of germinal epithelium degeneration in the testis was significantly increased in 256 mg/kg males at 39 weeks. 27- AND 43-WEEK DRINKING WATER STUDIES IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were exposed to drinking water containing 0, 80, 400, or 800 mg/L sodium bromate for 27 weeks (equivalent to average daily doses of approximately 13, 63, and 129 mg/kg to male mice and 15, 72, and 148 mg/kg to female mice). Additional groups of 10 male and 10 female Tg.AC hemizygous mice were exposed to drinking water containing 0, 80, 400, or 800 mg/L sodium bromate for 43 weeks (equivalent to average daily doses of approximately 11, 52, and 131 mg/kg to male mice and 15, 65, and 152 mg/kg to female mice). Survival of exposed groups was similar to that of control groups at 27 weeks. Survival was decreased in 400 mg/L females and 800 mg/L males and females at 43 weeks. Mean body weights of 400 mg/L males and 800 mg/L males and females were less than those of the control groups in both studies. Water consumption by exposed mice was generally similar to that by control groups throughout both studies. Minimal decreases in hematocrit, hemoglobin concentration, and erythrocyte count values occurred primarily in 400 and 800 mg/kg females at 27 weeks. There were also decreases in mean cell hemoglobin and mean cell hemoglobin concentration values, but these occurred primarily in treated males. Reticulocyte counts were increased in 400 mg/kg males and 800 mg/kg males and females. There were no increased incidences of neoplasms in male or female Tg.AC hemizygous mice exposed to sodium bromate in the drinking water. Absolute kidney weights were significantly decreased in 800 mg/L females and relative kidney weights were increased in 400 and 800 mg/L males at 27 weeks. Absolute testis weights were significantly decreased in 800 mg/L males at 43 weeks. Thyroid gland follicular cell hypertrophy and follicular secretory depletion occurred in most 400 and 800 mg/L males and females at 27 weeks and in most exposed females at 43 weeks, and the incidences of thyroid gland follicular cell hypertrophy were significantly increased in all exposed groups of males at 43 weeks. The incidences of thyroid gland lymphocytic cellular infiltrates were significantly increased in 400 and 800 mg/L females in both studies and in 800 mg/L males at 43 weeks. The incidences of nephropathy were significantly increased in all exposed groups of males and in 400 and 800 mg/L females at 27 weeks. Renal tubule degeneration occurred with significantly increased incidences in 800 mg/L males and females in both studies. The incidences of renal tubule hypertrophy were significantly increased in 400 and 800 mg/L females at 27 weeks and in 800 mg/L males and females at 43 weeks. Pituitary gland pars distalis hypertrophy occurred with a significantly increased incidence in 800 mg/L females in both studies. The incidence of hyperkeratosis of the forestomach epithelium was significantly increased in 800 mg/L females at 43 weeks. The incidences of tubular degeneration of the epididymis and germinal epithelium degeneration of the testis were significantly increased in 800 mg/L males at 43 weeks. 27- AND 43-WEEK DRINKING WATER STUDIES IN p53 HAPLOINSURFFICIENT MICE: Groups of 15 male and 15 female p53 haploinsufficient mice were exposed to drinking water containing 0, 80, 400, or 800 mg/L sodium bromate for 27 weeks (equivalent to average daily doses of approximately 8, 39, and 74 mg/kg to males and 13, 72, and 136 mg/kg to females). Additional groups of 10 male and 10 female p53 haploinsufficient mice were exposed to drinking water containing 0, 80, 400, or 800 mg/L sodium bromate for 43 weeks (equivalent to average daily doses of approximately 7, 37, and 65 mg/kg to males and 11, 58, and 107 mg/kg to females). In both studies, survival of exposed groups was similar to that of control groups. Mean body weights of 400 and 800 mg/L females were less than those of the control groups during most of the studies. Water consumption by exposed mice was generally similar to that by control groups in both studies. No neoplasms or nonneoplastic lesions in male or female p53 haploinsufficient mice were attributed to exposure to sodium bromate in either study. Sodium bromate exposure resulted in significantly increased frequencies of micronucleated erythrocytes in male and female Tg.AC hemizygous and p53 haploinsufficient mice administered the chemical in drinking water for 27 weeks or by dermal application for 26 weeks. Tg.AC hemizygous mice were treated by both routes; p53 haploinsufficient mice were exposed only through drinking water. In all three micronucleus tests, a clear dose response was observed in male and female mice. Significant increases in the percentage of polychromatic erythrocytes among total erythrocytes were observed in male and female Tg.AC hemizygous mice exposed via drinking water and in male Tg.AC hemizygous mice dosed dermally with sodium bromate. The percentage of polychromatic erythrocytes was not significantly altered in male or female p53 mice. Under the conditions of these drinking water studies, there was no evidence of carcinogenic activity of sodium bromate in male or female p53 haploinsufficient mice exposed to 80, 400, or 800 mg/L for 27 or 43 weeks. No treatment-related neoplasms were seen in male or female Tg.AC hemizygous mice exposed dermally to 64, 128, or 256 mg sodium bromate/kg body weight for 26 or 39 weeks. No treatment-related neoplasms were seen in male or female Tg.AC hemizygous mice exposed by drinking water to 80, 400, or 800 mg sodium bromate/L for 27 or 43 weeks. In drinking water and dermal studies in Tg.AC hemizygous mice there were increased incidences of nonneoplastic lesions in the thyroid gland and kidney.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. 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Personal exposures and ambient concentrations of air toxics were characterized in a pollution "hot spot" and an urban reference site, both in Camden, New Jersey. The hot spot was the city's Waterfront South neighborhood; the reference site was a neighborhood, about 1 km to the east, around the intersection of Copewood and Davis streets. Using personal exposure measurements, residential ambient air measurements, statistical analyses, and exposure modeling, we examined the impact of local industrial and mobile pollution sources, particularly diesel trucks, on personal exposures and ambient concentrations in the two neighborhoods. Presented in the report are details of our study design, sample and data collection methods, data- and model-analysis approaches, and results and key findings of the study. In summary, 107 participants were recruited from nonsmoking households, including 54 from Waterfront South and 53 from the Copewood-Davis area. Personal air samples were collected for 24 hr and measured for 32 target compounds--11 volatile organic compounds (VOCs*), four aldehydes, 16 polycyclic aromatic hydrocarbons (PAHs), and particulate matter (PM) with an aerodynamic diameter < or = 2.5 microm (PM2.5). Simultaneously with the personal monitoring, ambient concentrations of the target compounds were measured at two fixed monitoring sites, one each in the Waterfront South and Copewood-Davis neighborhoods. To understand the potential impact of local sources of air toxics on personal exposures caused by temporal (weekdays versus weekend days) and seasonal (summer versus winter) variations in source intensities of the air toxics, four measurements were made of each subject, two in summer and two in winter. Within each season, one measurement was made on a weekday and the other on a weekend day. A baseline questionnaire and a time diary with an activity questionnaire were administered to each participant in order to obtain information that could be used to understand personal exposure to specific air toxics measured during each sampling period. Given the number of emission sources of air toxics in Waterfront South, a spatial variation study consisting of three saturation-sampling campaigns was conducted to characterize the spatial distribution of VOCs and aldehydes in the two neighborhoods. Passive samplers were used to collect VOC and aldehyde samples for 24- and 48-hr sampling periods simultaneously at 22 and 16 grid-based sampling sites in Waterfront South and Copewood-Davis, respectively. Results showed that measured ambient concentrations of some target pollutants (mean +/- standard deviation [SD]), such as PM2.5 (31.3 +/- 12.5 microg/m3), toluene (4.24 +/- 5.23 microg/m3), and benzo[a]pyrene (0.36 +/- 0.45 ng/m3), were significantly higher (P < 0.05) in Waterfront South than in Copewood-Davis, where the concentrations of PM2.5, toluene, and benzo[a]pyrene were 25.3 +/- 11.9 microg/m3, 2.46 +/- 3.19 microg/m3, and 0.21 +/- 0.26 ng/m3, respectively. High concentrations of specific air toxics, such as 60 microg/m3 for toluene and 159 microg/m3 for methyl tert-butyl ether (MTBE), were also found in areas close to local stationary sources in Waterfront South during the saturation-sampling campaigns. Greater spatial variation in benzene, toluene, ethylbenzene, and xylenes (known collectively as BTEX) as well as of MTBE was observed in Waterfront South than in Copewood-Davis during days with low wind speed. These observations indicated the significant impact of local emission sources of these pollutants and possibly of other pollutants emitted by individual source types on air pollution in Waterfront South. (Waterfront South is a known hot spot for these pollutants.) There were no significant differences between Waterfront South and Copewood-Davis in mean concentrations of benzene or MTBE, although some stationary sources of the two compounds have been reported in Waterfront South. Further, a good correlation (R > 0.6) was found between benzene and MTBE in both locations. These results suggest that automobile exhausts were the main contributors to benzene and MTBE air pollution in both neighborhoods. Formaldehyde and acetaldehyde concentrations were found to be high in both neighborhoods. Mean (+/- SD) concentrations of formaldehyde were 20.2 +/- 19.5 microg/m3 in Waterfront South and 24.8 +/- 20.8 microg/m3 in Copewood-Davis. A similar trend was observed for the two compounds during the saturation-sampling campaigns. The results indicate that mobile sources (i.e., diesel trucks) had a large impact on formaldehyde and acetaldehyde concentrations in both neighborhoods and that both are aldehyde hot spots. The study also showed that PM2.5, aldehydes, BTEX, and MTBE concentrations in both Waterfront South and Copewood-Davis were higher than ambient background concentrations in New Jersey and than national average concentrations, indicating that both neighborhoods are in fact hot spots for these pollutants. Higher concentrations were observed on weekdays than on weekend days for several compounds, including toluene, ethylbenzene, and xylenes (known collectively as TEX) as well as PAHs and PM2.5. These observations showed the impact on ambient air pollution of higher traffic volumes and more active industrial and commercial operations in the study areas on weekdays. Seasonal variations differed by species. Concentrations of TEX, for example, were found to be higher in winter than in summer in both locations, possibly because of higher emission rates from automobiles and reduced photochemical reactivity in winter. In contrast, concentrations of MTBE were found to be significantly higher in summer than in winter in both locations, possibly because of higher evaporation rates from gasoline in summer. Similarly, concentrations of heavier PAHs, such as benzo[a]pyrene, were found to be higher in winter in both locations, possibly because of higher emission rates from mobile sources, the use of home heating, and the reduced photochemical reactivity of benzo[a]pyrene in winter. In contrast, concentrations of lighter PAHs were found to be higher in summer in both locations, possibly because of volatilization of these compounds from various surfaces in summer. In addition, higher concentrations of formaldehyde were observed in summer than in winter, possibly because of significant contributions from photochemical reactions to formaldehyde air pollution in summer. Personal concentrations of toluene (25.4 +/- 13.5 microg/m3) and acrolein (1.78 +/- 3.7 microg/m3) in Waterfront South were found to be higher than those in the Copewood-Davis neighborhood (13.1 +/- 15.3 microg/m3 for toluene and 1.27 +/- 2.36 microg/m3 for acrolein). However, personal concentrations for most of the other compounds measured in Waterfront South were found to be similar to or lower than those than in Copewood-Davis. (For example, mean +/- SD concentrations were 4.58 +/- 17.3 microg/m3 for benzene, 4.06 +/- 5.32 microg/m3 for MTBE, 16.8 +/- 15.5 microg/m3 for formaldehyde, and 0.40 +/- 0.94 ng/m3 for benzo[a]pyrene in Waterfront South and 9.19 +/- 34.0 microg/m3 for benzene, 6.22 +/- 19.0 microg/m3 for MTBE, 16.0 +/- 16.7 microg/m3 for formaldehyde, and 0.42 +/- 1.08 ng/m3 for benzo[a]pyrene in Copewood-Davis.) This was probably because many of the target compounds had both outdoor and indoor sources. The higher personal concentrations of these compounds in Copewood-Davis might have resulted in part from higher exposure to environmental tobacco smoke (ETS) of subjects from Copewood-Davis. The Spearman correlation coefficient (R) was found to be high for pollutants with significant outdoor sources. The R's for MTBE and carbon tetrachloride, for example, were > 0.65 in both Waterfront South and Copewood-Davis. The R's were moderate or low (0.3-0.6) for compounds with both outdoor and indoor sources, such as BTEX and formaldehyde. A weaker association (R < 0.5) was found for compounds with significant indoor sources, such as BTEX, formaldehyde, PAHs, and PM2.5. The correlations between personal and ambient concentrations of MTBE and BTEX were found to be stronger in Waterfront South than in Copewood-Davis, reflecting the significant impact of local air pollution sources on personal exposure to these pollutants in Waterfront South. Emission-based ambient concentrations of benzene, toluene, and formaldehyde and contributions of ambient exposure to personal concentrations of these three compounds were modeled using atmospheric dispersion modeling and Individual Based Exposure Modeling (IBEM) software, respectively, which were coupled for analysis in the Modeling Environment for Total Risk (MENTOR) system. The compounds were associated with the three types of dominant sources in the two neighborhoods: industrial sources (toluene), exhaust from gasoline-powered motor vehicles (benzene), and exhaust from diesel-powered motor vehicles (formaldehyde). Subsequently, both the calculated and measured ambient concentrations of each of the three compounds were separately combined with the time diaries and activity questionnaires completed by the subjects as inputs to IBEM-MENTOR for estimating personal exposures from ambient sources. Modeled ambient concentrations of benzene and toluene were generally in agreement with the measured ambient concentrations within a factor of two, but the values were underestimated at the high-end percentiles. The major local (neighborhood) contributors to ambient benzene concentrations were from mobile sources in the study areas; both mobile and stationary (point and area) sources contributed to the ambient toluene concentrations. This finding can be used as guidance for developing better emission inventories to characterize, through modeling, the ambient concentrations of air toxics in the study areas. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The objective of this review is to examine conceptual and/or theoretical frameworks that are relevant to nurse practitioner education.The specific review question is: What conceptual and/or theoretical frameworks are available that are relevant to the structuring of nurse practitioner education? The use of conceptual and theoretical frameworks to organize the educational curriculum of nursing programs is essential to protect and preserve the focus and clarity of nursing's distinct contribution to health care. Conceptual frameworks of nursing provide a means to look at nursing in relationship to external factors, thereby assigning meaning to the practice. Graduate level nursing education in the preparation of Nurse Practitioners (NPs) specifically and Advanced Practice Nurses (APNs) in general, is significantly compromised by the tendency to conceptualize the learning in these complex programs as being primarily related to skills-based tasks and competencies alone. According to Baumann, advanced nursing education must focus on the uniqueness of the NP position, in contrast to other health care professions. To do this, Baumann suggests using a conceptual nursing model and nursing theory as opposed to a strictly biomedical model. This allows NPs to interpret information in a way that differs from the strict biomedical model, providing opportunities for the NPs to be truly present in the lives of their patients.Canadian Nurse Practitioner (NP) practice competency documents are based primarily on the Canadian Nurses Association (CNA) Nurse Practitioner (NP) Core Competency Framework. This document defines the core set of entry-level competencies required for all NPs to practice in all Canadian jurisdictions, settings and client populations. The Core Competencies in the CNA NP Framework are organized within four main categories: professional role, responsibility and accountability; health assessment and diagnosis; therapeutic management; and health promotion and prevention of illness and injury. Although vital to the organization of provincial entry-level registration standards, this framework provides little direction to educational providers for curricula organization and philosophical perspectives.The Canadian Association of Schools of Nursing developed a national framework for NP education following a multi-phase consultation and literature and curriculum synthesis project. While the task force addressed the guiding principles and essential components of NP education along with contextual factors that impact on the delivery of curricula in Canadian jurisdictions, the philosophical approaches guiding and organizing the education were not addressed.A similar set of documents has been created in the United States by the National Organization of Nurse Practitioner Faculties (NONPF). These documents are organized by six population level foci (including the specialty of family/individual across the lifespan) and outline core competencies for entry to practice and registration and educational standards. The Core Competency documents provided by the NONPF are presented in the same manner as the CNA NP Framework and likewise, do not provide a guiding or organizing framework or philosophy for NP education.A full curriculum overhaul based on the NONPF competency requirements was performed at a university center in Oregon. The new curriculum was based on competencies that students must acquire, rather than learning objectives. While the NONPF Framework does provide an extensive list of entry-level requirements for NPs, the challenges faced by the institution as it aimed to incorporate the framework into the curriculum clearly provide evidence that these overarching frameworks need to include both a philosophical and organizational component to help guide educators.Conceptual frameworks are useful for establishing a congruent relationship between program curricula, objectives and content. Walker and Avant advance the utility of conceptual frameworks as providing the logic behind the interrelationships of terms and variables, and improving explanation and understanding. Gold, Haas & King assert that conceptual frameworks facilitate grounding of a nursing lens in the curricula of advanced practice nursing programs. It has been noted that newly practicing NPs have demonstrated an allegiance withmedical model thinking, second only in importance to wellness/health promotion considerations. Blasdell and colleagues surveyed 188 practicing NPs to investigate the relationship between education and the use of theory in clinical practice. Educated graduate NPs rated the importance of nursing theory to the NP practice role significantly higher than did diploma and baccalaureate degree NPs (4.05±2.06 versus 2.65±1.69, p<.001) but both groups rated the nursing models as less important for practice than a medical model approach.Huckabay highlighted the need for the use of a harmonized nursing model at the undergraduate level to ensure that students have a thorough understanding of what nursing is and what nursing care entails. At the graduate level, Huckabay suggested the use of multiple nursing models, depending on specialty. Regardless of the educational level, a conceptual framework used for education must enable nurse educators to have sufficient guidelines to construct a curriculum and determine what knowledge and skills are needed by the nursing students. Further, Furlong identified the need for Advanced Practice Nursing (APN) curriculae to be innovative and critically reflective, preparing students to be readily adaptable to challenges in the work place. Furlong suggests that to do this, the curriculum must rely upon an interdisciplinary framework to deliver content. Gold, Haas & King suggest that core curricula based on a medical model or a skill-related task list do not reflect the critical thinking of nurses, nor the uniqueness of the profession. Thus, conceptual models used for curricula development must: encompass the distinct nursing worldview, promote learning, and be efficient and comprehensive.Frameworks have been proposed and tested to guide the development and implementation of inter-professional education (IPE) and collaborative practice curricula for NP and medical students. A qualitative assessment of a framework guided IPE module illustrated the benefit of improving the focus on role awareness in participating students. However, this particular curriculum was limited to a two-week period and not presented as a pervasive approach to the educational programs of each discipline.In education, an overarching philosophy can provide a road map for goal identification, teaching material development and the formulation of evaluation methods. For instance, when creating a curriculum that was a result of the collaboration of three different post-secondary institutions, the SHARE (students, humor, administrative support, resources, and educational technology) model was used. This model brings together resources, students and faculty, surrounding them with humor, which was viewed as a fundamental part of the process while the program was still in its early stages. According to the authors, the program has been widely successful and the reliance on humor as an underlying philosophy has enabled the students and faculty to deal with problems arising in the new program.Focusing on evaluation, Kapborg & Fischbein promoted the use of the Education Interaction Model. The model identifies how educational influences can interact with abilities of students and how the consequences of this interaction can be evaluated by observing changes in both students and programs. The authors argue that, while the educational interaction model is effective, it is not the only model that can be used to carry out evaluations. The authors stress that the model chosen to perform an evaluation should be based upon what or who is going to be evaluated.The standards outlined in the CNA NP framework are an essential part of organizing the education process for NPs and ensuring that NPs have acquired the necessary skills to practice in Canada as an NP. However, the framework is lacking philosophy and organization regarding NP education programs to ensure that the curriculum is preparing the NPs for the ever-changing work environment.An Australian survey of NP education documents from relevant universities as well as interviews with NPs and academic conveners from Australia and New Zealand found that, while NP educational programs need to have strong clinical and science based learning components, student directed and flexible learning models act to ensure the capability of NPs as they strive to adapt to practice situations. Capability, as an approach to the learning process, includes the flexibility to respond to the specific, self-identified learning needs of students. Knowing how to learn, having high self-efficacy, applying competencies to new tasks, collaborating with others, and being creative are all signs of a capable practitioner. Gardner et al. emphasized the need for a program that fosters both competent and capable NPs. In a follow-up study, using the same data, Gardner et al. confirmed that NPs viewed the attributes of a capable NP as imperative to practice. Thus, a framework for NP education must include both competency building elements, such as those currently found in the CNA NP framework and capability building elements which can be fostered through self-directed learning.Similarly, Schaefer investigated the role of caring in nursing practice through a class for APN students in which the students reflected on their narratives of caring for patients. This qualitative study revealed that when APN students provide care by meeting the complex needs of suffering patients, the art and science of nursing combine. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
To assess the efficacy of osteogenic protein-1 (OP-1) for long bone nonunion. Although most fractures heal within a normal period, about 5% to 10% do not heal and are classified as delayed or nonunion fractures. Nonunion and segmental bone loss after fracture, reconstructive surgery, or lesion excision can present complex orthopedic problems, and the multiple surgical procedures often needed are associated with patient morbidity and reduced quality of life. Many factors contribute to the pathogenesis of a delayed union or nonunion fractures, including deficiencies of calcium, vitamin D, or vitamin C, and side effects of medications such as anticoagulants, steroids, some anti-inflammatory drugs, and radiation. It has been shown that smoking interferes with bone repair in several ways. INCIDENCE OF NONUNION AND DELAYED UNION CASES: An estimated 5% to 10% of fractures do not heal properly and go on to delayed union or nonunion. If this overall estimate of incidence were applied to the Ontario population, the estimated number of delayed union or nonunion in the province would be between 3,863 and 7,725. TREATMENT OF NONUNION CASES: The treatment of nonunion cases is a challenge to orthopedic surgeons. However, the basic principle behind treatment is to provide both mechanical and biological support to the nonunion site. Fracture stabilization and immobilization is frequently used with the other treatment modalities that provide biological support to the fractured bone. Biological support includes materials that could be served as a source of osteogenic cells (osteogenesis), a stimulator of mesenchymal cells (osteoinduction), or a scaffold-like structure (osteoconduction). The capacity to heal a fracture is a latent potential of the stromal stem cells, which synthesize new bone. This process has been defined as osteogenesis. Activation of the stem cells to initiate osteogenic response and to differentiate into bone-forming osteoblasts is called osteoinduction. These 2 properties accelerate the rate of fracture healing or reactivate the ineffective healing process. Osteoconduction occurs when passive structures facilitate the migration of osteoprogenitor cells, the perivascular tissue, and capillaries into these structures. BONE GRAFTS AND BONE GRAFT SUBSTITUTES: Bone graft and bone graft substitutes have one or more of the following components: Undifferentiated stem cellsGrowth factorsStructural latticeUndifferentiated stem cells are unspecialized, multipotential cells that can differentiate into a variety of specialized cells. They can also replicate themselves. The role of stem cells is to maintain and repair the tissue in which they are residing. A single stem cell can generate all cell types of that tissue. Bone marrow is a source of at least 2 kinds of stem cells. Hematopoietic stem cells that form all types of blood cells, and bone marrow stromal stem cells that have osteogenic properties and can generate bone, cartilage, and fibrous tissue. Bone marrow has been used to stimulate bone formation in bone defects and cases of nonunion fractures. Bone marrow can be aspirated from the iliac crest and injected percutaneously with fluoroscopic guidance into the site of the nonunion fracture. The effectiveness of this technique depends on the number and activity of stem cells in the aspirated bone marrow. It may be possible to increase the proliferation and speed differentiation of stem cells by exposing them to growth factor or by combining them with collagen. Many growth factors and cytokines induced in response to injury are believed to have a considerable role in the process of repair. Of the many bone growth factors studied, bone morphogenetics (BMPs) have generated the greatest attention because of their osteoinductive potential. The BMPs that have been most widely studied for their ability to induce bone regeneration in humans include BMP-2 and BMP-7 (osteogenic protein). Human osteogenic protein-1 (OP-1) has been cloned and produced with recombinant technology and is free from the risk of infection or allergic reaction. The structural lattice is osteoconductive; it supports the ingrowth of developing capillaries and perivascular tissues. Three distinct groups of structural lattice have been identified: collagen, calcium sulphate, and calcium phosphate. These materials can be used to replace a lost segment of bone. GRAFTS USED FOR NONUNION: Autologous bone graft is generally considered the gold standard and the best material for grafting because it contains several elements that are critical in promoting bone formation, including osteoprogenitor cells, the matrix, and bone morphogenetic proteins. The osteoconductive property of cancellous autograft is related to the porosity of bone. The highly porous, scaffold-like structure of the graft allows host osteoblasts and host osteoprogenitor cells to migrate easily into the area of the defect and to begin regeneration of bone. Sources of cancellous bone are the iliac crest, the distal femur, the greater trochanter, and the proximal tibia. However, harvesting the autologous bone graft is associated with postoperative pain at the donor site, potential injury to the surrounding arteries, nerves, and tissues, and the risk of infection. Thus the development of synthetic materials with osteoconductive and osteoinductive properties that can eliminate the need for harvesting has become a major goal of orthopedic research. Allograft is the graft of tissue between individuals who are of the same species but are of a disparate genotype. Allograft has osteoconductive and limited osteoinductive properties. Demineralized bone matrix (DBM) is human cortical and cancellous allograft. These products are prepared by acid extraction of allograft bone, resulting in the loss of most of the mineralized component while collagen and noncollagenous proteins, including growth factors, are retained. Figures 1 to 5 demonstrate the osteogenic, osteoinduction, and osteoconduction properties of autologous bone graft, allograft, OP-1, bone graft substitutes, and bone marrow. Figure 1.Autologous Bone GraftFigure 2.Osteogenic Protein-1Figure 3.Allograft bone and Demineralized Bone MatrixFigure 4.Bone Graft SubstitutesFigure 5.Autologous Bone Marrow Graft NEW TECHNOLOGY BEING REVIEWED: OSTEOGENIC PROTEIN-1 Health Canada issued a Class IV licence for OP-1 in June 2004 (licence number 36320). The manufacturer of OP-1 is Stryker Biotech (Hapkinton, MA). The United States Food and Drug Administration (FDA) issued a humanitarian device exemption for the application of the OP-1 implant as an "alternative to autograft in recalcitrant long bone nonunions where use of autograft is unfeasible and alternative treatments have failed." Regulatory agencies in Europe, Australia, and New Zealand have permitted the use of this implant in specific cases, such as in tibial nonunions, or in more general cases, such as in long bone nonunions. According to the manufacturer, OP-1 is indicated for the treatment of long bone nonunions. It is contraindicated in the patient has a hypersensitivity to the active substance or collagen, and it should not be applied at the site of a resected tumour that is at or near the defect or fracture. Finally, it should not be used in patients who are skeletally immature (< 18 years of age), or if there is no radiological evidence of closure of epiphysis. To summarize the safety profile and effectiveness of OP-1 in the treatment of cases of long bone nonunion and bone defectsTo compare the effectiveness and cost effectiveness of OP-1 in the treatment of long bone nonunions and bone defects with the alternative technologies, particularly the gold standard autologous bone graft. International Network of Agencies for Health Technology Assessments (INAHTA), the Cochrane Database of Systematic Reviews and the CCTR (formerly Cochrane Controlled Trials Register) were searched for health technology assessments. MEDLINE, EMBASE, Medline In Process and Other Non-Indexed Citations were searched from January 1, 1996 to January 27, 2004 for studies on OP-1. The search was limited to English-language articles and human studies. The search yielded 47 citations. Three studies met inclusion criteria (2 RCTs and 1 Ontario-based study presented at an international conference. Friedlaender et al. conducted a prospective, randomized, partially blinded clinical trial on the treatment tibial nonunions with OP-1. Tibial nonunions were chosen for this study because of their high frequency, challenging treatment requirements, and substantial morbidity. All of the nonunions were at least 9 months old and had shown no progress toward healing over the previous 3 months. The patients were randomized to receive either treatment with autologous bone grafting or treatment with OP-1 in a type-1 collagen carrier. Both groups received reduction and fixation with an intramedullary rod. Table 1 summarizes the clinical outcomes of this study. Table 1:Outcomes in a Randomized Clinical Trial on Tibial Nonunions: Osteogenic Protein-1 versus Autologous Bone GraftingClinical Indicator at 9 monthsSuccess by ProcedureOP-1 % (range)Autograft % (range)PWeight-bearing8685not significantPain on Weight-bearing8990not significantBridging seen on radiograph (at least 1 view)7584not significantBridging seen on radiograph (at least 3 views)6274not significantRepeated surgery*510not significantPhysician satisfaction8690not significantMean operative time in minutes (range)169 (58 - 420)178 (58 - 420)not significantMean operative blood loss in ml (range)254 (10-1,150)345 (35 - 1,200).049Mean length of stay in days (range)3.7 (0 - 18)4.1 (1 - 24)not significantPain at the donor siteN/A80N/AAt 6 months postsurgery20At 12 months postsurgery13Osteomyelitis % (number)3 (2/61)21 (13/61). (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
PTA is a collection of pus located between the tonsillar capsule and the pharyngeal constrictor muscle. It is considered a complication of acute tonsillitis and is the most prevalent deep neck infection (approximately 2000 cases annually in Denmark) and cause of acute admission to Danish ENT departments. Teenagers and young adults are most commonly affected and males may predominate over females. However, no studies of age- and gender-stratified incidence rates have previously been published. Furthermore, smoking may be associated with increased risk of peritonsillar abscess (PTA) development, although the magnitude of the association has not been estimated. Complications are relatively rare. They include parapharyngeal abscess (PPA), upper airway obstruction, Lemierre´s syndrome, necrotizing fasciitis, mediastinitis, erosion of the internal carotid artery, brain abscess, and streptococcal toxic shock syndrome. The treatment consists of abscess drainage and antimicrobial therapy. There are three accepted methods of surgical intervension: needle aspiration, incision and drainage (ID), and acute tonsillectomy (á chaud). Internationally, there is a strong trend towards less invasive surgical approach to PTA treatment with avoidance of acute tonsillectomy, needle aspiration instead of ID, and in some cases even antibiotic treatment without surgical drainage. The preferred antibiotic regimen varies greatly between countries and centers. Group A streptococcus (GAS) is the only established pathogen in PTA. However, GAS is only recovered from approximately 20% of PTA patients. The pathogens in the remaining 80% are unknown. Culturing of PTA pus aspirates often yields a polymicrobial mixture of aerobes and anaerobes. As the tonsils of healthy individuals are already heavily and diversely colonized, the identification of significant pathogens is challenging. In addition, when studying PTA microbiology, one must consider diagnostic precision, collection, handling, and transportation of appropriate specimens, choice of methodology for detection and quantification of microorganisms, current or recent antibiotic treatment of patients, potential shift in significant pathogens during the course of infection, and factors associated with increased risk of PTA development. The trend towards de-escalated surgical intervention and increasing reliance on antibiotic treatment, require studies defining the significant pathogens in PTA in order to determine optimal antibiotic regimens. Complications secondary to PTA may be avoided or better controlled with improved knowledge concerning the significant pathogens in PTA. Furthermore, identification of pathogens other than GAS, may lead the way for earlier bacterial diagnosis and timely intervention before abscess formation in sore throat patients. The identification and quantification of risk factors for PTA development constitutes another approach to reduce the incidence of PTA. As clinicians, we noticed that FN was recovered from PTA patients with increasing frequency and that patients infected with Fusobacterium necrophorum (FN) seemed to be more severely affected than patients infected with other bacteria. Furthermore, we occationally observed concomitant PPA in addition to a PTA, which made us hypothesize that PPA and PTA is often closely related and may share significant pathogens. Hence, our aims were: 1. To explore the microbiology of PTA with a special attention to Fusobacterium necrophorum (FN). 2. To elucidate whether smoking, age, gender, and seasons are risk factors for the development of PTA. 3. To characterize patients with PPA, explore the relationship between PPA and PTA, identify the pathogens associated with PPA, and review our management of PPA. In a retrospective study on all 847 PTA patients admitted to the ENT department at Aarhus University Hospital (AUH) from 2001 to 2006, we found that FN was the most prevalent (23%) bacterial strain in pus specimens. FN-positive patients displayed significantly higher infection markers (CRP and neutrophil counts) than patients infected with other bacteria (P = 0.01 and P < 0.001, respectively). In a subsequent prospective and comparative study on 36 PTA patients and 80 patients undergoing elective tonsillectomy (controls), we recovered FN from 58% of PTA aspirates. Furthermore, FN was detected significantly more frequently in the tonsillar cores of PTA patients (56%) compared to the tonsillar cores of the controls (24%) (P = 0.001). We also analysed sera taken acutely and at least two weeks after surgery for the presence of anti-FN antibodies. We found increasing levels (at least two-fold) of anti-FN antibodies in eight of 11 FN-positive (in the tonsillar cultures) PTA patients, which was significantly more frequent compared to none of four FN-negative PTA patients and nine of 47 electively tonsillectomized controls (P = 0.026 and P < 0.001, respectively). Blood cultures obtained during acute tonsillectomy mirrored the bacterial findings in the tonsillar specimens with 22% of patients having bacteremia with FN. However, bacteremia during elective tonsillectomy was at least as prevalent as bacteremia during quinsy tonsillectomy, which challenges the distinction made by the European Society of Cardiology between quinsy and elective tonsillectomy, namely that antibiotic prophylaxis is only recommended to patients undergoing procedures to treat an established infection (i.e. PTA). Using PCR analysis for the presence of herpes simplex 1 and 2, adenovirus, influenza A and B, Epstein-Barr virus (EBV), and respiratory syncytial virus A and B, we explored a possible role of viruses in PTA. However, our results did not indicate that any of these viruses are involved in the development of PTA. Privious studies have documented an association between EBV and PTA in approximately 4% of PTA cases. In addition to the involvement of GAS, the following findings suggest a pathogenic role for FN in PTA: 1. Repeated high isolation rates of FN in PTA pus aspirates. 2. Higher isolation rates in PTA patients compared to electively tonsillectomised controls. 3. Development of anti-FN antibodies in FN-positive patients with PTA. 4. Significantly higher inflammatory markers in FN-positive patients compared to PTA patients infected with other bacteria. We studied the smoking habits among the same 847 PTA patients admitted to the ENT department, AUH from 2001 to 2006. We found that smoking was associated with increased risk of PTA for both genders and across all age groups. The increased risk of PTA among smokers was not related to specific bacteria. Conclusions on causality cannot be drawn from this retrospective study, but the pathophysiology behind the increased risk of PTA in smokers may be related to, previously shown, alterations in the tonsillar, bacterial flora or the local and systemical inflammatory and immunological milieu. Studying all 1,620 patients with PTA in Aarhus County from 2001 to 2006 and using population data for Aarhus County for the same six years, age- and gender-stratified mean annual incidence rates of PTA were calculated. The incidence of PTA was highly related to age and gender. The seasonal variation of PTA was insignificant. However, the microbiology of PTA fluctuated with seasons: GAS-positive PTA cases were significantly more prevalent in the winter and spring compared to the summer, while FN-positive PTA patients exhibited a more even distribution over the year, but with a trend towards higher prevalence in the summer than in the winter. In a series of 63 patients with PPA, we found that 33 (52%) patients had concomitant PTA. This association between PPA and PTA was much higher than previously documented. We therefore suggest that combined tonsillectomy and intrapharyngeal incision in cases where PTA is present or suspected. The results of our routine cultures could not support a frequent role of FN in PPA. Based on our findings suggesting that FN is a frequent pathogen in PTA, we recommend clindamycin instead of a macrolide in penicillin-allergic patients with PTA. Furthermore, cultures made from PTA aspirates should include a selective FN-agar plate in order to identify growth of this bacterium. Recent studies of sore throat patients document an association between recovery of FN and acute tonsillitis. Studying the bacterial flora of both tonsils in study II, we found almost perfect concordance between the bacterial findings of the tonsillar core at the side of the abscess and contralaterally. This finding suggests that FN is not a subsequent overgrowth phenomenon after abscess development, but that FN can act as pathogen in severe acute tonsillitis. Future studies of patients with FN-positive acute tonsillitis focusing on the optimal methods (clinical characteristics, culture, polymerase chain reaction, or other) for diagnosis and whether antibiotics (and which) can reduce symptoms and avoid complications are warranted. Until further studies are undertaken, we recommend clinicians to have increased focus on acute tonsillitis patients aged 15-24 years with regards to symptoms and findings suggestive of incipient peritonsillar involvement. We have conducted a number of studies with novel findings: 1. FN is a significant and prevalent pathogen in PTA. 2. Bacteremia during abscess tonsillectomy is no more prevalent than during elective tonsillectomy. 3. The development of anti-FN antibodies in FN-positive PTA patients. We have used novel approaches as principles to suggest pathogenic significance of candidate microorganisms: 1. Comparative microbiology between PTA patients and "normal tonsils". 2. Measurements indicating larger inflammatory response compared to clinically equivalent infection.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
In 2002, (before the establishment of the Ontario Health Technology Advisory Committee), the Medical Advisory Secretariat conducted a health technology policy assessment on biventricular (BiV) pacing, also called cardiac resynchronization therapy (CRT). The goal of treatment with BiV pacing is to improve cardiac output for people in heart failure (HF) with conduction defect on ECG (wide QRS interval) by synchronizing ventricular contraction. The Medical Advisory Secretariat concluded that there was evidence of short (6 months) and longer-term (12 months) effectiveness in terms of cardiac function and quality of life (QoL). More recently, a hospital submitted an application to the Ontario Health Technology Advisory Committee to review CRT, and the Medical Advisory Secretariat subsequently updated its health technology assessment. Chronic HF results from any structural or functional cardiac disorder that impairs the ability of the heart to act as a pump. It is estimated that 1% to 5% of the general population (all ages) in Europe have chronic HF. (1;2) About one-half of the patients with HF are women, and about 40% of men and 60% of women with this condition are aged older than 75 years. The incidence (i.e., the number of new cases in a specified period) of chronic HF is age dependent: from 1 to 5 per 1,000 people each year in the total population, to as high as 30 to 40 per 1,000 people each year in those aged 75 years and older. Hence, in an aging society, the prevalence (i.e., the number of people with a given disease or condition at any time) of HF is increasing, despite a reduction in cardiovascular mortality. A recent study revealed 28,702 patients were hospitalized for first-time HF in Ontario between April 1994 and March 1997. (3) Women comprised 51% of the cohort. Eighty-five percent were aged 65 years or older, and 58% were aged 75 years or older. Patients with chronic HF experience shortness of breath, a limited capacity for exercise, high rates of hospitalization and rehospitalization, and die prematurely. (2;4) The New York Heart Association (NYHA) has provided a commonly used functional classification for the severity of HF (2;5): CLASS I: No limitation of physical activity. No symptoms with ordinary exertion.CLASS II: Slight limitations of physical activity. Ordinary activity causes symptoms.CLASS III: Marked limitation of physical activity. Less than ordinary activity causes symptoms. Asymptomatic at rest.CLASS IV: Inability to carry out any physical activity without discomfort. Symptoms at rest.The National Heart, Lung, and Blood Institute estimates that 35% of patients with HF are in functional NYHA class I; 35% are in class II; 25%, class III; and 5%, class IV. (5) Surveys (2) suggest that from 5% to 15% of patients with HF have persistent severe symptoms, and that the remainder of patients with HF is evenly divided between those with mild and moderately severe symptoms. Overall, patients with chronic, stable HF have an annual mortality rate of about 10%. (2) One-third of patients with new-onset HF will die within 6 months of diagnosis. These patients do not survive to enter the pool of those with "chronic" HF. About 60% of patients with incident HF will die within 3 years, and there is limited evidence that the overall prognosis has improved in the last 15 years. To date, the diagnosis and management of chronic HF has concentrated on patients with the clinical syndrome of HF accompanied by severe left ventricular systolic dysfunction. Major changes in treatment have resulted from a better understanding of the pathophysiology of HF and the results of large clinical trials. Treatment for chronic HF includes lifestyle management, drugs, cardiac surgery, or implantable pacemakers and defibrillators. Despite pharmacologic advances, which include diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, spironolactone, and digoxin, many patients remain symptomatic on maximally tolerated doses. Owing to the limitations of drug therapy, cardiac transplantation and device therapies have been used to try to improve QoL and survival of patients with chronic HF. Ventricular pacing is an emerging treatment option for patients with severe HF that does not respond well to medical therapy. Traditionally, indications for pacing include bradyarrhythmia, sick sinus syndrome, atrioventricular block, and other indications, including combined sick sinus syndrome with atrioventricular block and neurocardiogenic syncope. Recently, BiV pacing as a new, adjuvant therapy for patients with chronic HF and mechanical dyssynchrony has been investigated. Ventricular dysfunction is a sign of HF; and, if associated with severe intraventricular conduction delay, it can cause dyssynchronous ventricular contractions resulting in decreased ventricular filling. The therapeutic intent is to activate both ventricles simultaneously, thereby improving the mechanical efficiency of the ventricles. About 30% of patients with chronic HF have intraventricular conduction defects. (6) These conduction abnormalities progress over time and lead to discoordinated contraction of an already hemodynamically compromised ventricle. Intraventricular conduction delay has been associated with clinical instability and an increased risk of death in patients with HF. (7) Hence, BiV pacing, which involves pacing left and right ventricles simultaneously, may provide a more coordinated pattern of ventricular contraction and thereby potentially reduce QRS duration, and intraventricular and interventricular asynchrony. People with advanced chronic HF, a wide QRS complex (i.e., the portion of the electrocardiogram comprising the Q, R, and S waves, together representing ventricular depolarization), low left ventricular ejection fraction and contraction dyssynchrony in a viable myocardium and normal sinus rhythm, are the target patients group for BiV pacing. One-half of all deaths in HF patients are sudden, and the mode of death is arrhythmic in most cases. Internal cardioverter defibrillators (ICDs) combined with BiV pacemakers are therefore being increasingly considered for patients with HF who are at high risk of sudden death. CURRENT IMPLANTATION TECHNIQUE FOR CARDIAC RESYNCHRONIZATION: Conventional dual-chamber pacemakers have only 2 leads: 1 placed in the right atrium and the other in the right ventricle. The technique used for BiV pacemaker implantation also uses right atrial and ventricular pacing leads, in addition to a left ventricle lead advanced through the coronary sinus into a vein that runs along the ventricular free wall. This permits simultaneous pacing of both ventricles to allow resynchronization of the left ventricle septum and free wall. MODE OF OPERATION: Permanent pacing systems consist of an implantable pulse generator that contains a battery and electronic circuitry, together with 1 (single-chamber pacemaker) or 2 (dual-chamber pacemaker) leads. Leads conduct intrinsic atrial or ventricular signals to the sensing circuitry and deliver the pulse generator charge to the myocardium (muscle of the heart). COMPLICATIONS OF BIVENTRICULAR PACEMAKER IMPLANTATION: The complications that may arise when a BiV pacemaker is implanted are similar to those that occur with standard pacemaker implantation, including pneumothorax, perforation of the great vessels or the myocardium, air embolus, infection, bleeding, and arrhythmias. Moreover, left ventricular pacing through the coronary sinus can be associated with rupture of the sinus as another complication. CONCLUSION OF 2003 REVIEW OF BIVENTRICULAR PACEMAKERS BY THE MEDICAL ADVISORY SECRETARIAT: The randomized controlled trials (RCTs) the Medical Advisory Secretariat retrieved analyzed chronic HF patients that were assessed for up to 6 months. Other studies have been prospective, but nonrandomized, not double-blinded, uncontrolled and/or have had a limited or uncalculated sample size. Short-term studies have focused on acute hemodynamic analyses. The authors of the RCTs reported improved cardiac function and QoL up to 6 months after BiV pacemaker implantation; therefore, there is level 1 evidence that patients in ventricular dyssynchrony who remain symptomatic after medication might benefit from this technology. Based on evidence made available to the Medical Advisory Secretariat by a manufacturer, (8) it appears that these 6-month improvements are maintained at 12-month follow-up. To date, however, there is insufficient evidence to support the routine use of combined ICD/BiV devices in patients with chronic HF with prolonged QRS intervals. SUMMARY OF UPDATED FINDINGS SINCE THE 2003 REVIEW: Since the Medical Advisory Secretariat's review in 2003 of biventricular pacemakers, 2 large RCTs have been published: COMPANION (9) and CARE-HF. (10) The characteristics of each trial are shown in Table 1. The COMPANION trial had a number of major methodological limitations compared with the CARE-HF trial. Table 1:Characteristics of the COMPANION and CARE-HF TrialsCOMPANION, 2004CARE-HF, 2005Optimal Therapy vs. BiV Pacing vs. BiV Pacing/ICD†Optimal Therapy vs. BiV PacingPopulationNew York Heart Association class III/IV heart failureEF† ≤ 0.35QRS† ≥ 120 msN1,520(optimal therapy, n = 308; BiV pacing, n = 617; BiV pacing/ICD, n = 595)813Follow-up (months)Median, 16Mean, 29Comment- Definition of "hospitalization" in primary outcome changed 3 times during trial w/o documentation in protocol and FDA† not notified (dominant outcome for composite endpoint).- Dropouts/withdrawals/crossovers not clearly described.- Study terminated early.- No direct comparison between BiV pacing vs. BiV pacing/ICD.- High number of patients withdrew from optimal therapy to device arms.- Not blinded.Not blindedCOMPANION; (9) CARE-HF. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
To determine the effectiveness and cost-effectiveness of coil embolization compared with surgical clipping to treat intracranial aneurysms. Endovascular coil embolization is a percutaneous approach to treat an intracranial aneurysm from within the blood vessel without the need of a craniotomy. In this procedure, a microcatheter is inserted into the femoral artery near the groin and navigated to the site of the aneurysm. Small helical platinum coils are deployed through the microcatheter to fill the aneurysm, and prevent it from further expansion and rupture. Health Canada has approved numerous types of coils and coil delivery systems to treat intracranial aneurysms. The most favoured are controlled detachable coils. Coil embolization may be used with other adjunct endovascular devices such as stents and balloons. INTRACRANIAL ANEURYSMS: Intracranial aneurysms are the dilation or ballooning of part of a blood vessel in the brain. Intracranial aneurysms range in size from small (<12 mm in diameter) to large (12-25 mm), and to giant (>25 mm). There are 3 main types of aneurysms. Fusiform aneurysms involve the entire circumference of the artery; saccular aneurysms have outpouchings; and dissecting aneurysms have tears in the arterial wall. Berry aneurysms are saccular aneurysms with well-defined necks. Intracranial aneurysms may occur in any blood vessel of the brain; however, they are most commonly found at the branch points of large arteries that form the circle of Willis at the base of the brain. In 85% to 95% of patients, they are found in the anterior circulation. Aneurysms in the posterior circulation are less frequent, and are more difficult to treat surgically due to inaccessibility. Most intracranial aneurysms are small and asymptomatic. Large aneurysms may have a mass effect, causing compression on the brain and cranial nerves and neurological deficits. When an intracranial aneurysm ruptures and bleeds, resulting in a subarachnoid hemorrhage (SAH), the mortality rate can be 40% to 50%, with severe morbidity of 10% to 20%. The reported overall risk of rupture is 1.9% per year and is higher for women, cigarette smokers, and cocaine users, and in aneurysms that are symptomatic, greater than 10 mm in diameter, or located in the posterior circulation. If left untreated, there is a considerable risk of repeat hemorrhage in a ruptured aneurysm that results in increased mortality. In Ontario, intracranial aneurysms occur in about 1% to 4% of the population, and the annual incidence of SAH is about 10 cases per 100,000 people. In 2004-2005, about 660 intracranial aneurysm repairs were performed in Ontario. TREATMENT OF INTRACRANIAL ANEURYSMS: Treatment of an unruptured aneurysm attempts to prevent the aneurysm from rupturing. The treatment of a ruptured intracranial aneurysm aims to prevent further hemorrhage. There are 3 approaches to treating an intracranial aneurysm. Small, asymptomatic aneurysms less than 10 mm in diameter may be monitored without any intervention other than treatment for underlying risk factors such as hypertension. Open surgical clipping, involves craniotomy, brain retraction, and placement of a silver clip across the neck of the aneurysm while a patient is under general anesthesia. This procedure is associated with surgical risks and neurological deficits. Endovascular coil embolization, introduced in the 1990s, is the health technology under review. The Medical Advisory Secretariat searched the International Health Technology Assessment (INAHTA) Database and the Cochrane Database of Systematic Reviews to identify relevant systematic reviews. OVID Medline, Medline In-Process and Other Non-Indexed Citations, and Embase were searched for English-language journal articles that reported primary data on the effectiveness or cost-effectiveness of treatments for intracranial aneurysms, obtained in a clinical setting or analyses of primary data maintained in registers or institutional databases. Internet searches of Medscape and manufacturers' databases were conducted to identify product information and recent reports on trials that were unpublished but that were presented at international conferences. Four systematic reviews, 3 reports on 2 randomized controlled trials comparing coil embolization with surgical clipping of ruptured aneurysms, 30 observational studies, and 3 economic analysis reports were included in this review. SAFETY AND EFFECTIVENESS: Coil embolization appears to be a safe procedure. Complications associated with coil embolization ranged from 8.6% to 18.6% with a median of about 10.6%. Observational studies showed that coil embolization is associated with lower complication rates than surgical clipping (permanent complication 3-7% versus 10.9%; overall 23% versus 46% respectively, p=0.009). Common complications of coil embolization are thrombo-embolic events (2.5%-14.5%), perforation of aneurysm (2.3%-4.7%), parent artery obstruction (2%-3%), collapsed coils (8%), coil malposition (14.6%), and coil migration (0.5%-3%). Randomized controlled trials showed that for ruptured intracranial aneurysms with SAH, suitable for both coil embolization and surgical clipping (mostly saccular aneurysms <10 mm in diameter located in the anterior circulation) in people with good clinical condition:Coil embolization resulted in a statistically significant 23.9% relative risk reduction and 7% absolute risk reduction in the composite rate of death and dependency compared to surgical clipping (modified Rankin score 3-6) at 1-year. The advantage of coil embolization over surgical clipping varies widely with aneurysm location, but endovascular treatment seems beneficial for all sites. There were less deaths in the first 7 years following coil embolization compared to surgical clipping (10.8% vs 13.7%). This survival benefit seemed to be consistent over time, and was statistically significant (log-rank p= 0.03). Coil embolization is associated with less frequent MRI-detected superficial brain deficits and ischemic lesions at 1-year. The 1- year rebleeding rate was 2.4% after coil embolization and 1% for surgical clipping. Confirmed rebleeding from the repaired aneurysm after the first year and up to year eight was low and not significantly different between coil embolization and surgical clipping (7 patients for coil embolization vs 2 patients for surgical clipping, log-rank p=0.22). Observational studies showed that patients with SAH and good clinical grade had better 6-month outcomes and lower risk of symptomatic cerebral vasospasm after coil embolization compared to surgical clipping. For unruptured intracranial aneurysms, there were no randomized controlled trials that compared coil embolization to surgical clipping. Large observational studies showed that: The risk of rupture in unruptured aneurysms less than 10 mm in diameter is about 0.05% per year for patients with no pervious history of SAH from another aneurysm. The risk of rupture increases with history of SAH and as the diameter of the aneurysm reaches 10 mm or more. Coil embolization reduced the composite rate of in hospital deaths and discharge to long-term or short-term care facilities compared to surgical clipping (Odds Ratio 2.2, 95% CI 1.6-3.1, p<0.001). The improvement in discharge disposition was highest in people older than 65 years. In-hospital mortality rate following treatment of intracranial aneurysm ranged from 0.5% to 1.7% for coil embolization and from 2.1% to 3.5% for surgical clipping. The overall 1-year mortality rate was 3.1% for coil embolization and 2.3% for surgical clipping. One-year morbidity rate was 6.4% for coil embolization and 9.8% for surgical clipping. It is not clear whether these differences were statistically significant. Coil embolization is associated with shorter hospital stay compared to surgical clipping. For both ruptured and unruptured aneurysms, the outcome of coil embolization does not appear to be dependent on age, whereas surgical clipping has been shown to yield worse outcome for patients older than 64 years. ANGIOGRAPHIC EFFICIENCY AND RECURRENCES: The main drawback of coil embolization is its low angiographic efficiency. The percentage of complete aneurysm occlusion after coil embolization (27%-79%, median 55%) remains lower than that achieved with surgical clipping (82%-100%). However, about 90% of coiled aneurysms achieve near total occlusion or better. Incompletely coiled aneurysms have been shown to have higher aneurysm recurrence rates ranging from 7% to 39% for coil embolization compared to 2.9% for surgical clipping. Recurrence is defined as refilling of the neck, sac, or dome of a successfully treated aneurysm as shown on an angiogram. The long-term clinical significance of incomplete occlusion following coil embolization is unknown, but in one case series, 20% of patients had major recurrences, and 50% of these required further treatment. LONG-TERM OUTCOMES: A large international randomized trial reported that the survival benefit from coil embolization was sustained for at least 7 years. The rebleeding rate between year 2 and year 8 following coil embolization was low and not significantly different from that of surgical clipping. However, high quality long-term angiographic evidence is lacking. Accordingly, there is uncertainty about long-term occlusion status, coil durability, and recurrence rates. While surgical clipping is associated with higher immediate procedural risks, its long-term effectiveness has been established. INDICATIONS AND CONTRAINDICATIONS: Coil embolization offers treatment for people at increased risk for craniotomy, such as those over 65 years of age, with poor clinical status, or with comorbid conditions. The technology also makes it possible to treat surgical high-risk aneurysms. Not all aneurysms are suitable for coil embolization. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Traditionally, total thyroidectomy was performed through an open transcervical incision; in cases where there was evident nodal metastasis, the conventional surgical approach was to extend the incision into a large single transverse incision to complete the required neck dissection. However, recent innovation in the surgical technique of thyroidectomy has offered the opportunity to reduce the patient's burden from these prominent surgical scars in the neck. Minimally invasive surgical techniques have been developed and applied by many institutions worldwide, and more recently, various techniques of remote access surgery have been suggested and actively applied.1-6 Since the advent of robotic surgical systems, some have adopted the concept of remote access surgery into developing various robotic thyroidectomy techniques. The more former and widely acknowledged robotic thyroidectomy technique uses a transaxillary (TA) approach, which has been developed by Chung et al. in Korea.7,8 This particular technique has some limitations in the sense that accessing the lymph nodes of the central compartment is troublesome. Terris et al. realized some shortcomings of robotic TA thyroidectomy, especially in their patients in the United States, and developed and reported the feasibility of robotic facelift thyroidectomy.9-13 In cases of thyroid carcinomas with lateral neck node metastases, most abandoned the concept of minimally invasive or remote access surgery and safely adopted conventional open surgical methods to remove the tumor burden. However, Chung et al. have attempted to perform concomitant modified radical neck dissection (MRND) after robotic thyroidectomy through the same TA port.14 This type of robot-assisted neck dissection (RAND) had some inherent limitations, due to fact that lymph nodes of the upper neck were difficult to remove. Over the past few years, we have developed a RAND via modified facelift (MFL) or retroauricular (RA) approach and reported the feasibility and safety of this technique.15, 16 Since then, we have actively applied such RAND techniques in various head and neck cancers. In our country, almost all cases of robotic total thyroidectomy utilize the TA approach. According to the reports made by Terris et al., robotic facelift thyroidectomy technique has been solely applied for ipsilateral hemithyroidectomy. For total thyroidectomy, Terris et al. performed the robotic surgery with bilateral RA incisions. Here, we intend to introduce our novel surgical method after successfully attempting simultaneous robotic total thyroidectomy and RAND via a single RA approach without an axillary incision. To our knowledge, this is the first to report in the medical literature. We present four cases of our surgical experience since the beginning of 2013. All patients received robotic total thyroidectomy with MRND via single RA port without axillary incision after approval from the institutional review board at Severance Hospital, Yonsei University College of Medicine. The inclusion criteria for this operation were as follows: (1) patients with malignant carcinomas of the thyroid gland with evident cervical lymph node metastasis on preoperative imaging studies which are indicated for surgery; (2) patients with no previous history of treatment for thyroid carcinoma. The exclusion criteria were as follows: (1) patients with recurred thyroid tumors; (2) patients with thyroid carcinomas that showed gross invasion to local structures or extensive extrathyroidal capsular spread; (3) patients with clinically evident neck nodal metastasis with extracapsular spread; (4) patients with past history of neck surgery of any kind. In order to assess the extent of disease, neck ultrasonography with fine needle aspiration, neck CT or MRI and PET-CT were performed as preoperative evaluation. All patients were given full information of the possible treatment options for their thyroid cancer comprising of open transcervical approach and robotic surgery via RA approach, including the advantages and disadvantages of each treatment choice and provided written, informed consents before the surgery. General clinical information of the patients is outlined in Table 1. The skin incision for the operation was designed just like the approach for robotic facelift thyroidectomy by Terris et al. and RAND, which has been first reported by our institution.11 (,) 16 The operation was performed by the following sequence. Initially, the skin-subplatysmal flap was elevated after making the skin incision to create sufficient working space. During this process, the elevated skin flap was retracted and maintained by retractors held by the assistant. After application of the self-retaining retractor (Sangdosa Inc., Seoul), neck dissection of the upper neck levels was performed under gross vision. Next, RAND through the RA incision was conducted followed by ipsilateral thyroidectomy with central compartment neck dissection (CCND) via the same approach. Finally, contralateral thyroidectomy with CCND was performed via the single RA port. During these steps, the operator is aided by the bedside assistant with long-suction tips to manipulate and direct the dissected specimen to maintain optimal surgical view or to suck out the fume created by the thermocoagulation from the Harmonic shears. The da Vinci robotic surgical system (Intuitive Surgical, Sunnyvale, CA) was introduced via the RA port with a facedown 30° dual-channel endoscopic arm placed in the center, and two instrument arms equipped at either side with 5-mm Maryland forceps and Harmonic curved shears. During the step of robotic contralateral thyroidectomy, a ProGrasp forceps was utilized at times, instead of 5-mm Maryland forceps. The rest of the surgery was completed with the robotic system (see Video for demonstration of operation for patient 2). Table 1 Clinical characteristics of the patients Patient Sex/age (yr) BMI Side(a) Approach Pathology(b) Tumor size(c) (cm) CCND(d) MRND(d) Drain removal day Drainage amount (ml) Hospital stay (days) 1 F/38 23.8 L RA PC 0.7 2/5 8/23 8 788 11 2 F/18 18.3 L RA PC 0.8 2/8 7/35 6 398 9 3 F/44 23.1 L RA PC 0.9 5/12 5/27 6 607 9 4 F/26 32.9 L RA PC 1.4 3/14 9/48 7 476 15 BMI body mass index, RA retroauricular approach, PC papillary carcinoma, CCND central compartment neck dissection, MRND modified radical neck dissection (a)Side refers to the site of main lesion (b)Pathology refers to the primary tumor within the thyroid gland (c)Tumor size refers to the diameter of the largest tumor in the thyroid gland (d)For each type of lymph node dissection, the number of positive nodes/total number of retrieved nodes is stated For all of the patients, robotic total thyroidectomy with MRND (levels II, III, IV, V) via unilateral RA approach was successfully completed without any significant intraoperative complications or conversion to open or other approach methods. The total operation time was defined as the time from initial skin incision to removal of the final specimen, which was an average 306.1 ± 11.1 min (Table 2). This included the time for skin flap elevation and neck dissection under gross vision (87 ± 2.8 min), setting up the robotic system for RAND (6.8 ± 2.4 min), console time using the robotic system for RAND (59.3 ± 2.2 min), flap elevation for thyroidectomy (11.3 ± 2.5 min), robotic arms docking for ipsilateral thyroidectomy (6.3 ± 2.5 min), console time for ipsilateral thyroidectomy (61.3 ± 2.1 min), robotic arms docking for contralateral thyroidectomy (6.3 ± 2.5 min), and console time for contralateral thyroidectomy (61.8 ± 2.1 min). The working space created from RA incision was sufficient, and manipulations of the robotic instruments through this approach were technically feasible and safe without any mutual collisions throughout the entire operation. It also allowed for an excellent magnified surgical view enabling visualization of important local anatomical structures. There was no postoperative vocal cord palsy due to recurrent laryngeal nerve injury. However, two patients developed transient hypoparathyroidism, which resolved in the end without the need for calcium or vitamin D supplementation after certain period of medical management (Table 3). Also, there was no incidence of postoperative hemorrhage or hematoma formation, although a single patient developed a postoperative seroma on postoperative day 9, which was managed conservatively without the need for further surgical intervention. On average, the wound catheter was removed 6.8 ± 1 days after surgery and the patient was discharged from the hospital at an average 11 ± 2.8 days from admission (Table 1). Final surgical pathology confirmed the diagnosis of papillary carcinoma for every patient. The total number of cervical nodes retrieved from CCND and MRND was 9.8 ± 4 and 33.1 ± 11 respectively, and the number of positive metastatic nodes was 3 ± 1.4 and 7.3 ± 1.7 respectively (Table 1). In three patients (patients 2, 3, and 4), the presence of one parathyroid gland was each verified in the pathology specimen. All four patients have received high-dose (150 mCi) radioiodine ablation (RAI) therapy after the operation and are being followed up (average 11.3 months, range 9-13 months) on a regular basis with no evidence of recurrence (post-RAI, most recent, nonsuppressed thyroglobulin range 0.1-0.4 ng/ml, antithyroglobulin antibody range 13.7-147.5 IU/ml). (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Chou R, Fu R, Carrino JA, Deyo RA. Imaging strategies for low-back pain: systematic review and meta-analysis. Lancet. 2009;373(9662):463-472. In patients with low back pain (LBP) who do not have indications of a serious underlying condition, does routine, immediate lumbar imaging result in improved patient outcomes when compared with clinical care without immediate imaging? Studies were identified by searching MEDLINE (1966 through first week of August 2008) and the Cochrane Central Register of Controlled Trials (third quarter of 2008). The reference lists of identified studies were manually reviewed for additional citations. The search terms spine, low-back pain, diagnostic imaging, and randomized controlled trials were used in both databases. The complete search strategy was made available as an online supplement. The search criteria were applied to the articles obtained from the electronic searches and the subsequent manual searches with no language restrictions. This systematic review and meta-analysis included randomized, controlled trials that compared immediate, routine lumbar imaging (or routine provision of imaging findings) with usual clinical care without immediate lumbar imaging (or not routinely providing results of imaging) for LBP without indications of serious underlying conditions. Data extraction and assessment of study quality were well described. The trials assessed one or more of the following outcomes: pain, function, mental health, quality of life, patient satisfaction, and overall patient-reported improvement. Two reviewers independently appraised citations considered potentially relevant, with disagreements between reviewers resolved by consensus. Two independent reviewers abstracted data from the trials and assessed quality with modified Cochrane Back Review Group criteria. The criterion for blinding of patients and providers was excluded because of lack of applicability to imaging studies. In addition, the criterion of co-intervention similarity was excluded because a potential effect of different imaging strategies is to alter subsequent treatment decisions. As a result of excluding these criteria, quality ratings were based on the remaining 8 criteria. The authors resolved disagreements about quality ratings through discussion and consensus. Trials that met 4 or more of the 8 criteria were classified as higher quality, whereas those that met 3 or fewer of the 8 criteria were classified as lower quality. In addition, the authors categorized duration of symptoms as acute (<4 weeks), subacute (4-12 weeks), or chronic (>12 weeks). The investigators also contacted the study authors for additional data if included outcomes were not published or if median (rather than mean) outcomes were reported. Statistical analysis was conducted on the primary outcomes of improvement in pain or function. Secondary outcomes of improvement in mental health, quality of life, patient satisfaction, and overall improvement were also analyzed. Outcomes were categorized as short term (≤ 3 months), long term (>6 months to ≤ 1 year), or extended (>1 year). For continuous outcomes, standardized mean differences (SMDs) of interventions for change between baseline and follow-up measurements were calculated. In studies reporting the same pain (visual analog scale [VAS] or Short Form-36 bodily pain score) or function (Roland-Morris Disability Questionnaire [RDQ]) outcomes, weighted mean differences (WMDs) were calculated. In all analyses, lower pain and function scores indicated better outcomes. For quality-of-life and mental health outcomes, higher scores indicated improved outcomes. All statistical analyses were performed with Stata 10.0. For outcomes in which SMDs were calculated, values of 0.2 to 0.5 were considered small, 0.5 to 0.8 were considered moderate, and values greater than 0.8 were considered large. For WMDs, mean improvements of 5 to 10 points on a 100-point scale (or equivalent) were considered small, 10-point to 20-point changes were considered moderate, and changes greater than 20 points were considered large. For the RDQ, mean improvements of 1 to 2 points were termed small, and improvements of 2 to 5 points were termed moderate. The total number of citations identified using the search criteria was 479 articles and abstracts. Of these, 466 were excluded because either they were not randomized trials or they did not use imaging strategies for LBP. At this step, 13 articles were retrieved for further analysis. This analysis resulted in 3 additional articles being excluded (1 was not a randomized trial and the other 2 compared 2 imaging techniques rather than immediate imaging versus no imaging). The final step resulted in the inclusion of 6 trials reported in 10 publications for the meta-analysis. In the studies meeting the inclusion criteria, 4 assessed lumbar radiography and 2 assessed magnetic resonance imaging (MRI) or computed tomography (CT) scans. In these 6 trials, 1804 patients were randomly assigned to the intervention group. The duration of patient follow-up ranged from 3 weeks to 2 years. In addition, 1 trial excluded patients with sciatica or other radiculopathy symptoms, whereas another did not report the proportion of patients with these symptoms. In the other 4 studies, the proportion of patients with sciatica or radiculopathy ranged from 24% to 44%. Of the included trials, 3 compared immediate lumbar radiography with usual clinical care without immediate radiography, and a fourth study compared immediate lumbar radiography and a brief educational intervention with lumbar radiography if no improvement was seen by 3 weeks. The final 2 studies assessed advanced imaging modalities. Specifically, one group compared immediate MRI or CT with usual clinical care without advanced imaging in patients with primarily chronic LBP (82% with LBP for >3 months) who were referred to a surgeon. In the other advanced imaging study, all patients with LBP for <3 weeks underwent MRI and were then randomized to routine notification of results or to notification of results only if clinically indicated. With respect to study quality, 5 trials met at least 4 of the 8 predetermined quality criteria, leading to a classification of higher quality. In addition, 5 trials were included in the primary meta-analysis on pain or function improvement at 1 or more follow-up periods. With regard to short-term and long-term improvements in pain, no differences were noted between routine, immediate lumbar imaging and usual clinical care without immediate imaging ( Table 1 ). In studies using the VAS pain score, the WMD (0.62, 95% confidence interval [CI] = 0.03, 1.21) at short-term follow-up slightly favored no immediate imaging. No differences in outcome were seen in studies using the Short Form-36 bodily pain score. No improvements in function at short-term or long-term follow-up were noted between imaging strategies. Specifically, short-term function measured with the RDQ in 3 studies showed a WMD of 0.48 points (95% CI = -1.39, 2.35) between imaging strategies, whereas long-term function in 3 studies, also measured with the RDQ, showed a WMD of 0.33 points (95% CI = -0.65, 1.32). One included trial reported pain outcomes at extended (2-year) follow-up and found no differences between imaging strategies for pain (Short Form-36 bodily pain or Aberdeen pain score), with SMDs of -2.7 (95% CI = -6.17, 0.79) and -1.6 (-4.04, 0.84), respectively. The outcomes between immediate imaging and usual clinical care without immediate imaging did not differ for short-term follow-up in those studies reporting quality of life (SMD = -0.10, 95% CI = -0.53, 0.34), mental health (SMD = 0.12, 95% CI = -0.37, 0.62), or overall improvement (mean risk ratio = 0.83, 95% CI = 0.65, 1.06). In those studies reporting long-term follow-up periods, similar results can be seen for quality of life (SMD = -0.15, 95% CI = -0.33, 0.04) and mental health (SMD = 0.01, 95% CI = -0.32, 0.34). In the study reporting extended follow-up, immediate imaging was not better in terms of improving quality of life (SMD = 0.02, 95% CI = -0.02, 0.07) or mental health (SMD = -1.50, 95% CI = -4.09, 1.09) when compared with usual clinical care without immediate imaging. In the included studies, no cases of cancer, infection, cauda equina syndrome, or other serious diagnoses were reported in patients randomly assigned to either imaging strategy. Available evidence indicates that immediate, routine lumbar spine imaging in patients with LBP and without features indicating a serious underlying condition did not improve outcomes compared with usual clinical care without immediate imaging. Clinical care without immediate imaging seems to result in no increased odds of failure in identifying serious underlying conditions in patients without risk factors for these conditions. In addition to lacking clinical benefit, routine lumbar imaging is associated with radiation exposure (radiography and CT) and increased direct expenses for patients and may lead to unnecessary procedures. This evidence confirms that clinicians should refrain from routine, immediate lumbar imaging in primary care patients with nonspecific, acute or subacute LBP and no indications of underlying serious conditions. Specific consideration of patient expectations about the value of imaging was not addressed here; however, this aspect must be considered to avoid unnecessary imaging while also meeting patient expectations and increasing patient satisfaction.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
In France, as in the European Union, the number of psychologists continues to increase and constitutes by far the most important source of professionals in this field. The requests for services of psychologists in many various domains have also increased in an unprecedented way over a number of years. In spite of this development, which should continue to increase considerably, the initial training of psychologists remains uneven and disparate and often remote from, even unsuitable to, the legitimate expectations of users. It is therefore important to reform this training by extending, updating, homogenising and adapting it to current knowledge and needs, and by marking it by a single and specific degree: that of a doctorate. This new eight-year doctoral curriculum would be at the same time more complete and simpler than the European Diploma in Psychology model (EuroPsy), for instance. This latter is a very complicated and insufficient subject and would not completely resolve the great problems of psychologists' training and the competences they need to gain in order to access professional practise, research and teaching. This extension of the psychologists' training would make it possible to integrate new data concerning traditional fields of psychology and data concerning new fields of application of psychology and should obviously include the essential training for psychotherapies referred to the great theoretical and practical models, since their interest is clinically acknowledged (psychoanalysis and psychoanalytical therapies, cognitive and behavioural therapies, systemic therapies, therapies for individuals, couples, families, groups...). This polyreferred training would make it possible to go from a culture still too often axed on orientation and deficiencies of the therapist, to a culture of indication, opening and competence, focused on the patient's interest. Teaching of psychophysiology and neurosciences should be updated and harmonised by taking into account the great current and future stakes of public health. It should be supplemented by psychopharmacology lectures. This reform of psychologists' training would ensure a common pedestal of increased knowledge coupled with theoretical/practical competence. The positive consequences of such a reform would relate to many fields. Here are six examples. Education: prevention, tracking, treatment of personal problems or of instruction from nursery school to university; orientation; council, assistance with managing difficulties of teaching staff, etc. Health: tracking, prevention, diagnosis, treatment of psychic and behavioural disorders, of addictive attitudes, of psychological problems related to somatic pathologies (cancer, HIV, etc.), of problems related to ageing of population; training and supervision of medical staff, etc. Justice: caring of victims, of offenders in prison or out of prison, fight against repetition, expertise, staff training (magistrates, lawyers, penitentiary staff, social workers...). Work context: (companies, public and private organisations): recruitment, management of staff problems, human resources management, coaching, competence assessment, orientation, etc. Sport: assessment, management and improvement of performances, management of stress, success, failures, and career; fight against doping; help for retraining after suspension of activity, etc. development of many useful research axes in relation to ground needs in all application fields of psychology. Such a reform, which would make it possible to shift towards a training more adapted to reality, more homogeneous and aiming at excellence, would ensure better guarantees of service to psychologist users and to their possible employers. Beyond a deep improvement of their initial training and their offer of competence, it would also enable psychologists to witness a very clear improvement of their professional status as well as their level of remuneration. The number of trained psychologists could be adapted to the needs of our society by organizing a numerus clausus for access in a Master 1. This regulation would leave at least three years to students to show their motivations and competence. It would also give a valuable licence level (clearly recognized on the European scene) to students who do not continue the university course in psychology and want to reorientate themselves (entrance exams, studies or professions requiring good prerequisite in social studies and nature studies, etc.). Those already authorised to hold the title of psychologist when this doctorate is created would not be obliged to validate it, but would profit from the progress generated by this important improvement in the initial training (status, remuneration, etc). If some of these people wished to validate it, they could do so within a defined time and according to defined methods (additional training, validation of experience assets, thesis, etc.). To help students to materially take up the extension of the curriculum, systems of financial assistance for the last three years of studies should be set up either in the form of study allowances, or in the form of internship with remunerated professional implication in the great sectors of exercise of psychology (education, legal and paralegal sectors, industry and work sectors, health, etc.) in parallel and in addition to university training. Internship should be privileged because it would permit the achievement of four objectives: immersion of very advanced students in professional exercise while maintaining training them under supervision, to offer them various and crucial grounds of exercise and research that are adapted to reality, to remunerate them and hence also, offer an important professional service to users (individuals or institutions). The most important and essential improvement added to the initial training of psychologists by the creation of this new doctoral course would not exclude continuous training when necessary in career course. This reform aiming at excellence, which is socially and humanly highly necessary, must obviously also be accompanied by an indispensable and important revision of the criteria in the selection and competence of those who will dispense this renewed training (the current criteria used to recruit psychology teachers have been widely contested and deemed to be, justly so, the main cause of shortcomings of the initial training of psychologists and of their professional segmentation). An aggregative or postdoctoral route should thus be created to recruit future psychology teachers in the higher education (public and private). This recruitment should take into account candidates' theoretical knowledge, but also their knowledge of the profession and their qualities in its exercise. Thus the following criteria are essential when recruiting psychology teachers: validation of the reformed doctorate in psychology (and possibly validation of trainings complementing this doctorate); practice in the field of the psychologist's job (during at least 10 years full-time, followed by the possibility of becoming practitioner-teacher-researcher in psychology, in the sector of experiments and acquired competences, if the candidate is selected at aggregation); ability to teach and capacity to train the future psychologists for the professional acts they will be susceptible to conduct; capacity to conceive, initiate, carry out, direct and communicate useful research. Recruiting all psychology teachers in the stock of professional psychologists who are experienced, talented, skilled and who perform in all the application fields of the discipline as practitioner-teacher-researcher, is vital to implement these essential improvements in psychologists' training, exercise and research. It is therefore a priority for the future of French and European psychologists to set up as fast as possible a reformed doctorate and an aggregation (or, with regard to the aggregation, an equivalent formalised cursus); it is the common interest of psychology professionals, of their trainers and even more so of their users (people or institutions). This reform, based on the excellence of training and services offered, would also make it possible to preserve the essential unity of discipline and profession beyond the multiplicity of their sectors of application and intervention. It would also facilitate possibilities for insertion, for change of sector in career course and for professional geographical mobility. It would finally clarify the "psy" nebula for users, which is very important and necessary. It is more than ever essential to develop and update in excellence the high level "psy" generalist profession, the profession of psychologist, which users need in many fields of their private, professional or social life. We should guarantee that European Union countries, eager for development and modernity, will rapidly be able to initiate this type of good sense reform, which, by improving care for people and collective balance, would be a new and important step in their humanistic traditions (according to the World Health Organization, one person out of four is in psychological distress). Since psychism and human behaviour are complex and central in all fields of life, the existence of highly qualified psychologists to help them is imperative. Reaching this high level of updated qualification is technically possible and humanly impossible to avoid. Fast reforms must make this requirement achievable. It is in the interest of all the European Union, and all its member states must become a reference and an example in the world for teaching and professional practise of what has become a key discipline: psychology.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The treatment of primary breast cancer usually consists of surgery often followed by adjuvant therapy (radiotherapy, chemotherapy, hormonal treatment, etc.) to reduce the risk of recurrence. The cancer diagnosis and the treatments may have significant impact on the patients' quality of life. This thesis deals with scientific aspects and clinical results of a study aimed at assessing the impact of breast cancer (and its treatment) on the patients' quality of life. Studies such as this assessing the problems and symptoms experienced by the patients are often referred to as health-related quality of life (HRQL) research. HRQL research deals with subjective experiences and raises challenging, scientific questions. Therefore, much attention was directed towards methodological issues in this clinically motivated project. The study was a prospective, longitudinal, questionnaire-based investigation of women with newly diagnosed breast cancer registered in the Danish Breast Cancer Co-operative Group's DBCG 89 Program. The patients were sub-divided into low-risk and high-risk patients. High-risk patients were offered randomisation in one of three randomised adjuvant therapy trials involving chemotherapy, ovarian ablation, and endocrine therapy. After a literature study and interviews with breast cancer patients, a questionnaire was composed that included two widely used standard questionnaires (EORTC QLQ-C30 and Hospital Anxiety and Depression (HAD) Scale) and a DBCG 89 Questionnaire developed for this study. A total of 1,898 eligible patients were invited by post to participate in the study involving six assessments over a 2-year period, and 1,713 patients (90%) completed the first questionnaire. Furthermore, a questionnaire was sent to 872 women selected at random from the general population; 608 (70%) responded. The multi-item scales of the two standard questionnaires were analysed for so-called differential item functioning (DIF) in order to investigate whether the (summary) scale scores were adequate representations of the information obtained by the individual items. The DIF analyses identified a number of cases of DIF, which, among other things, contributed to detection of possible problems in the HAD Scale. It was concluded that DIF analyses are relevant when important analyses based on multi-item scales are made. A new way to evaluate the validity of questionnaires was developed. The results from questionnaires completed by patients were compared against results from open ended interviews with the same patients rated by observers. The idea was that if results were similar, the patients had then probably understood and completed the questionnaire items as intended. On the other hand, if results from self-assessment and interviews deviated, misunderstandings or other errors might have taken place, and the study would give insight into possible problems. Of 57 breast cancer patients, 46 (81%) were successfully interviewed. In general, the agreement between patient-completed questionnaires and interviews was excellent, indicating very good validity. The median weighted kappa for the EORTC QLQ-C30 was 0.85 (range 0.49-1.00); it was 0.79 (range 0.65-0.95) for the HAD Scale, and 0.92 (range 0.51-1.00) for the DBCG 89 Questionnaire. However, the study identified a mechanism called selective reporting, which may affect results from most HRQL questionnaires: in order to provide correct and useful answers some patients do not report symptoms they believe are irrelevant to the study, e.g., symptoms unrelated to cancer. This mechanism may lead to bias if results from patients are compared to results from populations reporting their symptoms more completely, e.g., general population samples. In contrast, this mechanism has little importance when results from different sub-groups of cancer patients are compared. In this study multiple variables were assessed at multiple points in time and we did not have a priori hypotheses for all these potential comparisons. Therefore, a staff survey involving experienced doctors and nurses was conducted in order to generate hypotheses that could be tested in the data from patients. We contacted 46 health care professionals and 36 (78%) responded. Overall, the staff survey did not prove very useful for the intended purpose. The main reason for this was probably that the health care professionals had limited insight into the patients' HRQL. A different approach to the problem of multiple hypothesis testing proved more useful. Hypotheses generated from the initial literature review were tested in the comparison of patients in chemotherapy against patients not in chemotherapy. The study of women selected at random from the general population showed that these women experienced a considerable degree of "morbidity" according to all three questionnaires. This shows that symptoms and problems reported by cancer patients may have causes other than cancer, and thus constitutes a good justification for the use of data from general population studies when interpreting data from cancer patients. The levels of anxiety and depression of low-risk breast cancer patients were found to be lower than those from the general population sample. After careful consideration we concluded that this finding was probably incorrect. The most important explanations were thought to be the wording of some HAD Scale items as well as two mechanisms that are not specific to the HAD Scale, the "selective reporting mechanism" found in the validation study, and the response-shift problem. These findings indicate - in contrast to the conclusion above - that the comparability of HRQL data from cancer patients and general population data must be questioned. However, as this is the first study to raise the problem, this issue needs further investigation. Based on the initial literature review and interviews we hypothesised that 30 different HRQL issues would be impaired in patients undergoing CMF chemotherapy compared to patients not in chemotherapy; 23 of these hypotheses were confirmed. In addition, our study and other research suggest that other HRQL aspects may also be affected by chemotherapy. Thus, there is considerable evidence that patients in chemotherapy may experience effects on a wide spectrum of HRQL issues. Most other studies have assessed surprisingly few of the HRQL issues shown in our study to be impaired in patients receiving chemotherapy. Similarly, current review articles on HRQL effects of adjuvant chemotherapy mention only relatively few of these topics. Concerning HRQL after the treatment period, our main finding was that many symptoms and problems had declined or disappeared, but some persisted: anticipatory nausea, weight gain, endocrine effects (e.g., hot flushes/sweats, irregular bleedings/amenorrhea, vaginal dryness), disturbed sleep, and sexual dysfunction. These findings are in agreement with the literature. The staff study showed that experienced physicians and nurses did not expect many of the "scientifically well documented" consequences of chemotherapy. Taken together, our findings suggest that information to patients about chemotherapy should be more comprehensive than that which has been practised in most places. When compared against ovarian ablation, chemotherapy was associated with more impact on HRQL during the treatment period; only hot flushes/sweats were more pronounced in the ovarian ablation group. Thus, from an overall "HRQL perspective" ovarian ablation or suppression may be preferable. However, younger women may preserve their premenopausal status (including fertility) by having chemotherapy, and this may be an argument for chemotherapy or for temporary ovarian ablation via goserelin, rather than permanent ovarian ablation. Furthermore, while ovarian ablation/suppression may be preferable because of less impairment of HRQL, contemporary chemotherapeutic regimens may be more effective. These results indicate that for some patients, the HRQL data and results on treatment efficiency may be in conflict. There is no simple, universally correct solution to this dilemma. More research into patients' views and expectations to the health-care system in cases where medical decision-making involves complex trade-offs between treatment efficiency and HRQL issues is needed. Contrary to expectations, the analyses showed that fatigue and emotional function predicted the risk of recurrence and death independently of biological and clinical prognostic variables. In multivariate Cox regression analyses patients who were more fatigued or had poorer emotional function had a worse prognosis. These results are consistent with one small study, but are inconsistent with five similar studies in patients with primary breast cancer, which found no such associations. The reasons for these important differences are currently unknown. In conclusion, this study consisted of methodological and clinical investigations of HRQL in primary breast cancer patients. The initial questionnaire development resulted in a combination of questionnaires that was more comprehensive than in other similar studies. The results of the methodological studies generally supported the validity of the questionnaires but also gave important insights into potential scientific problems that are probably not restricted to the present study. These insights helped to prevent misinterpretations of the clinical data. The study provided the most detailed description of HRQL during and after breast cancer adjuvant chemotherapy to date, and compared results of chemotherapy against ovarian ablation. It also provided controversial results concerning the prognostic value of HRQL data. The combination of a large empirical study and several methodological sub-studies thus proved useful and gave new results.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Improving quality and effectiveness of health care is one of the priorities of health policies. Hospital or physician volume represents a measurable variable with a relevant impact on effectiveness of health care. A recent Italian law, the "spending review", calls for the definition of "qualitative, structural, technological and quantitative standards of hospital care". There is a need for an accurate evaluation of the available scientific evidence in order to identify these standards, including the volume of care above or below which the public and private hospitals may be accredited (or not) to provide specific health care interventions. Since 2009, the National Outcomes Programme evaluates outcomes of care of the Italian hospitals; nowadays it represents an official tool to assess the National Health System (NHS). In addition to outcome indicators, the last edition of the Programme (2013) includes a set of volume indicators for the conditions with available evidence of an association between volume and outcome. The assessment of factors, such as volume, that may affect the outcomes of care is one of its objectives. To identify clinical conditions or interventions for which an association between volume and outcome has been investigated. To identify clinical conditions or interventions for which an association between volume and outcome has been proved. To analyse the distribution of Italian health providers by volume of activity. To measure the association between volume of care and outcomes of the health providers of the Italian NHS. Systematic review. An overview of systematic reviews and Health Technology Assessment (HTA) reports performed searching electronic databases (PubMed, EMBASE, Cochrane Library), websites of HTA Agencies, National Guideline Clearinghouse up to February 2012. Studies were evaluated for inclusion by two researchers independently; the quality assessment of included reviews was performed using the AMSTAR checklist. For each health condition and for each outcome considered, total number of studies, participants, high volume cut-off values (range, average and median) have been reported, where presented. Number of studies (and participants) with statistically significant positive association and metanalysis performed were also reported, if available. Analysis of the distribution of Italian hospitals by volume of activity and the association between volume of activity and outcomes. Outcomes National Programme 2011 The analyses were performed using the Hospital Information System and the National Tax Register pertaining the year 2011. For each condition, the number of hospitals by volume of activity was calculated. Hospitals with a volume of activity lower than 3-5 cases/year for the condition under study were excluded from the analysis. For conditions with more than 1,500 cases per year and frequency of outcome ≥ 3%, the association between volume of care and outcome was analysed. For these conditions, risk-adjusted outcomes were estimated according to the selection criteria and the statistical methodology of the National Outcome Programme. The systematic reviews identified were 107, of which 47, evaluating 38 clinical areas, were included. Many outcomes were assessed according to the clinical condition/procedure considered. The main outcome common to all clinical condition/procedures was intrahospital/30-day mortality. Health topics were classified in the following groups according to this outcome: Positive association: a statistically significant positive association was demonstrated in the majority of studies/participants and/or a pooled measure (metanalysis) with positive results was reported. Lack of association: no association was demonstrated in the majority of studies/participants and/or no metanalysis with positive results was reported. No sufficient evidence of association: both results of single studies and metanalysis do not allow to draw firm conclusions on the association between volume and outcome. Evidence of a positive association between volumes and intrahospital/ 30-day mortality was demonstrated for 26 clinical areas: AIDS, abdominal aortic aneurysm (ruptured and unruptured), coronary angioplasty, myocardial infarction, knee arthroplasty, coronary artery bypass, cancer surgery (breast, lung, colon, colon rectum, kidney, liver, stomach, bladder, oesophagus, pancreas, prostate); cholecystectomy, brain aneurysm, carotid endarterectomy, hip fracture, lower extremity bypass surgery, subarachnoid haemorrhage, neonatal intensive care, paediatric heart surgery. For 2 clinical conditions (hip arthroplasty and rectal cancer surgery) no association has been reported. Due to a lack of evidence, it was not possible to draw firm conclusion for 10 clinical areas (appendectomy, colectomy, aortofemoral bypass, testicle cancer surgery, cardiac catheterization, trauma, hysterectomy, inguinal hernia, paediatric oncology). The relationship between volume of clinician and outcomes has been assessed only through the literature review; to date, it is not possible to analyse this association for Italian health providers hospitals, since information on the clinician/surgeon on the hospital discharge chart is missing. The literature found a positive association for: AIDS, coronary angioplasty, unruptured abdominal aortic aneurysm, hip arthroplasty, coronary artery bypass, cancer surgery (colon, stomach, bladder, breast, oesophagus), lower extremity bypass surgery. The analysis of the distribution of Italian hospitals per volume of activity concerned the 26 conditions for which the systematic review has shown a positive association between volume of activity and intrahospital/30-day mortality. For the following conditions it was possible to conduct the analysis of the association between volume and outcome of treatment using national data: unruptured abdominal aortic aneurysm, coronary angioplasty, knee arthroplasty, coronary artery bypass, cancer surgery (colon, pancreas, lung, prostate, stomach, bladder), laparoscopic cholecystectomy, endarterectomy, hip fracture and acute myocardial infarction. For them, the association between volume and outcome of care has been observed. The shape of the relationship is variable among different conditions, with heterogeneous "slope" of the curves. DISCUSSION For many conditions, the systematic review of the literature has shown a strong evidence of association between higher volumes and better outcomes. Due to the difficulty to test such an association in randomized controlled studies, the studies included in the reviews were mainly observational studies: however, the quality of the available evidence can be considered good both for the consistency of the results between the studies and for the strength of the association. Where national data had sufficient statistical power, this association has been observed by the empirical analysis conducted on the health providers of the NHS in 2011. Analysing national data, potential confounders, including age and the presence of comorbidities in the admission under study and in the admissions of the two previous years, have been considered. The systematic review of the literature does not permit to identify predefined volume thresholds. The analysis of national data shows a strong improvement in outcomes in the first part of the curve (from very low volumes to higher volumes) for the majority of the studied conditions. In some cases the improvement in outcomes remains gradual or constant with the increasing volume of care, in other the analysis could allow the identification of threshold values beyond which the outcome does not improve further. However, a good knowledge of the relationship between effectiveness of treatments and their costs, the geographical distribution and the accessibility to health care services are necessary to choose the minimum volumes of care, under which specific health procedures in the NHS should not be provided. Some potential biases due to the use of information systems data should also be taken into account. In particular, it is necessary to consider possible selection bias due to the different way of coding among hospitals that could lead to a different selection of cases for some conditions (e.g. acute myocardial infarction), less likely to occur in the selection of cases for oncologic, orthopaedic, vascular, abdominal, and cardiac surgery. Regarding the definition of the exposure (volume of care), a possible bias could result from misclassification of health providers with high volume of activity. In fact, performing the intervention in different departments/units of the same hospital would result in an overestimation of the volume of care measured for hospital rather than for department/unit. A similar bias could occur if the main determinant of the outcome of treatment was the case load of each surgeon: the results of the analysis may be biased when the same procedure was carried out by different operators in the same hospital/unit. In any case, the observed association between volumes of care and outcome is very strong, and it is unlikely to be attributable to biases of the study design. However, the foreseen bias is likely to be non-differential, and, therefore, it would eventually lead to an underestimation of the true association between volume of care and outcome. Health systems operate, by definition, in a context of limited resources, especially when societies and governments choose to reduce the amount of resources to allocate to the health system. In such conditions, the rationalisation of the organization of health services based on the volume of care may make resources available to improve the effectiveness of interventions. The identification and certification of services and provider with high volume of activity can help to reduce differences in the access to no effective procedures.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Since the first U.S. infant conceived with Assisted Reproductive Technology (ART) was born in 1981, both the use of advanced technologies to overcome infertility and the number of fertility clinics providing ART services have increased steadily in the United States. ART includes fertility treatments in which eggs or embryos are handled in the laboratory (i.e., in vitro fertilization [IVF] and related procedures). Because more than one embryo might be transferred during a procedure, women who undergo ART procedures, compared with those who conceive naturally, are more likely to deliver multiple birth infants. Multiple births pose substantial risks to both mothers and infants, including obstetric complications, preterm delivery, and low birthweight infants. This report provides state-specific information for the United States (including Puerto Rico) on ART procedures performed in 2012 and compares infant outcomes that occurred in 2012 (resulting from ART procedures performed in 2011 and 2012) with outcomes for all infants born in the United States in 2012. 2012. In 1996, CDC began collecting data on ART procedures performed in fertility clinics in the United States, as mandated by the Fertility Clinic Success Rate and Certification Act of 1992 (FCSRCA) (Public Law 102-493). Data are collected through the National ART Surveillance System, a web-based data collecting system developed by CDC. This report includes data from 52 reporting areas (the 50 states, the District of Columbia [DC], and Puerto Rico). In 2012, a total of 157,635 ART procedures performed in 456 U.S. fertility clinics were reported to CDC. These procedures resulted in 51,261 live-birth deliveries and 65,151 infants. The largest numbers of ART procedures were performed among residents of six states: California (20,241), New York (19,618), Illinois (10,449), Texas (10,281), Massachusetts (9,754), and New Jersey (8,590). These six states also had the highest number of live-birth deliveries as a result of ART procedures, and together they accounted for 50.1% of all ART procedures performed, 48.3% of all infants born from ART, and 48.3% of all ART multiple live-birth deliveries. Nationally, the total number of ART procedures performed per 1 million women of reproductive age (15-44 years), which is a proxy indicator of ART use, was 2,483. This indicator of ART use exceeded the national ratio in 13 reporting areas (California, Connecticut, Delaware, Hawaii, Illinois, Maryland, Massachusetts, New Hampshire, New Jersey, New York, Rhode Island, Virginia, and DC) and was more than twice the national ratio in three reporting areas (Massachusetts, New Jersey, and DC). Nationally, among ART cycles with patients using fresh embryos from their own eggs, in which at least one embryo was transferred, the average number of embryos transferred increased with the increasing age of the woman (1.9 among women aged <35 years, 2.2 among women aged 35-40 years, and 2.7 among women aged >40 years). The percentage of elective single-embryo transfer (eSET) procedures varied substantially between reporting areas for all ages. Among women aged <35 years, who are typically considered to be good candidates for eSET procedures, the national eSET rate was 15.3% (range: 2.1% in Oklahoma to 60.4% in Delaware). Overall, ART contributed to 1.5% of all infants born in the United States (range: 0.2% in Puerto Rico to 4.7% in Massachusetts) with the highest rates (≥3.0% of all infants born) observed in four reporting areas (Connecticut, Massachusetts, New Jersey, and DC). Infants conceived with ART comprised 19.6% of all multiple-birth infants (range: 5.5% in Maine to 39.3% in Massachusetts), 19.2% of all twin infants (range: 4.4% in Puerto Rico to 39.1% in Massachusetts), and 29.6% of all triplet or higher order infants (range: 0 in West Virginia to 69.7% in Idaho). Among infants conceived with ART, 43.6% were born in multiple-birth deliveries (range: 18.7% in Delaware to 56.0% in Idaho), compared with only 3.4% among all infants born in the general population (range: 2.1% in Puerto Rico to 4.5% in New Jersey). Approximately 41% of ART-conceived infants were twin infants, and 2% were triplet and higher order infants. Nationally, infants conceived with ART comprised 5.7% of all low birthweight (<2,500 grams) infants (range: 0.8% in Puerto Rico to 15.3% in Massachusetts) and 5.8% of all very low birthweight (<1,500 grams) infants (range: 0 in West Virginia to 15.1% in New Jersey). Overall, among ART-conceived infants, 30.2% were low birthweight (range: 18.8% in DC to 45.1% in New Mexico), compared with 8.0% among all infants (range: 5.6% in Alaska to 11.6% in Mississippi and Puerto Rico); 5.5% of ART infants were very low birthweight (range: 0 in West Virginia to 12.9% in Puerto Rico), compared with 1.4% among all infants (range: 0.9% in Alaska and Idaho to 2.1% in Mississippi). ART-conceived infants comprised 4.6% of all preterm (<37 weeks) infants (range: 0.7% in Puerto Rico to 13.4% in Massachusetts) and 5.2% of all very preterm (<32 weeks) infants (range: 1.0% in Puerto Rico to 14.9% in Vermont). Overall, among infants conceived with ART, 34.9% were born preterm (range: 20.8% in Delaware and DC to 49.4% in Puerto Rico), compared with 11.6% among all infants born in the general population (range: 8.7% in Vermont to 17.1% in Mississippi); 6.5% of ART infants were born very preterm (range: 3.3% in Nevada to 14.8% in South Dakota), compared with 1.9% among all infants born in the general population (range: 1.1% in Vermont to 2.9% in Mississippi). The percentage of infants conceived with ART who were low birthweight varied from 9.3% (range: 4.1% in South Carolina to 20.9% in Puerto Rico) among singletons, to 55.2% (range: 41.5% in New Hampshire to 83.3% in South Dakota) among twins, and 95.3% (range: 85.2% in Oklahoma to 100% in several reporting areas) among triplets or higher-order multiples; comparable percentages for all infants were 6.3% (range: 4.5% in Alaska to 10.3% in Puerto Rico), 55.4% (range: 46.0% in Alaska to 69.0% in Puerto Rico), and 91.6% (range: 80.6% in Missouri to 100% in several reporting areas), respectively. The percentage of ART infants who were preterm varied from 13.2% (range: 9.4% in West Virginia to 25.4% in North Dakota) among singletons, to 61.0% (range: 47.8% in DC to 80.0% in Maine and West Virginia) among twins, and 97.7% (range: 92.7% in Massachusetts to 100% in several reporting areas) among triplets or higher-order multiples; comparable percentages for all infants were 9.9% (range: 7.3% in Vermont to 15.8% in Puerto Rico), 56.8% (range: 47.2% in Connecticut to 67.2% in Puerto Rico), and 92.6% (range: 36.4% in Oregon to 96.8% in Ohio), respectively. The percentage of infants conceived with ART varied considerably by reporting area. In most reporting areas, multiples from ART comprised a substantial proportion of all twin, triplet, and higher-order infants born, and the rates of low birthweight and preterm infants were disproportionately higher among ART infants than in the birth population overall. Among women aged <35 years, eSET procedures warrant consideration because these patients might have extra embryos available for cryopreservation, which is a good predictor of embryo quality, and might have a more favorable prognosis for a live birth than older patients. However, on average, two embryos were transferred per cycle in ART procedures among women aged <35 years, influencing the overall multiple-birth rates in the United States. Compared with ART singletons, ART twins were approximately four and a half times more likely to be born preterm, and approximately six times more likely to be born with low birthweight. Singleton infants conceived with ART had slightly higher rates of preterm delivery and low birthweight than all singleton infants born in the United States. ART use per population unit was geographically varied, with 12 states showing ART use above the national rate. Of the four states (Illinois, Massachusetts, New Jersey, and Rhode Island) with comprehensive statewide-mandated health insurance coverage for ART procedures (e.g., coverage for at least four cycles of in vitro fertilization), two states (Massachusetts and New Jersey) had rates of ART use exceeding twice the national level. This type of mandated insurance has been associated with greater use of ART and might account for some of the difference in per capita ART use observed among states. Reducing the number of embryos transferred per ART procedure and increasing use of eSET, when clinically appropriate (typically age <35 years), might reduce multiple births and related adverse consequences of ART. Improved patient education and counseling on the maternal and infant health risks of having twins are needed given that twins account for the majority of ART-conceived multiple births. Although ART contributes to increasing rates of multiple births, it does not explain all of the increases. Other explanations for multiple births not investigated in this report might include age-related factors and the role of non-ART fertility treatments, and warrant further study.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Ginger (<iZingiber officinale</i L.) and turmeric (<iCurcuma longa</i L.) are two her baceous perennial plant species with rhizomes that are commonly used for flavoring or medicinal purposes. In January 2018, stunting and poorly developed root systems typically associated with plant-parasitic nematode infection were observed on organically grown edible ginger and turmeric in a hoop house in Wheeler County, Georgia. Examination of soil and root samples from symptomatic plants revealed the presence of high populations of root-knot nematodes (<iMeloidogyne</i spp.). The second-stage juveniles (J2s) were extracted from soil samples as described by Jenkins (1964). Nematode counts were 285 and 155 J2s per 100 cm<sup3</sup soil in the areas planted with ginger and turmeric, respectively. Nematode eggs were recovered from infected root systems using the bleach (1%) and blending method (Hussey and Barker, 1973). Examination of the root samples showed the presence of 840 and 320 eggs per g of roots in ginger and turmeric, respectively. Primary diagnosis of the <iMeloidogyne</i specimens was done by comparing morphological features observed in the J2s (n = 10) and perineal pattern of females (n = 11) based on the description given by Eisenback and Triantaphyllou (1991) and were tentatively identified as <iM. javanica</i (Treub, 1885; Chitwood, 1949). For species identification, DNA sequencing was performed using multiple markers located in 18S ribosomal RNA and 5.8S internal transcribed spacer 1 regions, (18S + ITS) (GenBank Accession No. MK390613), 28S domain 2 and 3 (28S D2/D3) (MK385596), cytochrome oxidase subunit I (COI) (MK391558), and subunit II and 16S (COII + 16S) (MK391557) of mitochondrial DNA following methods as described in Ye et al. (2015). PCR assays by species-specific primers were also conducted to confirm species identity as described by Zijlstra et al. (2000). The blast search results of DNA sequences of 18S + ITS, 28S (D2/D3), COI and COII + 16S revealed the best match as <iM. javanica</i, <iM. incognita</i (Kofoid and White, 1912; Chitwood, 1949) and <iM. arenaria</i (Neal, 1889; Chitwood, 1949) with 99-100% identity. These genes are highly conserved across these three most common root-knot nematode species. However, results of PCR assays by species-specific primers were only positive for <iM. javanica</i using primers Fjav/Rjav, but negative for <iM. incognita</i by Finc/Rinc and <iM. arenaria</i by Far/Rar as described by Zijlstra et al. (2000). Based on morphological characteristics and molecular analyses, the root-knot nematodes infecting ginger and turmeric were identified as <iM. javanica</i. After confirmation of the nematode species, a test was conducted in the greenhouse to assess the pathogenicity of the nematode on ginger and turmeric. Five seedlings per plant species (cultivars unknown) were grown in 15 cm-diam plastic pots containing equal parts of pasteurized field soil and sand, and then inoculated with 2,000 eggs of <iM. javanica</i. The egg suspension was added into three holes around the base of each seedling. Non-inoculated seedlings (n2 = 25) were used as controls. Plants were arranged in completely randomized design and grown at 25 ± 3 °C for 10 weeks. At the termination of the experiment, small galls were noticed on the roots of the inoculated seedlings of both ginger and turmeric. No galls were observed on the roots of non-inoculated plants. Egg were extracted from the galled roots (Hussey and Barker, 1973) yielding an average of 1040 ± 96 and 732 ± 54 eggs per g of root of ginger and turmeric, respectively. On ginger, the nematode produced large numbers of galls and egg masses on both primary and secondary (feeder) roots, but the galls produced on turmeric were often observed only on primary roots (Fig. 1). No symptoms of root-knot nematode infestation including galls or water-soaked lesions were observed on the outer surface of rhizomes of both ginger and turmeric. However, the size of rhizomes in the <iM. javanica</i-infested areas was visibly smaller than that in non-infested areas (Fig. 2). A similar reduction in the growth of turmeric rhizomes was also observed. <iMeloidogyne incognita</i has been commonly reported as a nematode pest of ginger (Myers et al., 2017) and turmeric (Hall et al., 2017) in the USA and both <iM. incognita</i and <iM. javanica</i are known to cause damage on these plant hosts (Ray et al., 1995; Singh and Gupta, 2011). To the best of our knowledge, this is the first report of <iM. javanica</i on ginger and turmeric in the USA. Ginger (<iZingiber officinale</i L.) and turmeric (<iCurcuma longa</i L.) are two her baceous perennial plant species with rhizomes that are commonly used for flavoring or medicinal purposes. In January 2018, stunting and poorly developed root systems typically associated with plant-parasitic nematode infection were observed on organically grown edible ginger and turmeric in a hoop house in Wheeler County, Georgia. Examination of soil and root samples from symptomatic plants revealed the presence of high populations of root-knot nematodes (<iMeloidogyne</i spp.). The second-stage juveniles (J2s) were extracted from soil samples as described by Jenkins (1964). Nematode counts were 285 and 155 J2s per 100 cm<sup3</sup soil in the areas planted with ginger and turmeric, respectively. Nematode eggs were recovered from infected root systems using the bleach (1%) and blending method (Hussey and Barker, 1973). Examination of the root samples showed the presence of 840 and 320 eggs per g of roots in ginger and turmeric, respectively. Primary diagnosis of the <iMeloidogyne</i specimens was done by comparing morphological features observed in the J2s (n = 10) and perineal pattern of females (n = 11) based on the description given by Eisenback and Triantaphyllou (1991) and were tentatively identified as <iM. javanica</i (Treub, 1885; Chitwood, 1949). For species identification, DNA sequencing was performed using multiple markers located in 18S ribosomal RNA and 5.8S internal transcribed spacer 1 regions, (18S + ITS) (GenBank Accession No. MK390613), 28S domain 2 and 3 (28S D2/D3) (MK385596), cytochrome oxidase subunit I (COI) (MK391558), and subunit II and 16S (COII + 16S) (MK391557) of mitochondrial DNA following methods as described in Ye et al. (2015). PCR assays by species-specific primers were also conducted to confirm species identity as described by Zijlstra et al. (2000). The blast search results of DNA sequences of 18S + ITS, 28S (D2/D3), COI and COII + 16S revealed the best match as <iM. javanica</i, <iM. incognita</i (Kofoid and White, 1912; Chitwood, 1949) and <iM. arenaria</i (Neal, 1889; Chitwood, 1949) with 99–100% identity. These genes are highly conserved across these three most common root-knot nematode species. However, results of PCR assays by species-specific primers were only positive for <iM. javanica</i using primers Fjav/Rjav, but negative for <iM. incognita</i by Finc/Rinc and <iM. arenaria</i by Far/Rar as described by Zijlstra et al. (2000). Based on morphological characteristics and molecular analyses, the root-knot nematodes infecting ginger and turmeric were identified as <iM. javanica</i. After confirmation of the nematode species, a test was conducted in the greenhouse to assess the pathogenicity of the nematode on ginger and turmeric. Five seedlings per plant species (cultivars unknown) were grown in 15 cm-diam plastic pots containing equal parts of pasteurized field soil and sand, and then inoculated with 2,000 eggs of <iM. javanica</i. The egg suspension was added into three holes around the base of each seedling. Non-inoculated seedlings (n2 = 25) were used as controls. Plants were arranged in completely randomized design and grown at 25 ± 3 °C for 10 weeks. At the termination of the experiment, small galls were noticed on the roots of the inoculated seedlings of both ginger and turmeric. No galls were observed on the roots of non-inoculated plants. Egg were extracted from the galled roots (Hussey and Barker, 1973) yielding an average of 1040 ± 96 and 732 ± 54 eggs per g of root of ginger and turmeric, respectively. On ginger, the nematode produced large numbers of galls and egg masses on both primary and secondary (feeder) roots, but the galls produced on turmeric were often observed only on primary roots (Fig. 1). No symptoms of root-knot nematode infestation including galls or water-soaked lesions were observed on the outer surface of rhizomes of both ginger and turmeric. However, the size of rhizomes in the <iM. javanica</i-infested areas was visibly smaller than that in non-infested areas (Fig. 2). A similar reduction in the growth of turmeric rhizomes was also observed. <iMeloidogyne incognita</i has been commonly reported as a nematode pest of ginger (Myers et al., 2017) and turmeric (Hall et al., 2017) in the USA and both <iM. incognita</i and <iM. javanica</i are known to cause damage on these plant hosts (Ray et al., 1995; Singh and Gupta, 2011). To the best of our knowledge, this is the first report of <iM. javanica</i on ginger and turmeric in the USA.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Dimethyl methylphosphonate (98% pure) is one of four chemicals nominated by the U.S. Army for toxicology and carcinogenesis studies because it was being considered for use to simulate the physical and spectroscopic (but not the biologic) properties of anticholinesterase (nerve) agents. Dimethyl methylphosphonate is also used as a flame retardant, a preignition additive for gasoline, an antifoam agent, a plasticizer and stabilizer, a textile conditioner and antistatic agent, and an additive for solvents and low-temperature hydraulic fluids. The United States produces 0.2-2 million pounds (91,000-910,000 kg) of per year. Gavage was chosen as the route of administration for all four candidate "simulants" to mimic potential exposure. Experimental Design: Dimethyl methylphosphonate was administered in corn oil by gavage to male and female F344/N rats and B6C3F1 mice in single-administration, 15-day, and 13-week studies to obtain toxicity data, to establish dose levels for the 2-year studies, and to identify target tissues. Additional studies were also performed to determine toxicity to the reproductive system of male F344/N rats and B6C3F1 mice and to study the potential for genetic damage in bacteria, mammalian cells, and Drosophila. Single-Administration Studies: In the single-administration studies, dimethyl methylphosphonate was given to rats and mice at doses up to 6,810 mg/kg body weight. No compound-related deaths were seen in male or female rats or male mice; two high dose female mice died. Rats exhibited inactivity, unsteady gait, and prostration after dosing; mice were inactive after dosing. Fifteen-Day Studies: Rats and mice received doses of 0, 1,250, 2,500, 5,000, 10,000, or 15,000 mg/kg dimethyl methylphosphonate per day. Compound-related deaths occurred in the three highest dose groups of rats and the two highest dose groups of mice. Rats receiving doses of 2,500 mg/kg or higher were inactive and at 5,000 or 10,000 mg/kg had an unsteady gait after dosing; mice exhibited inactivity, shallow breathing, and prostration at doses of 10,000 mg/kg or higher. No lesions were reported in rats. Nonneoplastic lesions of the stomach were seen in some male mice at doses of 1,250 mg/kg and higher and in some female mice at doses of 5,000 mg/kg and higher. Thirteen-Week Studies: Dimethyl methylphosphonate was given at doses up to 8,000 mg/kg per day. Compound-related deaths occurred at 2,000, 4,000, and 8,000 mg/kg in rats and at 4,000 and 8,000 mg/kg in mice. Mean body weights of rats at 1,000 mg/kg and mice at 2,000 mg/kg were similar to those of the vehicle controls; decreased weight gain was seen at higher doses. No compound-related clinical signs were reported. Minimal to mild renal and testicular lesions were seen at all doses in male rats, but the severity of these lesions did not increase with increasing dose of the chemical. No apparent target tissues were identified in female rats or male and female mice. Doses selected for the 2-year studies were based on body weight effects and mortality seen in the 13-week studies; the lesions seen in the kidney of male rats at the end of the 13-week studies were judged not to be life threatening. In the 2-year studies, dimethyl methylphosphonate was administered in corn oil by gavage at doses of 0, 500, or 1,000 mg/kg per day to groups of 50 F344/N rats of each sex and at 0, 1,000, or 2,000 mg/kg per day to groups of 50 B6C3F1 mice of each sex. All animals were dosed 5 days per week for 103 weeks. Body Weight and Survival in the Two-Year Studies: Mean body weights of high dose male rats were 5%-10% lower than those of the vehicle controls between weeks 28 and 76 and were 10%-24% lower between weeks 80 and 104. Mean body weights of high dose female rats were 8%-12% lower than those of the vehicle controls after week 80. Survival of male rats was greater than 50% in all groups until week 80, and after this time, survival decreased in both groups, with the survival at the end of the study being 27/50 in vehicle control, 17/50 in low dose, and 4/50 in high dose groups. Survival of in low dose, and 4/50 in high dose groups. Survival of low dose female rats was comparable to that of the vehicle controls, but the final survival of high dose female rats was decreased (vehicle control, 30/50; low dose, 33/50; high dose, 23/50). No other compound-related clinical signs were observed. Mean body weights of high dose male mice were 7&percnt;-16&percnt; lower than those of the vehicle control males between weeks 36 and 76, and those of high dose female mice were 6&percnt;-12&percnt; lower between weeks 88 and 103. Decreased survival between weeks 23 and 45 in high dose male mice was associated with fighting. Seventeen high dose male and 22 high dose female mice died during week 45; these deaths were associated with the accidental administration of a dose mixture that had a concentration 34&percnt; greater than the targeted amount. Eleven low dose male mice died on the same day during week 77. By the end of the study, 29/50 vehicle control, 12/50 low dose, and 0/50 high dose male mice were alive; 41/50, 30/50, and 2/50 female mice survived to the end of the study. Renal Effects in the Two-Year Studies: Administration of dimethyl methylphosphonate to male rats increased the average severity of nephropathy and caused mineralization (calcification) of the collecting tubules in the renal papilla (12/50; 41/50; 36/49), hyperplasia of the transitional epithelium lining the renal pelvis and overlying the renal papilla (0/50; 23/50; 21/49), and focal hyperplasia of the renal tubular epithelium (0/50; 8/50; 9/49). Administration of dimethyl methylphosphonate to male rats was also associated with the occurrence of rare renal tubular cell adenocarcinomas (0/50; 2/50; 3/49) and papillomas of the transitional epithelium lining of the renal pelvis (0/50; 2/50; 3/49); a transitional cell carcinoma occurred in a low dose male rat. There were no tubular cell or transitional cell neoplasms of the kidney in female rats. Hematopoietic System Effects in the Two-Year Studies: The incidence of mononuclear cell leukemia was increased in high dose male rats (10/50; 11/50; 17/50). Genetic Toxicity: Dimethyl methylphosphonate was not mutagenic when tested in the Salmonella typhimurium/microsome assay by the preincubational protocol with strains TA98, TA100, TA1535, or TA1537 with or without metabolic activation. The chemical did induce forward mutations in the mouse lymphoma L5178Y/TK&plusmn; assay system in the absence of metabolic activation. Treatment of cultured Chinese hamster ovary cells with dimethyl methylphosphonate did not induce chromosomal aberrations; however, sister chromatid exchanges were induced after exposure to this chemical in both the presence and absence of metabolic activation. When fed to Drosophila, dimethyl methylphosphonate induced a significant increase in the frequency of sex-linked recessive lethal mutations but did not induce reciprocal translocations. Dimethyl methylphosphonate caused a dominant lethal effect in male rats and mice. Studies of Reproductive Effects: Dimethyl methylphosphonate caused a dose-related increase in the number of fetal resorptions in undosed female rats and mice mated with males that received the chemical by gavage in water 5 days per week for 13 weeks at doses of 0-2,000 mg/kg per day. After the 13-week dosing period, histopathologic changes were seen in the kidney and testis of male rats but not in male mice; dosed male rats sired fewer litters and fewer pups per litter. Dose-related decreases in sperm count and sperm motility occurred in male rats but not in male mice. Toxic effects to the reproductive system of male rats and mice were reversible after a 13-to 14-week recovery period. Data Audit: An audit of the experimental data was conducted for the 2-year studies on dimethyl methylphosphonate. No data discrepancies were found that influenced the final interpretations. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of dimethyl methylphosphonate for male F344/N rats as shown by increased incidences of tubular cell hyperplasia, tubular cell adenocarcinomas, hyperplasia of the transitional cell epithelium, and transitional cell papillomas of the kidney. There was an increased incidence of mononuclear cell leukemia in male rats at 1,000 mg/kg. Renal toxicity and decreased survival occurred in dosed male rats. There was no evidence of carcinogenic activity of dimethyl methylphosphonate for female F344/N rats given doses of 500 or 1,000 mg/kg. The study in male B6C3F1 mice was an inadequate study of carcinogenic activity because of decreased survival in both dosed groups. There was no evidence of carcinogenic activity for female B6C3F1 mice receiving dimethyl methylphosphonate at 1,000 mg/kg; decreased survival of female mice at 2,000 mg/kg made this group inadequate for determination of carcinogenic activity. Synonyms: fyrol DMMP; methyl phosphonic acid, dimethyl ester; DMMP; methanephosphonic acid dimethyl ester; dimethyl methanephosphonate	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The objectives of this evidence based review are: i) To determine the effectiveness of computed tomography (CT) and magnetic resonance imaging (MRI) scans in the evaluation of persons with a chronic headache and a normal neurological examination.ii) To determine the comparative effectiveness of CT and MRI scans for detecting significant intracranial abnormalities in persons with chronic headache and a normal neurological exam.iii) To determine the budget impact of CT and MRI scans for persons with a chronic headache and a normal neurological exam. CONDITION AND TARGET POPULATION Headaches disorders are generally classified as either primary or secondary with further sub-classifications into specific headache types. Primary headaches are those not caused by a disease or medical condition and include i) tension-type headache, ii) migraine, iii) cluster headache and, iv) other primary headaches, such as hemicrania continua and new daily persistent headache. Secondary headaches include those headaches caused by an underlying medical condition. While primary headaches disorders are far more frequent than secondary headache disorders, there is an urge to carry out neuroimaging studies (CT and/or MRI scans) out of fear of missing uncommon secondary causes and often to relieve patient anxiety. Tension type headaches are the most common primary headache disorder and migraines are the most common severe primary headache disorder. Cluster headaches are a type of trigeminal autonomic cephalalgia and are less common than migraines and tension type headaches. Chronic headaches are defined as headaches present for at least 3 months and lasting greater than or equal to 15 days per month. The International Classification of Headache Disorders states that for most secondary headaches the characteristics of the headache are poorly described in the literature and for those headache disorders where it is well described there are few diagnostically important features. The global prevalence of headache in general in the adult population is estimated at 46%, for tension-type headache it is 42% and 11% for migraine headache. The estimated prevalence of cluster headaches is 0.1% or 1 in 1000 persons. The prevalence of chronic daily headache is estimated at 3%. COMPUTED TOMOGRAPHY: Computed tomography (CT) is a medical imaging technique used to aid diagnosis and to guide interventional and therapeutic procedures. It allows rapid acquisition of high-resolution three-dimensional images, providing radiologists and other physicians with cross-sectional views of a person's anatomy. CT scanning poses risk of radiation exposure. The radiation exposure from a conventional CT scanner may emit effective doses of 2-4mSv for a typical head CT. MAGNETIC RESONANCE IMAGING: Magnetic resonance imaging (MRI) is a medical imaging technique used to aid diagnosis but unlike CT it does not use ionizing radiation. Instead, it uses a strong magnetic field to image a person's anatomy. Compared to CT, MRI can provide increased contrast between the soft tissues of the body. Because of the persistent magnetic field, extra care is required in the magnetic resonance environment to ensure that injury or harm does not come to any personnel while in the environment. What is the effectiveness of CT and MRI scanning in the evaluation of persons with a chronic headache and a normal neurological examination?What is the comparative effectiveness of CT and MRI scanning for detecting significant intracranial abnormality in persons with chronic headache and a normal neurological exam?What is the budget impact of CT and MRI scans for persons with a chronic headache and a normal neurological exam. A literature search was performed on February 18, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January, 2005 to February, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with an unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. Systematic reviews, randomized controlled trials, observational studiesOutpatient adult population with chronic headache and normal neurological examStudies reporting likelihood ratio of clinical variables for a significant intracranial abnormalityEnglish language studies2005-present Studies which report outcomes for persons with seizures, focal symptoms, recent/new onset headache, change in presentation, thunderclap headache, and headache due to traumaPersons with abnormal neurological examinationCase reports Probability for intracranial abnormality SECONDARY OUTCOME: Patient relief from anxietySystem service useSystem costsDetection rates for significant abnormalities in MRI and CT scans One systematic review, 1 small RCT, and 1 observational study met the inclusion and exclusion criteria. The systematic review completed by Detsky, et al. reported the likelihood ratios of specific clinical variables to predict significant intracranial abnormalities. The RCT completed by Howard et al., evaluated whether neuroimaging persons with chronic headache increased or reduced patient anxiety. The prospective observational study by Sempere et al., provided evidence for the pre-test probability of intracranial abnormalities in persons with chronic headache as well as minimal data on the comparative effectiveness of CT and MRI to detect intracranial abnormalities. OUTCOME 1: PRE-TEST PROBABILITY. The pre-test probability is usually related to the prevalence of the disease and can be adjusted depending on the characteristics of the population. The study by Sempere et al. determined the pre-test probability (prevalence) of significant intracranial abnormalities in persons with chronic headaches defined as headache experienced for at least a 4 week duration with a normal neurological exam. There is a pre-test probability of 0.9% (95% CI 0.5, 1.4) in persons with chronic headache and normal neurological exam. The highest pre-test probability of 5 found in persons with cluster headaches. The second highest, that of 3.7, was reported in persons with indeterminate type headache. There was a 0.75% rate of incidental findings. LIKELIHOOD RATIOS FOR DETECTING A SIGNIFICANT ABNORMALITY: Clinical findings from the history and physical may be used as screening test to predict abnormalities on neuroimaging. The extent to which the clinical variable may be a good predictive variable can be captured by reporting its likelihood ratio. The likelihood ratio provides an estimate of how much a test result will change the odds of having a disease or condition. The positive likelihood ratio (LR+) tells you how much the odds of having the disease increases when a test is positive. The negative likelihood ratio (LR-) tells you how much the odds of having the disease decreases when the test is negative. Detsky et al., determined the likelihood ratio for specific clinical variable from 11 studies. There were 4 clinical variables with both statistically significant positive and negative likelihood ratios. These included: abnormal neurological exam (LR+ 5.3, LR- 0.72), undefined headache (LR+ 3.8, LR- 0.66), headache aggravated by exertion or valsalva (LR+ 2.3, LR- 0.70), and headache with vomiting (LR+ 1.8, and LR- 0.47). There were two clinical variables with a statistically significant positive likelihood ratio and non significant negative likelihood ratio. These included: cluster-type headache (LR+ 11, LR- 0.95), and headache with aura (LR+ 12.9, LR- 0.52). Finally, there were 8 clinical variables with both statistically non significant positive and negative likelihood ratios. These included: headache with focal symptoms, new onset headache, quick onset headache, worsening headache, male gender, headache with nausea, increased headache severity, and migraine type headache. OUTCOME 2: RELIEF FROM ANXIETY Howard et al. completed an RCT of 150 persons to determine if neuroimaging for headaches was anxiolytic or anxiogenic. Persons were randomized to receiving either an MRI scan or no scan for investigation of their headache. The study population was stratified into those persons with a Hospital Anxiety and Depression scale (HADS) > 11 (the high anxiety and depression group) and those < 11 (the low anxiety and depression) so that there were 4 groups: Group 1: High anxiety and depression, no scan group Group 2: High anxiety and depression, scan group Group 3: Low anxiety and depression, no scan group Group 4: Low anxiety and depression, scan group ANXIETY: There was no evidence for any overall reduction in anxiety at 1 year as measured by a visual analogue scale of 'level of worry' when analysed by whether the person received a scan or not. Similarly, there was no interaction between anxiety and depression status and whether a scan was offered or not on patient anxiety. Anxiety did not decrease at 1 year to any statistically significant degree in the high anxiety and depression group (HADS positive) compared with the low anxiety and depression group (HADS negative). There are serious methodological limitations in this study design which may have contributed to these negative results. First, when considering the comparison of 'scan' vs. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Psoriasis is an immune-mediated disease for which some people have a genetic predisposition. The condition manifests in inflammatory effects on either the skin or joints, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. Several randomised controlled trials (RCTs) have compared the efficacy of the different systemic treatments in psoriasis against placebo. However, the relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head to head, which is why we chose to conduct a network meta-analysis. To compare the efficacy and safety of conventional systemic agents (acitretin, ciclosporin, fumaric acid esters, methotrexate), small molecules (apremilast, tofacitinib, ponesimod), anti-TNF alpha (etanercept, infliximab, adalimumab, certolizumab), anti-IL12/23 (ustekinumab), anti-IL17 (secukinumab, ixekizumab, brodalumab), anti-IL23 (guselkumab, tildrakizumab), and other biologics (alefacept, itolizumab) for patients with moderate to severe psoriasis and to provide a ranking of these treatments according to their efficacy and safety. We searched the following databases to December 2016: the Cochrane Skin Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and LILACS. We also searched five trials registers and the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) reports. We checked the reference lists of included and excluded studies for further references to relevant RCTs. We searched the trial results databases of a number of pharmaceutical companies and handsearched the conference proceedings of a number of dermatology meetings. Randomised controlled trials (RCTs) of systemic and biological treatments in adults (over 18 years of age) with moderate to severe plaque psoriasis or psoriatic arthritis whose skin had been clinically diagnosed with moderate to severe psoriasis, at any stage of treatment, in comparison to placebo or another active agent. Three groups of two review authors independently undertook study selection, data extraction, 'Risk of bias' assessment, and analyses. We synthesised the data using pair-wise and network meta-analysis (NMA) to compare the treatments of interest and rank them according to their effectiveness (as measured by the Psoriasis Area and Severity Index score (PASI) 90) and acceptability (the inverse of serious adverse effects). We assessed the certainty of the body of evidence from the NMA for the two primary outcomes, according to GRADE; we evaluated evidence as either very low, low, moderate, or high. We contacted study authors when data were unclear or missing. We included 109 studies in our review (39,882 randomised participants, 68% men, all recruited from a hospital). The overall average age was 44 years; the overall mean PASI score at baseline was 20 (range: 9.5 to 39). Most of these studies were placebo controlled (67%), 23% were head-to-head studies, and 10% were multi-armed studies with both an active comparator and placebo. We have assessed all treatments listed in the objectives (19 in total). In all, 86 trials were multicentric trials (two to 231 centres). All of the trials included in this review were limited to the induction phase (assessment at less than 24 weeks after randomisation); in fact, all trials included in the network meta-analysis were measured between 12 and 16 weeks after randomisation. We assessed the majority of studies (48/109) as being at high risk of bias; 38 were assessed as at an unclear risk, and 23, low risk.Network meta-analysis at class level showed that all of the interventions (conventional systemic agents, small molecules, and biological treatments) were significantly more effective than placebo in terms of reaching PASI 90.In terms of reaching PASI 90, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the conventional systemic agents. Small molecules were associated with a higher chance of reaching PASI 90 compared to conventional systemic agents.At drug level, in terms of reaching PASI 90, all of the anti-IL17 agents and guselkumab (an anti-IL23 drug) were significantly more effective than the anti-TNF alpha agents infliximab, adalimumab, and etanercept, but not certolizumab. Ustekinumab was superior to etanercept. No clear difference was shown between infliximab, adalimumab, and etanercept. Only one trial assessed the efficacy of infliximab in this network; thus, these results have to be interpreted with caution. Tofacitinib was significantly superior to methotrexate, and no clear difference was shown between any of the other small molecules versus conventional treatments.Network meta-analysis also showed that ixekizumab, secukinumab, brodalumab, guselkumab, certolizumab, and ustekinumab outperformed other drugs when compared to placebo in terms of reaching PASI 90: the most effective drug was ixekizumab (risk ratio (RR) 32.45, 95% confidence interval (CI) 23.61 to 44.60; Surface Under the Cumulative Ranking (SUCRA) = 94.3; high-certainty evidence), followed by secukinumab (RR 26.55, 95% CI 20.32 to 34.69; SUCRA = 86.5; high-certainty evidence), brodalumab (RR 25.45, 95% CI 18.74 to 34.57; SUCRA = 84.3; moderate-certainty evidence), guselkumab (RR 21.03, 95% CI 14.56 to 30.38; SUCRA = 77; moderate-certainty evidence), certolizumab (RR 24.58, 95% CI 3.46 to 174.73; SUCRA = 75.7; moderate-certainty evidence), and ustekinumab (RR 19.91, 95% CI 15.11 to 26.23; SUCRA = 72.6; high-certainty evidence).We found no significant difference between all of the interventions and the placebo regarding the risk of serious adverse effects (SAEs): the relative ranking strongly suggested that methotrexate was associated with the best safety profile regarding all of the SAEs (RR 0.23, 95% CI 0.05 to 0.99; SUCRA = 90.7; moderate-certainty evidence), followed by ciclosporin (RR 0.23, 95% CI 0.01 to 5.10; SUCRA = 78.2; very low-certainty evidence), certolizumab (RR 0.49, 95% CI 0.10 to 2.36; SUCRA = 70.9; moderate-certainty evidence), infliximab (RR 0.56, 95% CI 0.10 to 3.00; SUCRA = 64.4; very low-certainty evidence), alefacept (RR 0.72, 95% CI 0.34 to 1.55; SUCRA = 62.6; low-certainty evidence), and fumaric acid esters (RR 0.77, 95% CI 0.30 to 1.99; SUCRA = 57.7; very low-certainty evidence). Major adverse cardiac events, serious infections, or malignancies were reported in both the placebo and intervention groups. Nevertheless, the SAEs analyses were based on a very low number of events with low to very low certainty for just over half of the treatment estimates in total, moderate for the others. Thus, the results have to be considered with caution.Considering both efficacy (PASI 90 outcome) and acceptability (SAEs outcome), highly effective treatments also had more SAEs compared to the other treatments, and ustekinumab, infliximab, and certolizumab appeared to have the better trade-off between efficacy and acceptability.Regarding the other efficacy outcomes, PASI 75 and Physician Global Assessment (PGA) 0/1, the results were very similar to the results for PASI 90.Information on quality of life was often poorly reported and was absent for a third of the interventions. Our review shows that compared to placebo, the biologics ixekizumab, secukinumab, brodalumab, guselkumab, certolizumab, and ustekinumab are the best choices for achieving PASI 90 in people with moderate to severe psoriasis on the basis of moderate- to high-certainty evidence. At class level, the biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha were significantly more effective than the small molecules and the conventional systemic agents, too. This NMA evidence is limited to induction therapy (outcomes were measured between 12 to 16 weeks after randomisation) and is not sufficiently relevant for a chronic disease. Moreover, low numbers of studies were found for some of the interventions, and the young age (mean age of 44 years) and high level of disease severity (PASI 20 at baseline) may not be typical of patients seen in daily clinical practice.Another major concern is that short-term trials provide scanty and sometimes poorly reported safety data and thus do not provide useful evidence to create a reliable risk profile of treatments. Indeed, we found no significant difference in the assessed interventions and placebo in terms of SAEs. Methotrexate appeared to have the best safety profile, but as the evidence was of very low to moderate quality, we cannot be sure of the ranking. In order to provide long-term information on the safety of the treatments included in this review, it will be necessary to evaluate non-randomised studies and postmarketing reports released from regulatory agencies as well.In terms of future research, randomised trials comparing directly active agents are necessary once high-quality evidence of benefit against placebo is established, including head-to-head trials amongst and between conventional systemic and small molecules, and between biological agents (anti-IL17 versus anti-IL23, anti-IL23 versus anti-IL12/23, anti-TNF alpha versus anti-IL12/23). Future trials should also undertake systematic subgroup analyses (e.g. assessing biological-naïve patients, baseline psoriasis severity, presence of psoriatic arthritis, etc.). Finally, outcome measure harmonisation is needed in psoriasis trials, and researchers should look at the medium- and long-term benefit and safety of the interventions and the comparative safety of different agents.	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The types and levels of fats in the diet are known to affect the incidence of certain neoplasms in humans and rodents. In long-term toxicity and carcinogenicity studies in rodents, the level of dietary fat is altered by using oil as a vehicle to administer unpalatable or volatile chemicals. Control male rats receiving a corn oil vehicle have a higher incidence of pancreatic proliferative lesions and a lower incidence of mononuclear cell leukemia than untreated control males. Therefore, the National Toxicology Program (NTP) designed studies to evaluate the role of several oils in altering cancer rates in male rats. The NTP study reported here was part of a larger program that included cooperative agreements with Dartmouth Medical School, Northwestern Medical School, and the University of Missouri. The program was designed to study the mechanisms by which corn oil induces pancreatic cancer. To evaluate corn oil as well as two other gavage vehicles for potential toxicity, corn oil, safflower oil, and tricaprylin were administered by gavage to male F344/N rats for 2 years. The rats that received corn oil were also made available to the university investigators for study of the corn oil-induced pancreatic lesions. Each vehicle was administered by gavage at volumes of 2.5, 5, or 10 mL/kg body weight once daily for 5 days per week. In the corn oil study, a control of 10 mL saline/kg was also included. To evaluate the potential role of corn oil in promoting a pancreatic proliferative effect, 500 mg dichloromethane/kg body weight was administered in 2.5, 5, or 10 mL corn oil/kg body weight for 2 years to male F344/N rats. Dichloromethane was chosen because the chemical appeared to cause pancreatic proliferative lesions when administered by gavage in a corn oil vehicle but not when the exposure was by inhalation. In each of these studies, the term "dose" refers to the volume of gavage vehicle administered. 2-YEAR STUDIES OF CORN OIL, SAFFLOWER OIL, AND TRICAPRYLIN: Survival and Body Weights: Two-year survival was increased in male rats receiving corn oil (untreated control, 26/50; saline control, 32/50; 2.5 mL/kg, 33/50; 5 mL/kg, 38/50; 10 mL/kg, 40/50) primarily due to a dose-related decreased incidence of mononuclear cell leukemia. The mean body weights of all dosed groups were at least 5% higher than those of the untreated and saline controls by week 48, but the mean body weights of groups receiving 2.5 or 5 mL corn oil/kg decreased during the final weeks of the study (after week 89) and were similar to those of the controls at the end of the study. Two-year survival was slightly increased in male rats receiving safflower oil relative to that of the controls (untreated control, 30/50; 2.5 mL/kg, 33/50; 5 mL/kg, 40/50; 10 mL/kg, 36/50). The mean body weight of male rats receiving 10 mL safflower oil/kg was at least 5% greater than that of the controls after week 45 and was 16% greater by the end of the study. Two-year survival of high-dose tricaprylin males was lower than that of the controls (untreated control, 31/50; 2.5 mL/kg, 30/50; 5 mL/kg, 31/50; 10 mL/kg, 23/53) due to moribund kills and deaths that appeared to be related to toxicity. The mean body weight of the high-dose group was lower than that of the controls throughout the study, although the difference was less than 5% after week 61. Pathology Findings: In the corn oil study, there were significant dose-related increased incidences of pancreatic exocrine hyperplasia and adenoma (hyperplasia: 8/50, 28/47, 28/50, 35/50; adenoma: 1/50, 8/47, 10/50, 23/50; carcinoma: 0/50, 0/47, 1/50, 0/50 in the untreated control, 2.5, 5, and 10 mL/kg groups, respectively). The incidence and severity of nephropathy decreased with dose (incidence [mean severity grade]: 47/50 [2.1], 43/48 [1.8], 45/50 [1.4], 40/49 [1.2]). The incidences of pheochromocytomas (benign, malignant, or complex) of the adrenal medulla were also decreased in dosed rats (23/49, 21/50, 5/50, 9/50). The incidence of mononuclear cell leukemia was significantly decreased in rats dosed with corn oil (27/50, 16/50, 11h corn oil (27/50, 16/50, 11/50, 7/50). In rats receiving safflower oil, the incidences of pancreatic exocrine hyperplasia and adenoma increased significantly with dose (hyperplasia: 8/50, 14/50, 29/49, 30/50; adenoma: 1/50, 7/50,15/49, 28/50; carcinoma: 0/50, 0/50, 0/49, 1/50 in the untreated control, 2.5, 5, and 10 mL/kg groups, respectively). There was a decrease in the severity, but not in the incidence, of nephropathy, a common lesion in aging F344/N rats (incidence [mean severity grade]: 49/50 [2.0], 50/50 [1.8], 47/50 [1.1], 49/49 [1.1]). There were decreased incidences of mononuclear cell leukemia (33/50, 19/50, 18/50, 7/51). In the tricaprylin study, there were significant dose-related increased incidences of pancreatic exocrine hyperplasia and adenoma (hyperplasia: 8/49, 9/49, 18/49, 28/50; adenoma: 2/49, 6/49,13/49,18/50 in the untreated control, 2.5, 5, and 10 mL/kg groups, respectively). The incidence of proliferative lesions of the forestomach increased significantly with dose (basal cell hyperplasia: 4/50, 7/50, 12/49, 21/52; squamous cell papilloma: 0/50, 0/50, 3/50, 10/53). The incidence of nephropathy was significantly decreased in high-dose rats, and the severity of nephropathy decreased with dose (incidence [mean severity grade]: 46/50 [2.0], 42/50 [1.5], 45/50 [1.7], 27/49 [0.9]). In high-dose rats, the incidence of mononuclear cell leukemia was decreased (23/50, 28/50, 22/50, 9/53). 2-YEAR STUDY OF DICHLOROMETHANE IN CORN OIL: Survival and Body Weights: Two-year survival increased slightly with dose in the three groups receiving 500 mg dichloromethane/kg in 2.5, 5, or 10 mL corn oil/kg (23/50, 28/50, 31/50) due to a dose-related decrease in the incidence of mononuclear cell leukemia. The rats receiving 500 mg dichloromethane/kg without corn oil were sacrificed within the first 3 weeks of the study due to the severe toxicity of dichloromethane. The final mean body weight of the high-dose rats was greater than the final mean body weights of groups receiving dichloromethane in 2.5 or 5 mL corn oil/kg. Pathology Findings: There was a dose-related increase in the incidence of pancreatic proliferative exocrine lesions in rats receiving dichloromethane in 2.5, 5, and 10 mL corn oil/kg (hyperplasia: 28/50, 38/50, 44/50; adenoma: 9/50,19/50, 41/50; carcinoma: 0/50,1/50, 3/50). The incidences of pancreatic exocrine hyperplasia and adenoma in rats receiving dichloromethane in 5 or 10 mL, but not 2.5 mL, corn oil were increased compared to the incidences in rats receiving comparable volumes of corn oil alone (hyperplasia: 2.5 mL, 28/47; 5 mL, 28/50;10 mL, 35/50; adenoma: 8/47,10/50, 23/50; carcinoma: 0/47,1/50, 0/50). There were significantly increased incidences of pituitary gland pars distalis adenoma in rats receiving dichloromethane in corn oil (20/50, 18/49, 16/49) when compared to those in rats receiving comparable volumes of corn oil alone (10/50, 6/49, 7/50). The incidence of mammary gland adenoma and fibroadenoma (combined) was significantly increased in rats receiving dichloromethane in 10 mL corn oil/kg (7/50) when compared to rats receiving dichloromethane in 2.5 mL corn oil/kg (1/50), but was not significantly increased when compared to the group receiving 10 mL of corn oil alone (3/50). The incidences of mammary gland adenoma and fibroadenoma (combined) were 7/50 for the untreated safflower oil controls and 6/50 for the untreated tricaprylin controls. The incidence of mononuclear cell leukemia decreased in the group receiving dichloromethane in 10 mL corn oil/kg (13/50,14/50, 5/50). GENETIC TOXICOLOGY: Neither safflower oil nor corn oil was mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, or TA1535, with or without S9. Tricaprylin, in contrast, was mutagenic in strain TA1535 with, but not without, S9. Tricaprylin did not induce mutations in strains TA97, TA98, or TA100, with or without S9. SUMMARY: These studies were designed to evaluate the effects of various concentrations of an oil very high in polyunsaturated fat (safflower oil), an oil containing high levels of polyunsaturated and monounsaturated fats (corn oil), and an oil containing saturated medium-chain fatty acids (tricaprylin) on the incidence and pattern of neoplasms in the F344/N rat. In addition, safflower oil and tricaprylin were evaluated as replacements for the corn oil vehicle. These studies demonstrate that safflower oil and tricaprylin do not offer significant advantages over corn oil as a gavage vehicle in long-term rodent studies. Corn oil, safflower oil, and tricaprylin each caused hyperplasia and adenoma of the exocrine pancreas, decreased incidences of mononuclear cell leukemia, and reduced incidences or severity of nephropathy in male F344/N rats. There was an increased incidence of squamous cell papillomas of the forestomach in F344/N rats receiving 10 mL tricaprylin/kg. Further, the use of corn oil as a gavage vehicle may have a confounding effect on the interpretation of chemical-induced proliferative lesions of the exocrine pancreas and mononuclear cell leukemia in male F344/N rats. Synonyms: Corn Oil - Maize oil, Maydol Tricaprylin - Trioctanoin; 1,2,3-trioctanoyl glycerol; Glycerol trioctanoate	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Worldwide, tuberculosis (TB) remains the most frequent and important infectious disease causing morbidity and death. One-third of the world's population is infected with Mycobacterium tuberculosis (MTB), the etiologic agent of TB. The World Health Organization estimates that about eight to ten million new TB cases occur annually worldwide and the incidence of TB is currently increasing. In this context, TB is in the top three, with malaria and HIV being the leading causes of death from a single infectious agent, and approximately two million deaths are attributable to TB annually. In particular, pulmonary TB, the most common form of TB, is a highly contagious and life-threatening infection. Moreover, enhanced susceptibility to TB in HIV-infected populations is another serious health problem throughout the world. In addition, multidrug-resistant TB (MDR-TB) has been increasing in incidence in many areas, not only in developing countries but industrialized countries as well, during the past decade. These situations, particularly the global resurgence of TB and the rapid emergence of MDR-TB, underscore the importance of the development of new antituberculous drugs and new protocols for efficacious clinical control of TB patients using ordinary antimycobacterial drugs. Concerning the development of new antituberculous drugs, the following points are of particular importance. (1) Development of drugs which display lasting antimycobacterial activity in vivo is desirable, since they can be administered with long intervals and consequently facilitate directly observed therapy and enhance patient compliance. (2) Development of novel antituberculosis compounds to combat MDR-TB is urgently needed. (3) The eradication of slowly metabolizing and, if possible, dormant populations of MTB organisms that cause relapse, using new classes of anti-TB drugs is very promising for prevention of TB incidence, because it will markedly reduce the incidence of active TB from persons who are latently infected with MTB. Unfortunately, no new drugs except rifabutin and rifapentine has been marketed for TB in the US and other countries during the 40 years after release of rifampicin. There are a number of constraints that have deterred companies from investing in new anti-TB drugs. The research is expensive, slow and difficult, and requires specialized facilities for handling MTB. There are few animal models that closely mimic the human TB disease. Development time of any anti-TB drug will be long. In fact, clinical trials will require the minimum six-month therapy, with a follow-up period of one year or more. In addition, it is hard to demonstrate obvious benefit of a new anti-TB agents over pre-existing drugs, since clinical trials involve multidrug combination therapy using highly effective ordinary anti-TB drugs. Finaly, there is the perceived lack of commercial return to companies engaged in the development of new anti-TB drugs, because over 95% of TB cases worldwide are in developing countries. In this symposium, we reviewed the following areas. 1. Critical new information on the entire genome of MTB recently obtained and increasing knowledge of various mycobacterial virulence genes are greatly promoting the identification of genes that code for new drug targets. In this context, Dr. Namba reviewed the status of new types of compounds which are being developed as anti-TB drug. He also discussed the development of new antimycobacterial drugs according to new and potential pharmacological targets and the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Using such findings for mycobacterial genomes, bioinformatics/genomics/proteomics-based drug design and drug development using quantitative structure-activity relationships may be possible in the near future. In this context, Dr. Suwa and Dr. Suzuki reviewed the usefulness of chemical genomics in searching novel drug targets for development of new antituberculous drugs. The authors reviewed (1) the history and present status of chemical genomics that is defined as the systemic search for a selective small molecular modulator for each function of all gene products, (2) recent studies of the authors on profiles of the interactions between various kinds of human proteins and small molecule modulators using the new technology devised by Reverse Proteomics Research Institute, and (3) future prospects of the development of new antituberculous drugs based on chemical genomics. 3. It appears also promising to develop new types of drug administration systems using drug vehicles, which enable efficacious drug delivery to their target in vivo. Dr. Izumikawa, Dr. Ohno and Dr. Kohno reviewed the usefulness of liposome- and polymer-based technologies, which enable efficacious delivery of encapsulated drugs at required doses for prolonged periods of time with only a single shot without toxicity, and also enable highly targeted delivery of drugs to their target in vivo. They indicated that the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better clinical outcome. 4. Immunoadjunctive therapy appears to be promising in improving outcome of clinical control of refractory mycobacterial infections, including MDR-TB and M. avium complex infection. Dr. Shimizu, Dr. Sato and Dr. Tomioka reviewed the present status of immunotherapy of mycobacterial infections in combination with antimycobacterial drugs. They indicated that the development of new classes of immunomodulators other than cytokines (IL-2, IFN-gamma, GM-CSF, IL-12, etc.) particularly those with no severe side-effects, are urgently needed. Their review dealed with some promising immunoadjunctive agents, especially ATP and its analogues, which potentiate macrophage antimycobacterial activity via purinergic P2 receptors. The aim of this symposium is to address the future prospects of the development of new drugs and drug regimens for anti-TB chemotherapy. There are a number of difficulties in drug-design for the development of new drug formulations with increased potential for antimycobacterial effects, excellent pharmacokinetics, and tolerability. It should be emphasized that the most urgent goal of chemotherapy of TB and MAC infections, especially that associated with HIV infection, is to develop highly active, low-cost drugs which can be used not only in industrialized countries but also in developing countries, since the incidences of AIDS-associated intractable TB and MAC infections are rapidly increasing in the latter. We strongly wish a great advance of fundametal and practical studies in developing such kinds of new anti-TB drugs in the near future. 1. Prospects for non-clinical or clinical development of new antituberculous drugs in relation to corporate strategy: Kenji NAMBA (New Product Research Laboratories I, Daiichi Pharmaceutical Co., Ltd.) Tuberculosis (TB) remains one of the deadliest threats to public health. No new anti-TB drugs have been brought into the clinic in the past 40 years. Current non-clinical works with progressed technology and Global Alliance for TB Drug Development, a non-profit organization established in 2000, accelerate research and development of faster-acting anti-TB compounds. We reviewed the status of new types of compounds which are being developed as anti-TB drug, such as diarylquinoline (TMC 207), nitroimidazole (PA-824 and OPC-67683), and moxifloxacin (MFLX). We also discussed the best clinical development plans for new-TB drugs in relation to corporate strategy. 2. Exploring novel drug targets through the chemical genomics approach and its possible application to the development of anti-tuberculosis drugs: Yorimasa SUWA (Reverse Proteomics Research Institute Co., Ltd.), Yohji SUZUKI (Teijin Ltd.) Recently, chemical genomics approach has been focused as an emerging technology for the drug discovery. In advance to a very large scale national project in US started last year, Reverse Proteomics Research Institute Co., Ltd. (REPRORI) has developed the core technologies for chemical genomics. Here we describe the outline of chemical genomics study, especially that of REPRORI, and discuss about its possible application to the development of anti-tuberculosis drugs. 3. Anti-mycobacterial agents and drug delivery: Koichi IZUMIKAWA, Hideaki OHNO, Shigeru KOHNO (Second Department of Internal Medicine, Nagasaki University School of Medicine) Mycobacterium infection is a major clinical concern in whole world. Since the newly developed anti-mycobacterial agents are few and still unavailable in clinical settings, the applications of drug delivery system using conventional anti-mycobacterial agents are challenging to improve the compliance of treatment and better efficacy. The efficacy of anti-mycobacterial agents modified by liposome or polymer based technology have been investigated and reported using various animal models. Drug delivery system increased and prolonged the drug concentrations at the blood and targeted organs and the duration of sustained drug release, respectively. These effects lead to decrease in the frequency of drug administrations dramatically and better efficacy rates. The studies, however, were performed only in animal models, the further investigations and evaluations in human are required for practical use. 4. Adjunctive immunotherapy of mycobacterial infections: Toshiaki SHIMIZU, Katsumasa SATO, Haruaki TOMIOKA (Department of Microbiology and Immunology, Shimane University School of Medicine) There is an urgent need to develop new antimicrobials and protocols for the administration of drugs that are potently efficacious against intractable mycobacterial infections. Unfortunately, development of the new drugs for solving this problem is not progressing. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The objective of this health technology policy assessment was to determine the effectiveness and cost-effectiveness of using intravascular ultrasound (IVUS) as an adjunctive imaging tool to coronary angiography for guiding percutaneous coronary interventions. INTRAVASCULAR ULTRASOUND: Intravascular ultrasound is a procedure that uses high frequency sound waves to acquire 3-dimensional images from the lumen of a blood vessel. The equipment for performing IVUS consists of a percutaneous transducer catheter and a console for reconstructing images. IVUS has been used to study the structure of the arterial wall and nature of atherosclerotic plaques, and obtain measurements of the vessel lumen. Its role in guiding stent placement is also being investigated. IVUS is presently not an insured health service in Ontario. Coronary artery disease accounts for approximately 55% of cardiovascular deaths, the leading cause of death in Canada. In Ontario, the annual mortality rate due to ischemic heart disease was 141.8 per 100,000 population between 1995 and 1997. Percutaneous coronary intervention (PCI), a less invasive approach to treating coronary artery disease, is used more frequently than coronary bypass surgery in Ontario. The number of percutaneous coronary intervention procedures funded by the Ontario Ministry of Health and Long-term Care is expected to increase from approximately 17, 780 in 2004/2005 to 22,355 in 2006/2007 (an increase of 26%), with about 95% requiring the placement of one or more stents. Restenosis following percutaneous coronary interventions involving bare metal stents occurs in 15% to 30% of the cases, mainly because of smooth muscle proliferation and migration, and production of extracellular matrix. In-stent restenosis has been linked to suboptimal stent expansion and inadequate lesion coverage, while stent thrombosis has been attributed to incomplete stent-to-vessel wall apposition. Since coronary angiography (the imaging tool used to guide stent placement) has been shown to be inaccurate in assessing optimal stent placement, and IVUS can provide better views of the vessel lumen, the clinical utility of IVUS as an imaging tool adjunctive to coronary angiography in coronary intervention procedures has been explored in clinical studies. A systematic review was conducted to answer the following questions: What are the procedure-related complications associated with IVUS?Does IVUS used in conjunction with angiography to guide percutaneous interventions improve patient outcomes compared to angiographic guidance without IVUS?Who would benefit most in terms of clinical outcomes from the use of IVUS adjunctive to coronary angiography in guiding PCIs?What is the effectiveness of IVUS guidance in the context of drug-eluting stents?What is the cost-effectiveness ratio and budget impact of adjunctive IVUS in PCIs in Ontario?A systematic search of databases OVID MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) database for the period beginning in May 2001 until the day of the search, November 4, 2005 yielded 2 systematic reviews, 1 meta-analysis, 6 randomized controlled trials, and 2 non-randomized studies on left main coronary arteries. The quality of the studies ranged from moderate to high. These reports were combined with reports from a previous systematic review for analysis. In addition to qualitative synthesis, pooled analyses of data from randomized controlled studies using a random effect model in the Cochrane Review Manager 4.2 software were conducted when possible. FINDINGS OF LITERATURE REVIEW #ENTITYSTARTX00026; Intravascular ultrasound appears to be a safe tool when used in coronary interventions. Periprocedural complications associated with the use of IVUS in coronary interventions ranged from 0.5% in the largest study to 4%. Coronary rupture was reported in 1 study (1/54). Other complications included prolonged spasms of the artery after stenting, dissection, and femoral aneurysm. Based on pooled analyses of data from randomized controlled studies, the use of intravascular ultrasound adjunctive to coronary intervention in percutaneous coronary interventions using bare metal stents yielded the following findings: For lesions predominantly at low risk of restenosis: There were no significant differences in preintervention angiographic minimal lumen diameter between the IVUS-guided and angiography-guided groups.IVUS guidance resulted in a significantly larger mean postintervention angiographic minimal lumen diameter (weighted mean difference of 0.11 mm, P = .0003) compared to angiographic guidance alone.The benefit in angiographic minimal lumen diameter from IVUS guidance was not maintained at 6-month follow-up, when no significant difference in angiographic minimal lumen diameter could be detected between the two arms (weighted mean difference 0.08, P = .13).There were no statistically significant differences in angiographic binary restenosis rates between IVUS-guidance and no IVUS guidance (Odds ratio [OR] 0.87 in favour of IVUS, 95% Confidence Interval [CI] [0.64-1.18], P = 0.37).IVUS guidance resulted in a reduction in the odds of target lesion revascularization (repeat percutaneous coronary intervention or coronary bypass graft) compared to angiographic guidance alone. The reduction was statistically significant at a follow-up period of 6 months to 1 year, and at a follow-up period of 18 month to 2 years (OR 0.52 in favour of IVUS, 95% CI [0.33-0.81], P = .004).Total revascularization rate (either target lesion or target vessel revascularization) was significantly lower for IVUS-guided patients at 18 months to 2.5 years after intervention (OR 0.43 in favour of IVUS, 95% CI [0.29-0.63], p < .0001).There were no statistically significant differences in the odds of death (OR 1.36 in favour of no IVUS, P =0.65) or myocardial infarction (OR 0.95 in favour of IVUS, P = 0.93) between IVUS-guidance and angiographic guidance alone at up to 2.5 years of follow-upThe odds of having a major cardiac event (defined as death, myocardial infarction, and target lesion or target vessel revascularization) were significantly lower for patients with IVUS guidance compared to angiographic guidance alone during follow-up periods of up to 2.5 years (OR 0.53, 95% CI [0.36-0.78], P = 0.001). Since there were no significant reductions in the odds of death or myocardial infarction, the reduction in the odds of combined events reflected mainly the reduction in revascularization rates. FOR LESIONS AT HIGH RISK OF RESTENOSIS: There is evidence from one small, randomized controlled trial (n=150) that IVUS-guided percutaneous coronary intervention in long de novo lesions (>20 mm) of native coronary arteries resulted in statistically significant larger minimal lumen Diameter, and statistically significant lower 6-month angiographic binary restenosis rate. Target vessel revascularization rate and the rate of combined events were also significantly reduced at 12 months.A small subgroup analysis of a randomized controlled trial reported no benefit in clinical or angiographic outcomes for IVUS-guided percutaneous coronary interventions in patients with diabetes compared to those guided by angiography. However, due to the nature and size of the analysis, no firm conclusions could be reached.Based on 2 small, prospective, non-randomized controlled studies, IVUS guidance in percutaneous coronary interventions of left main coronary lesions using bare metal stents or drug-eluting stents did not result in any benefits in angiographic or clinical outcomes. These findings need to be confirmed. INTERVENTIONS USING DRUG-ELUTING STENTS: There is presently no evidence on whether the addition of IVUS guidance during the implantation of drug-eluting stents would reduce incomplete stent apposition, or improve the angiographic or clinical outcomes of patients. ONTARIO-BASED ECONOMIC ANALYSIS: Cost-effectiveness analysis showed that PCIs using IVUS guidance would likely be less costly and more effective than PCIs without IVUS guidance. The upfront cost of adjunctive use of IVUS in PCIs ranged from $1.56 million at 6% uptake to $13.04 million at 50% uptake. Taking into consideration cost avoidance from reduction in revascularization associated with the use of IVUS, a net saving of $0.63 million to $5.2 million is expected. However, since it is uncertain whether the reduction in revascularization rate resulting from the use of IVUS can be generalized to clinical settings in Ontario, further analysis on the budget impact and cost-effectiveness need to be conducted once Ontario-specific revascularization rates are verified. FACTORS TO BE CONSIDERED IN THE ONTARIO CONTEXT: APPLICABILITY OF FINDINGS TO ONTARIO: The interim analysis of an Ontario field evaluation that compared drug-eluting stents to bare metal stents showed that the revascularization rates in low-risk patients with bare metal stents were much lower in Ontario compared to rates reported in randomized controlled trials (7.2% vs >17 %). Even though IVUS is presently not routinely used in the stenting of low-risk patients in Ontario, the revascularization rates in these patients in Ontario were shown to be lower than those reported for the IVUS groups reported in published studies. Based on this information and previous findings from the Ontario field evaluation on stenting, it is uncertain whether the reduction in revascularization rates from IVUS guidance can be generalized to Ontario. In light of the above findings, it is advisable to validate the reported benefits of IVUS guidance in percutaneous coronary interventions involving bare metal stents in the Ontario context. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzymeand highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients. Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation on serine and threonine amino acid residues of several target molecules. The enzyme is involved in the regulation of many cellular processes and aberrant activity of GSK-3β has been linked to several disease conditions. There is now large evidence on the role of GSK-3β in the pathophysiology of mood disturbances with special regard to bipolar disorders. In the present study we further investigated the role of GSK-3β in bipolar disorders by studying AF3581, the prototype of a novel class of ATP-competitive GSK-3β inhibitors having the common N-[(1- alkylpiperidin-4-yl) methyl]-1H-indazole-3-carboxamide scaffold. Based on previous studies, AF3581 inhibits GSK-3β in the nanomolar range on purified human enzyme and highly selective with respect to other kinases. Current study demonstrates that the compound has efficacy both in the chronic mild stress paradigm of depression (mimicking the down phase of bipolar disorder) and on mice aggressiveness in the resident intruder model (mimicking the up phase). These findings underline the importance of aberrant GSK-3β activity in the development/ maintenance of mood oscillation in this peculiar pathological condition. Moreover, the present work also suggests a therapeutic potential for selective GSK-3 β inhibitors in the management of bipolar disorders patients.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Carcinomas arising in the thyroglossal duct cysts are rare, accounting only for about 0.7-1.5 % of all thyroglossal duct cysts. Synchronous occurrence of thyroglossal duct carcinoma and thyroid carcinoma is reported to be even rarer. Traditionally, surgical treatments of such coexisting thyroglossal duct cyst carcinoma (TGDCa) and papillary thyroid carcinoma (PTC) were typically performed through a single transverse or double incisions on the overlying skin. A longer, extended cervical incision might be required if neck dissection is necessary. Though this method provides the operator with the optimal surgical view, the detrimental cosmetic effect on the patient of possessing a scar cannot be avoided, despite the effort of the surgeon to camouflage the scar by placing the incision in natural skin creases. Recently, the authors have previously reported the feasibility of robot-assisted neck dissections via a transaxillary and retroauricular ("TARA") approach or modified face-lift approach in early head and neck cancers. On the basis of the forementioned surgical technique, we demonstrate our novel technique for robot-assisted Sistrunk's operation via retroauricular approach as well as robot-assisted neck dissection with total thyroidectomy via transaxillary approach. This is a case presentation of a 22-year-old woman with synchronous TGDCa and PTC with minimal lymph node metastasis who underwent resection of TGDCa and total thyroidectomy with left neck level III and IV lymph node dissection as well as central compartment lymph node dissection (CCND) via TARA approach with a robotic surgery system after approval from the institutional review board at Severance Hospital, Yonsei University College of Medicine. The incision was just like the TARA approach in head and neck cancer, which has been reported by our institute. The operation was proceeded as follows. First, excision of the TGDCa through the retroauricular incision was done followed by total thyroidectomy with CCND via transaxillary approach. Finally, neck dissection of left level III, IV was conducted via transaxillary approach. The da Vinci surgical system (Intuitive Surgical, Sunnyvale, CA) was introduced via retroauricular or transaxillary port. A 30° dual-channel endoscope was used, and the two instrument arms were equipped with 5 mm Maryland forceps and a 5 mm spatula monopolar cautery for TGDCa excision via retroauricular approach. When conducting total thyroidectomy and neck dissection via transaxillary approach, three instrument arms were utilized, each equipped with 5 mm Maryland forceps, ProGrasp forceps and a 5 mm spatula monopolar cautery or Harmonic curved shears. The rest of the surgery was completed with the robotic system (see Video). The operative procedure was successfully completed utilizing the robotic surgical system with no conversion to open surgery. The operation time for TGDCa excision was 97 min, including the time for skin flap elevation (15 min), setting up the robotic system (5 min), and console time using the robotic system (77 min). Also, the total operation time for the consecutive total thyroidectomy with CCND and level III, IV dissection was 142 min including the time for skin flap elevation (27 min), setting up the robotic system (3 min), and console time using the robotic system (112 min). There were no intraoperative complications. The retroauricular approach for the removal of the TGDCa allowed for an excellent magnified surgical view revealing important structures of the local anatomy. It also created sufficient space for the cutting of the relevant portion of the hyoid bone. Handling of the robotic instruments through the incision was technically feasible and safe without any mutual collisions throughout the operation. The patient's postoperative parathyroid hormone (PTH) level was within normal range and functions of her both vocal cords were intact. The histopathologic results of the specimens revealed thyroglossal duct cyst with internal papillary carcinoma measuring 1.1 cm with infiltrative tumor margins and papillary microcarcinoma measuring 0.9 cm within the left thyroid lobe with extrathyroidal soft tissue extension. There was no evidence of tumor in the right lobe and the pyramidal lobe of the thyroid gland. As for the lymph nodes resected, 7 out of 9 paratracheal nodes and 2 out of 7 left level III, IV nodes revealed metastatic carcinomas. The patient was discharged on the 8th day after the operation with no complications. The patient was extremely satisfied with the cosmetic results. The patient has received high-dose radioiodine ablation (RAI) therapy and is currently doing well with no evidence of recurrence. Although there is still a great deal of controversy regarding the treatment of TGDCa, there is little debate that for the cases of synchronous TGDCa and PTC, total thyroidectomy in addition to the Sistrunk procedure must be performed. As for the patient in our case where left level IV lymph node metastasis was detected under preoperative ultrasonography (USG), if the usual method of surgical procedure was to be selected, double incisions or a single extended transverse incision must be adopted for the Sistrunk's operation and total thyroidectomy with lateral neck dissection. The conventional method to remove neck masses was to do so by placing an incision on the overlying skin. This 'open' approach to viewing the lesion has an advantage of providing the operator with the best surgical view, but the recognizable surgical scar that results from the surgery can be displeasing for patients. Therefore the surgeon can try to make a small incision and camouflage the scar by placing the incision in natural skin creases, yet the cosmetic results can still be displeasing for the patient due to its visibility and permanence. This can be an even greater problem if the patient is young and an active member of his/her society and if the lesion is benign or low-grade malignancy which can be simply dissected and excised. Therefore it is the surgeon's best interest to perform an operation successfully with a 'least obvious' or 'hidden' scar whenever possible. Accordingly, we have adopted a novel approach, the transaxillary and retroauricular approach, in view of our increasing surgical experience with various indications such as submandibular gland (SMG) resections and neck dissections in head and neck cancer or thyroid papillary carcinoma. Some investigators have demonstrated that robot-assisted neck dissections performed on patients with thyroid cancer and lateral neck node metastasis are feasible and safe. We conducted total thyroidectomy with bilateral CCND and level III and IV dissection using the same approach. Although the technical feasibility and safety of neck dissection or SMG resection via retroauricular approach has already been reported previously at our institute, Sistrunk's operation via retroauricular approach will be challenging. In spite of that, we were able to demonstrate successfully Sistrunk's operation including the hyoid bone resection through the retroauricular approach. There are however, certain areas of potential difficulties which must be considered with caution during the operation procedure. First, when removing the TGDCa through the retroauricular port, identification of the ipsilateral hyoid bone is primarily important and it is also crucial that dissection along the capsule must be done carefully so as not to rupture the tumor. It is essential that sufficient working space must be created for the comfortable movement of the robotic arms through the retroauricular port and in order to do so, sufficient skin flap elevation in both superior and inferior directions must be performed. It is necessary to elevate the superior skin flap up to the level of the inferior border of the mandible but during this process, the platysma muscle must be identified and meticulous dissection along the subplatysmal plane must be carried out so as not to damage the marginal mandibular branch of the facial nerve. Another area of potential pitfalls concerns the total thyroidectomy with neck dissection through the transaxillary port. Sufficient amount of working space must be secured in order to perform comfortably the contralateral thyroidectomy and neck dissection and in order to do so, skin flap elevation must be done at least 2 cm further based on the ipsilateral omohyoid muscle and the contralateral thyroid gland must be adequately exposed. Using the robotic surgical system in removing the thyroglossal duct cyst, the free movement of wristed instrumentation through the retroauricular incision allowed for efficient dissection and easy handling of the tissue. In this particular case we could not identify the tract beyond the hyoid and up to the foramen cecum, but we anticipate that there would be no technical problems of dissection and excision had it been so. To our knowledge, Sistrunk's operation and total thyroidectomy with lateral neck dissection via TARA approach utilizing the robotic surgical system has never been attempted before. It has some advantages over the conventional surgery in terms of cosmesis. However, careful consideration in selecting appropriate cases is required and prospective trials should be conducted to recognize long-term outcomes and to overcome potential limitations.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
In the article The use of gaming technology for rehabilitation in people with multiple sclerosis, DOI: 10.1177/1352458514563593, published in Multiple Sclerosis Volume 21 Issue 4, Table 1 was printed incorrectly. The corrected Table 1 is below:spmsj;22/12/NP9/TABLE11352458515585718T1table1-1352458515585718Table 1.Exergaming studies.Ref.PlatformParticipants and interventionOutcomesPlow and Finlayson<sup31</supWiiPre-test vs. post-test repeated measures home-based Wii training. N=30, age 43.2 ± 9.3 years, 9 ± 6.8 years since diagnosis. 3 x per week programme consisting of yoga, balance, strength, and aerobic training in each session. Wii playing minutes ranged from 10-30 minutes based on participants' RPE when playing the "Basic Run" game. No therapist monitored training in the home. Participants were telephoned every other week (a total of four times) for the first seven weeks after receiving Wii-Fit to monitor adverse events and to encourage increases in the duration or frequency of using Wii-Fit. By the end of the seven weeks, all participants were encouraged to play Wii-Fit three to five times a week for 20 to 30 mins.TUG/TUG dual task; Maximum number of push-ups; timed number of sit-ups in 60s; Maximum number of steps in three mins onto a six-inch platform; Single/double leg balance with eyes open/closed on a soft/firm surface; Physical Activity and Disability Survey; SF-36; MFIS; The barrier self-efficacy scale.Improvements pre- vs. post-test: Number of steps and push-ups; Eyes/open closed, single leg balance on firm surface.Post-test vs. follow-up (14 weeks): measures returned to baseline.Kalron et al.<sup29</supWiiPilot intervention. No control group. N=32, age 43.6 ± 1.9 years, 6.9 ± 0.8 years since diagnosis, EDSS 3.1 ± 0.2. Wii Tennis played for one session of 30 mins (3x10 mins).FRT and FSST taken pre- and post-intervention. FRT and FSST both significantly improved by 9.1% and 17.5% respectively.Prosperini et al.<sup28</supWiiRandomized Crossover Trial - Home-Based. N=36, age 36.2 ± 8.6 years, 10.7 ± 5.8 years since diagnosis, and median EDSS of 3.5 (1.5-5.0). Wii group - 12-week duration, daily sessions (with the exception of the weekend) of home-based training with the Wii Balance Board, each lasting 30 mins. No intervention group - 12 weeks of no intervention. They then swapped to the Wii group after 12 weeks and the Wii group had no intervention for 12 weeks. Contact with physiotherapists every four weeks and phone contact once per week.CoP path, Four Square Step, 25-FWT, MSIS-29. Significant improvements for time × treatment interaction for all measures.Plow and Finlayson<sup35</supWiiA repeated measures longitudinal design with a baseline control period. See Plow and Finlayson<sup31</sup Intervention: All participants were prescribed a three-times-a-week exercise programme - see Plow and Finalyson.<sup31</supSemi-structured interviews conducted over the phone before and after the 14-week Wii-Fit programme. Examined the usability of Nintendo Wii-Fit and identified reasons for using or not using Wii-Fit on; a regular basis.Nilsagard et al.<sup25</supWiiA multicentre RCT with random (1:1) allocation to exercise group or non-exercise group. Wii group: participants N=42, age 50.0 ± 11.5 years, 12.5 ± 8.0 years since. Individual physiotherapist-supervised sessions of 30 mins of balance exercise using Wii-Fit Plus twice a week for six to seven weeks, a total of 12 sessions. Non-exercise group: participants N=42, age 49.4 ± 11.1 years, 12.2 ± 9.2 years since diagnosis. This group was invited to start exercising using Wii-Fit Plus after the second data collection.TUG; TUG dual task; Four Square Step; Timed Chair Stands; 25-FWT; Dynamic Gait Index; ABC; MSWS-12. Improvements in Wii Group pre- vs. post-test: TUG dual task, Four Square Step, Timed Chair Stands, Dynamic Gait Index.Improvements in Non-exercise group pre- vs. post-test: Dynamic Gait Index.Wii vs. non-exercise at follow-up: No significant difference.Guidi et al.<sup27</supWiiSingle-blind, RCT. Aged between 25-65 years, at least three years since diagnosis, EDSS score 0-3.5. Wii group (N=9) played Physiofun Balance Training - Physio Mode. Sessions 10x45-mins, twice a week for five weeks. Non-exercise group (N=8) received advice about strategies for behaviour and environment aimed at reducing falls.BBS significantly improved for Wii Group vs. Non-exercise group.Brichetto et al.<sup26</supWiiRCT: Wii vs. traditional rehabilitation strategies. Twelve sessions (three 60-minute sessions/week) of intervention. Wii group: participants N=18, age 40.7 ± 11.5 years, years since diagnosis 11.2 ± 6.4 years, mean EDSS 3.9 ± 1.6. One hour of supervised Wii Balance Board sessions. participants N=18, age 43.2 ± 10.6 years, years since diagnosis 12.3 ± 7.2 years, mean EDSS 4.3 ± 1.6. Exercises consisted of static and dynamic exercises in both single leg and double leg stance, with or without an equilibrium board and half-kneeling exercises of increasing difficulty.BBS and MFIS. Postural assessment was quantified with a stabilometric platform (quiet standing, barefoot with open/closed eyes). No significant differences between the groups at baseline. Significant improvements in outcomes for both modes at post-test. A significant group × time interaction, revealing a more marked improvement for BBS score, open/closed-eye stabilometry in the Wii group compared to the control group.Ortiz-Gutiérrez, et al.<sup32</supKinectXbox-group: participants N=24, age 39.7 ± 8.1 years, years since diagnosis 9.7 ± 6.8. 40 sessions - four sessions per week (20 mins per session) for 10 weeks. Individual Tele-Rehabilitation treatments using commercial games. Sessions were monitored via videoconference. participants N=23, age 42.8 ± 7.4 years, years since diagnosis 10.9 ± 5.4. Physiotherapy treatment twice a week (40 mins per session) at a clinic for 10 weeks. Low-load strength exercises, proprioception exercises on unstable surfaces, gait facilitation exercises, and muscle-tendon stretching.Computerized dynamic posturography and SOT. Improvement of general balance in both groups. Visual preference and the contribution of vestibular information, via SOT, yielded significant differences in the exercise group.Kramer et al.<sup34</supWiiMatched controlled trial (3 groups). Three weeks, nine supervised training sessions lasting 30 mins each. N=23, age 42.8 ± 7.4 years, years since diagnosis 10.9 ± 5.4. Conventional balance training (control) group: Consisted of various exercises on the floor. Exergame training (playing exergames on an unstable platform) group: Wii Sports/Sports Resort/Fit games that require arm movements (tennis, table tennis, boxing, archery, and sword fight) or displacements of the whole body to control the game avatar (ski slalom, balance bubble, penguin picnic, soccer heading, tilt city, and perfect ten). Table tennis, tennis, and tilt city were the preferred games. Single task (ST) exercises on the unstable platform group.Pre- and post-testing. Combination of single and dual tasks. Six static balance tests: four balance tests on an unstable surface, and two gait analyses (normal and dual task). All groups significantly improved balance and gait measures. The exergame training group showed significantly higher improvements in the gait dual task condition compared to the single task condition. Adherence to home-based balance training was highest in the exergame group.Goble et al.<sup24</supWiiCase study. N=1, 28 year old Male. Relapsing-remitting MS since age 11. EDSS 5.0. Six-week balance training, 3x30 mins per week. Wii-Fit games (yoga, table-tilt, penguin slide, ski jump and bubble balance).20s double leg standing. CoP path length (body sway). Participant relapsed after five weeks training. Follow-up measure taken post-relapse (two months). Over first two weeks 12% decrease in body sway from baseline. 22% increase in body sway over the next two weeks despite training. Relapse occurred week five. Balance impairment remained upon remittance (follow-up) when compared to week two.Forsberg et al.<sup33</supWiiParticipants: N=15, median age 55 years, median time since diagnosis 13 years. See Nilsagard et al.<sup25</supQualitative research approach. Interviewed (15-45 mins) within two weeks after the end of the intervention period. Interview covered reflections on using Wii-Fit for exercising. Patients considered Wii-Fit exercises to be fun, challenging, and self-motivating.Thomas et al.<sup24</supWiiPublished trial methodology multicentre definitive RCT to assess the clinical and cost-effectiveness of a home-based physiotherapist-supported Wii intervention. Immediate arm (N=15): Wii training for 12 months. Delayed arm (N=15): Wii training after six months. Comparison between first six months of immediate arm vs. six months of no training in delayed group, and then 12 months of Wii training in immediate group vs. six months Wii training in delayed group.Balance, gait and mobility: Two-minute walk test, Step test, Steady stance test, Instrumented TUG, Gait stride-time rhythmicity, Static posturography.Physical activity: GLTEQ, ActivPAL.Hand dexterity/coordination: Nine-hole peg test.Self-efficacy: SCI-ESES, MSSE.Psychological well-being and QoL: HADS, EQ-5D-5L, MSIS-29, FSI, SF-36v2. Adherence to training.published trial methodology25-FWT: 25 Foot Walk Time; ABC: Activities-specific Balance Confidence; AI: Ambulation Index; BBS: Berg Balance Score; CoP: Centre of Pressure; EDSS: Expanded Disability Status Scale; EQ-5D-5L: EuroQual 5 Dimensions-5 Levels; FRT: Functional Reach Test; FSI: Fatigue Symptom Inventory; FSST: Four Square Step Test; GLTEQ: Godin Leisure-Time Exercise Questionnaire; HADS: Hospital Anxiety and Depression Scale; MFIS: Modified Fatigue Impact Scale; MMSE: Mini-Mental State Examination; MS: Multiple Sclerosis; MSIS-29: Multiple Sclerosis Impact Scale; MSSE: Multiple Sclerosis Self-Efficacy Scale; MSWS-12: MS Walking Scale; QoL: Quality of Life; RCT: Randomized Control Trial; RPE: Ratings of Perceived Exertion; SCI-ESES: Spinal Cord Injury Exercise Self-Efficacy Scale; SF-36: Short-Form Health Survey; SOT: Sensory Organization Test; TUG: Timed-Up-and-Go.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
<bBackground:</b Sepsis, a medical emergency and life-threatening disorder, results from abnormal host response to infection that leads to acute organ dysfunction<sup1</sup. Sepsis is a major killer across all ages and countries and remains the most common cause of admission and death in the Intensive Care Unit (ICU)<sup2</sup. The true incidence remains elusive and estimates of the global burden of sepsis remain a wild guess. One study suggested over 19 million cases and 5 million sepsis-related deaths annually<sup3</sup. Addressing the challenge, the World Health Assembly of the World Health Organisation (WHO) passed a resolution on better prevention, diagnosis, and management of sepsis<sup4</sup. <bCurrent state of sepsis guidelines:</b Despite thousands of articles and hundreds of trials, sepsis remains a major killer. The cornerstones of sepsis care remain early recognition, adoption of a systematic evidence-based bundle of care, and timely escalation to higher level of care. The bundle approach has been advocated since 2004 but underwent major modifications in subsequent years with more emphasis on the time-critical nature of sepsis and need to restore physiological variables within one hour of recognition. A shift from a three and six-hour bundle to one-hour bundle has been recommended<sup5</sup. This single hour approach has been faced with an outcry and been challenged<sup6-8</sup. <bOne size never fits all:</b Over several decades, the individual components of the sepsis bundle have not changed. Encountering a patient with suspected sepsis, one should measure lactate, obtain blood cultures, swiftly administer broad spectrum antimicrobials and fluids, and infuse vasopressors. A critical question arises: should we do this for all patients? Sepsis is not septic shock and guidelines did not make distinctive recommendations for each. Septic patients will present differently with some having more subtle signs and symptoms. Phenotypically, we do not know which patient with infection will develop a dysregulated host response and will succumb to sepsis and/or shock<sup6-8</sup. The existing bundle lacks high quality evidence to support its recommendations and a blanket implementation for all patients with 'suspected' sepsis could be harmful<sup7</sup. Indeed, a significant reduction of sepsis and septic shock in Australia and New Zealand was observed in a bundle-free region<sup8</sup. <bEmergency Department (ED) challenges:</b Upon arrival in the ED, patients will be triaged. This is 'time zero'<sup5</sup. Those with hypotension and hypoperfusion will be easily recognised and at most need to receive emergent care. Sepsis, per se, may not manifest clear cut signs and expertise to identify it is required. Those with non-specific symptoms may trigger an early warning scoring system and receive unnecessary antimicrobials and a large volume of intravenous (IV) fluids. Both therapies are not without significant side effects. Putting pressure on ED physicians to implement the 60-minute bundle without individualisation of care puts our patients at risk<sup6-8</sup. <bDiagnostic challenges:</b Given the heterogenous nature and diverse pathobiological pathways, sepsis diagnosis can be challenging and both over and under-treatment can result. Established biomarkers such as procalcitonin and C-reactive protein lack specificity to rule out infection as the cause of inflammation. Currently, no laboratory test or biomarker helps predict which patients with infection or inflammation will develop organ dysfunction. A dire need for a specific sepsis biomarker exists<sup10</sup. Modern molecular-based technologies are evolving and utilise polymerase chain reaction (PCR), nanotechnology, and microfluidics for point-of-care testing. Some devices identify causative microorganisms and their sensitivity in less than an hour<sup10</sup. <bThe bundle components:</b Catecholamines along with IV fluids are indicated to restore perfusion. However, inadvertent side effects may arise, especially at higher doses. Anti-adrenergic ß-blockers improve cardiac performance, enhance receptor responsiveness, and possess anti-inflammatory action. All are desirable in patients with septic shock<sup11</sup. One randomised trial showed beneficial and protective effects of ß-blockers in septic shock. Rapidly acting titratable agents should be used in conjunction with appropriate hemodynamic monitoring and after adequate volume resuscitation. There is no consensus on target heart rate but an arbitrary cut off of 80-95 beats per minute is reasonable<sup11</sup. Fluid resuscitation is the cornerstone of sepsis management. There is also compelling evidence that too much fluid is bad. Starch-based colloids should not be used in septic shock. Albumin is an alternative when large volumes are required but is not appropriate in traumatic brain injury. Balanced, less chloride and less acidic crystalloids are safer for the kidneys and are preferred over normal saline. Doses of IV fluids should be tailored to the patient's condition and a 30 ml/kg recommendation should be reviewed.<sup12</sup Effective sepsis management requires adequate dosing of antimicrobials. Significant alteration of pharmacokinetics and pharmacodynamics is characteristic of septic shock<sup13</sup. Accurate and effective dosing is challenging particularly in patients with multiple comorbidities and those receiving extracorporeal organ support. Underdosing results in treatment failure, whilst overdosing leads to toxicity and the risk of developing multi-drug resistant organisms<sup13</sup. An individualised approach supported by therapeutic drug monitoring is suggested to ensure clinical efficacy<sup13</sup. <bSepsis research:</b The search for a cure for sepsis is ongoing. A large prospective, randomised two-arm, parallel group study aims to recruit over 200 patients with septic shock across critical care units in Qatar. Evaluation of Hydrocortisone, Vitamin C, and Thiamine (HYVITS) examines the safety and efficacy of this triple therapy<sup14</sup. <bSepsis in the young patient:</b Children are particularly vulnerable to sepsis. 1 in 6 children admitted with septic shock to ICU will die. As the majority of paediatric sepsis cases are community acquired, there is a strong need to raise awareness both for families and primary healthcare providers. Akin to adults, a bundle-approach to paediatric sepsis is strongly encouraged. National programs for paediatric sepsis have been established<sup15</sup. The Qatar paediatric multidisciplinary sepsis program was established under the umbrella of the adult programme in 2017. A structured and standardised approach to sepsis across all neonate and paediatric facilities has been developed and implemented. Improvement in timely sepsis recognition and administration of antimicrobials within the golden hour has been observed. The program aims to achieve a 95% compliance to the paediatric sepsis bundle by the end of 2019. A screening tool and order set have been put in place and are presented in this special issue of Qatar Medical Journal<sup16,17</sup. <bObstetric sepsis:</b Pregnancy and childbirth are risk factors for sepsis. Multi-organ failure and death can result from puerperal sepsis<sup18</sup. Sepsis is the direct and leading cause of maternal mortality in the UK<sup19</sup. Attention to maternal sepsis with a tailored approach is encouraged. The Qatar National Sepsis Program developed a sepsis care pathway for pregnant women and during their early post-partum period. <bChallenges in low socioeconomic societies:</b A broader, national -or better yet- a global approach to further sepsis management and outcome should be considered. There are a number of significant challenges to address. One such challenge is the inconsistency of the operational definition and diagnostic approaches for sepsis including coding and documentation<sup1,3</sup. Significant deficiencies in healthcare systems have been highlighted by sepsis. This is most obvious in medium- and low-income countries. A major limitation to effective sepsis management is inadequate medical staffing and poor knowledge and awareness of sepsis. Both have a negative impact on sepsis outcome<sup3</sup. Poor medical facilities in many countries pose significant challenges to sepsis care. Lack of critical care capacity - a global phenomenon - has been linked to poor outcome of sepsis cases and septic shock. This could be attributed to provision of suboptimal critical care, monitoring and critical interventions outside of the ICU. ICU availability is subject to inconsistency and inequity.<sup2,3</sup Lack of adequate surgical capacity to accomplish timely source control adversely affects sepsis management. This, unfortunately, in medium- and low-income countries, is accompanied by inadequate medical supplies, diagnostic capacity, and manpower which increases sepsis mortality and morbidity<sup3</sup. <bGlobal concerns:</b Antimicrobials are critical for sepsis care. A global concern is the development of multi-drug resistant organisms and the lack of novel antimicrobials and this adds pressure on those caring for septic patients. Effective antimicrobials should be utilised to eradicate infections. Misuse, inadequacy, inferior agents, and lack of timely access to effective and affordable agents significantly hinders patient's recovery from sepsis<sup2,3</sup. Optimum sepsis outcome mandates attention to acute sepsis complications (e.g. acute renal or respiratory failure) as well as addressing post-discharge complications and disability. These challenging issues remain poorly studied or addressed<sup3</sup. <bConclusion:</b Sepsis and septic shock are major global health concerns. Progress has been achieved in understanding this life-threatening syndrome at a biological, metabolic, and cellular level. Efforts should be coordinated to improve sepsis care. Better and more accurate diagnostics are needed and governments are encouraged to invest in sepsis research and care. More integrated, inclusive, and focused research is desperately needed. Public education and increased awareness among primary healthcare providers are also critical to improve sepsis outcome.	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Isobutyraldehyde, a branched alkyl aldehyde, is used as a chemical intermediate and flavoring agent. It was nominated by the National Cancer Institute for toxicity and carcinogenicity studies by the NTP. Reasons for nomination and selection of isobutyraldehyde for study included its high potential for human exposure as suggested by its high production volume, its use as a chemical intermediate and food flavoring agent, suspicion of carcinogenicity due to an increased incidence of cancer at an aldehyde manufacturing plant where workers were exposed to a variety of aldehydes, its structural relationship to formaldehyde (a nasal carcinogen in rats), and the lack of toxicity and carcinogenicity studies on isobutyraldehyde in animals. Although human exposure occurs orally, dermally, or via inhalation, the inhalation route of exposure was selected for these animal studies because of the instability of isobutyraldehyde in water and feed. Male and female F344/N rats and B6C3F1 mice were exposed to isobutyraldehyde (approximately 99% pure) by inhalation for 13 weeks or 2 years. Genetic toxicology studies were conducted in vitro in Salmonella typhimurium, L5178Y mouse lymphoma cells, and cultured Chinese hamster ovary cells; in vivo tests were conducted in Drosophila melanogaster germ cells and bone marrow cells of rats and mice. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were exposed to 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm isobutyraldehyde by inhalation, 6 hours per day, 5 days a week, for 13 weeks. All rats exposed to 8,000 ppm died before the end of the study. Three male rats and six female rats in the 4,000 ppm groups and one female in the 500 ppm group died before the end of the study. The final mean body weight of male rats in the 4,000 ppm group and the body weight gains of 4,000 ppm males and females were significantly less than those of the chamber controls. Clinical findings in rats exposed to 4,000 or 8,000 ppm included abnormal respiratory sounds, decreased activity, nasal discharge, prostration, and slowed respiration. A minimal mature neutrophilia, evidenced by increased segmented neutrophil numbers, occurred in exposed groups of male and female rats. Exposure to isobutyraldehyde resulted in minimal increases in alanine aminotransferase activity in all groups of male and female rats. Spermatozoal motility in 500 and 1,000 ppm males was significantly reduced and females exposed to 4,000 ppm differed significantly from the chamber control females in the relative time spent in the estrous stages. No gross lesions were observed at necropsy that could be associated with isobutyraldehyde exposure. In the 8,000 ppm groups, severe necrosis of the epithelium, and occasionally of the entire mucosa, of the nasal turbinates accompanied by an acute inflammatory reaction was observed. Increased incidences of squamous metaplasia and mild acute inflammation occurred in male and female rats exposed to 4,000 ppm. Minimal to mild degeneration of the olfactory epithelium was observed in all male rats in the 2,000 and 4,000 ppm groups. Male rats exposed to 4,000 or 8,000 ppm and females exposed to 4,000 ppm had mild osteodystrophy of the turbinate bone. The incidences of necrosis/degeneration of the larynx and trachea were increased in male rats in the 8,000 ppm group. The incidences of mild to moderate lymphoid depletion of the spleen and thymus and lymphoid necrosis of the thymus were significantly increased in male and female rats exposed to 8,000 ppm. 13-WEEK STUDY IN MICE: Ten male and 10 female B6C3F1 mice were exposed to 0, 500, 1,000, 2,000, 4,000, or 8,000 ppm isobutyraldehyde by inhalation, 6 hours per day, 5 days per week, for 13 weeks. One male in the chamber control group, one male in the 1,000 ppm group, nine males and all females in the 4,000 ppm groups, and all males and females in the 8,000 ppm groups died before the end of the study. The final mean body weight and body weight gain of female mice in the 1,000 ppm group were significantly less than those of the chamber controls. Clinical findal findings included decreased activity, tremors, prostration, and slower and labored respiration. The absolute and relative kidney weights of males in the 1,000 and 2,000 ppm groups were significantly increased. There were no gross lesions observed at necropsy that could be associated with isobutyraldehyde exposure. Histopathologically, the nasal cavity and lymphopoietic tissues were considered target organs, with changes similar, but not identical, to those observed in rats. Increased incidences of nonneoplastic lesions of the nasal cavity were observed in male and female mice exposed to 1,000 ppm or greater. These lesions included necrosis, inflammation, hyperplasia, and squamous metaplasia of the epithelium; serous and suppurative exudate within the nasal passages; olfactory epithelial degeneration; and osteodystrophy of the turbinate bone. Mild to moderate lymphoid depletion and/or lymphoid necrosis were observed in the thymus of male and female mice exposed to 8,000 ppm. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female F344/N rats were exposed to 0, 500, 1,000, or 2,000 ppm isobutyraldehyde by inhalation, 6 hours per day, 5 days per week, for 105 weeks Survival, Body Weights, and Clinical Findings No differences in survival rates between exposed and chamber control rats were found. The mean body weights of male and female rats were generally similar to those of the chamber controls throughout the study. Pathology Findings No increase in neoplasm incidences that could be attributed to exposure to isobutyraldehyde was observed in male or female rats. Nonneoplastic lesions related to isobutyraldehyde exposure were limited to the nose and consisted of squamous metaplasia of the respiratory epithelium, degeneration of the olfactory epithelium, and suppurative inflammation. Incidences of minimal to mild squamous metaplasia in 1,000 and 2,000 ppm males and females and in 500 ppm females were significantly greater than those in the chamber controls. Another lesion associated with isobutyraldehyde exposure was minimal to mild degeneration of the olfactory epithelium in 2,000 ppm males and females. The incidences of suppurative inflammation (rhinitis) in male and female rats exposed to 2,000 ppm were increased compared to the chamber controls. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 500, 1,000, or 2,000 ppm isobutyraldehyde by inhalation, 6 hours per day, 5 days per week, for 105 weeks. Survival, Body Weights, and Clinical Findings There was an exposure-related decrease in survival of male mice, and the survival of males exposed to 2,000 ppm was marginally lower than that of the chamber controls. The mean body weights of female mice exposed to 1,000 or 2,000 ppm were lower than those of the chamber controls during the second year of the study. Pathology Findings No neoplasms that could be attributed to iso butyraldehyde exposure were observed in mice. Non neoplastic lesions related to isobutyraldehyde exposure were limited to the nose. The incidences of olfactory epithelial degeneration in 1,000 and 2,000 ppm males and females were significantly greater than in the chamber controls. GENETIC TOXICOLOGY: Isobutyraldehyde is mutagenic in vitro and in vivo, with the strongest responses observed in mammalian cell assays that measured chromosomal damage. Results of an initial mutagenicity test in S. typhimurium were negative; a second test, con ducted with different strains and varying concentrations of induced S9 activation enzymes, gave equivocal results. Strongly positive responses were obtained in the mouse lymphoma assay for mutation induction in L5178Y cells without S9 and in cytogenetic tests for induction of sister chromatid exchanges and chromosomal aberrations in cultured Chinese hamster ovary cells. Sister chromatid exchanges were significantly increased with and without S9, but induction of chromosomal aberrations was noted unequivocally only in the absence of S9. No induction of sex-linked recessive lethal mutations was observed in germ cells of male D. melanogaster administered isobutyraldehyde by feeding or by injection. In vivo, isobutyraldehyde was demonstrated to induce chromosomal aberrations in bone marrow cells of male mice, but no increases in micronuclei were observed in bone marrow cells of mice or rats after administration of isobutyraldehyde. All these in vivo cytogenetic studies used doses that reached lethality CONCLUSIONS: Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenic activity of isobutyraldehyde in male or female F344/N rats or male or female B6C3F1 mice exposed to 500, 1,000, or 2,000 ppm isobutyraldehyde. In male and female rats, exposure to isobutyraldehyde induced squamous metaplasia and suppurative inflammation of the nasal respiratory epithelium and degeneration of the nasal olfactory epithelium. In male and female mice, exposure to isobutyraldehyde caused degeneration of the nasal olfactory epithelium. Synonyms: Dimethylacetaldehyde; 2-formylpropane; isobutanal; isobutylcarboxaldehyde; isobutyral; isobutyric aldehyde; isobutyrylaldehyde; isopropylformaldehyde; 2-methylpropanal; 2-methyl-1-propanal; a-methylpropionaldehyde; 2-methylpropionaldehyde; valine aldehyde	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
[structure--see text] Elmiron, a white powder, is the sodium salt of pentosan polysulfate, a semisynthetic sulfated polyanion composed of beta-D-xylopyranose residues with biological properties similar to heparin. Elmiron is used in the United States for the relief of urinary bladder pain associated with interstitial cystitis. Because of its stimulating effect on fibrinolysis, Elmiron has been used clinically in the treatment and prevention of thrombotic disorders. The United States Food and Drug Administration nominated Elmiron for toxicology and carcinogenicity testing by the National Toxicology Program because of its orphan drug status. Male and female F344/N rats and B6C3F1 mice received Elmiron, which met product specifications provided by the manufacturer, in deionized water by gavage for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were administered 0, 33, 111, 333, 1,000, or 3,000 mg Elmiron/kg body weight in deionized water by gavage, 5 days per week, for 16 days. Elmiron administration had no effect on survival or body weight gain. Activated partial thromboplastin time was significantly increased in 3,000 mg/kg rats. Liver weights of 3,000 mg/kg rats were significantly greater than those of the vehicle controls. Hepatocellular cytoplasmic vacuolization occurred in all 3,000 mg/kg females. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were administered Elmiron in deionized water by gavage at doses of 0, 33, 111, 333, 1,000, or 3,000 mg/kg, 5 days per week, for 16 days. All mice survived to the end of the study. Mean body weight gains of male mice administered 333 mg/kg or greater were significantly greater than that of the vehicle control group. Liver weights of 1,000 and 3,000 mg/kg males were significantly increased. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were administered Elmiron in deionized water by gavage at doses of 0, 63, 125, 250, 500, or 1,000 mg/kg, 5 days per week, for 14 weeks. No deaths were attributed to administration of Elmiron. Mean body weights of 125 mg/kg males were less than those of vehicle controls and the mean body weights of all dosed groups of females were greater. Hematology results indicated that Elmiron, at the doses selected, induced a minimal erythron decrease and leukocyte and platelet count increases that may have been secondarily related to the inflammatory lesions observed in various tissues of rats. Liver and spleen weights of males administered 250 mg/kg or greater were significantly increased. Liver weights of all dosed groups of females, and kidney, lung, and spleen weights of 1,000 mg/kg females were significantly increased. Histiocytic cellular infiltration, chronic active inflammation, and ulcers of the rectum occurred in most 500 and 1,000 mg/kg rats. Administration of Elmiron was associated with the presence of vacuolated histiocytes in the mandibular and mesenteric lymph nodes, lung, kidney, and liver of male and female rats. Histochemical investigations of the vacuolated histiocytes indicated the presence of neutral and acidic mucins and lipid material within the vacuoles. Transmission electron microscopy identified these vacuoles as lysosomal structures that exhibited a variety of contents. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were administered Elmiron in deionized water by gavage at doses of 0, 63, 125, 250, 500, or 1,000 mg/kg, 5 days per week, for 14 weeks. One 250 mg/kg female mouse was sacrificed moribund on day 84; all other mice survived to the end of the study. Mean body weights of dosed groups were similar to those of the vehicle control groups. Hematology results indicated that Elmiron, at the doses selected, induced a minimal erythron decrease and leukocyte and platelet count increases that may have been secondarily related to the inflammatory lesions observed in various tissues of mice. in various tissues of mice. Liver weights of 500 mg/kg males and 1,000 mg/kg males and females, and spleen weights of 1,000 mg/kg males were significantly increased. Histiocytic cellular infiltration and chronic active inflammation of the rectum occurred in most 1,000 mg/kg mice. Administration of Elmiron was associated with the presence of vacuolated histiocytes in the mandibular and mesenteric lymph nodes, liver, and spleen of males and females. Histochemical investigations of the vacuolated histiocytes indicated the presence of neutral and acidic mucins within the vacuoles. Transmission electron microscopy identified these vacuoles as lysosomal structures that exhibited a variety of contents. 2-YEAR STUDY IN RATS: Groups of 50 males and 50 females were administered Elmiron in deionized water by gavage at doses of 0, 14, 42, or 126 mg/kg to males and 0, 28, 84, or 252 mg/kg to females, 5 days per week, for 104 or 105 weeks. Survival of all dosed groups of rats was similar to that of the vehicle control groups. Mean body weights of all dosed groups were similar to those of the vehicle controls throughout the 2-year study. Microscopically, myxomatous changes were present in the rectum of 56% of 126 mg/kg males and 83% of 252 mg/kg females. The incidences of chronic active focal alveolar inflammation of the lung were increased in all dosed groups. The incidences of histiocytic cellular infiltration of the mesenteric lymph nodes were increased in 42 and 126 mg/kg males and in 84 and 252 mg/kg females, and lymphohistiocytic hyperplasia was present in the spleen of 126 mg/kg males and 252 mg/kg females. 2-YEAR STUDY IN MICE: Groups of 50 males and 50 females were administered Elmiron in deionized water by gavage at doses of 0, 56, 168, or 504 mg/kg, 5 days per week, for 104 or 105 weeks. Survival of all dosed groups of mice was similar to that of the vehicle control groups. Mean body weights of males were similar to those of vehicle controls. Mean body weights of 504 mg/kg females were progressively less than those of the vehicle controls during the second year of the study. Increased incidences of hemangiosarcomas of the liver and hepatocellular neoplasms were observed in male and female mice. The incidences of hemangiosarcomas in the 504 mg/kg groups exceeded the historical control ranges for males and females; both the trend and the incidence in the 504 mg/kg groups were significant for males. Hemangiosarcomas in males and females were attributed to Elmiron administration. The incidence of hepatocellular adenoma in 504 mg/kg females was significantly increased and exceeded the historical control range; the trends for hepatocellular adenoma and for hepatocellular adenoma or carcinoma (combined) were also significant in females and were attributed to Elmiron administration. There was also a marginal increase in the incidences of hepatocellular neoplasms in male mice, which may have been associated with Elmiron administration. Malignant lymphomas occurred with a positive trend in female mice; the incidence in the 504 mg/kg group was also significantly increased and matched the upper limit of the historical control range. These malignant lymphomas may have been associated with Elmiron administration. Nonneoplastic lesions related to the administration of Elmiron occurred in the liver, rectum, mesenteric lymph node, and spleen of 504 mg/kg mice and to a lesser extent in 168 mg/kg mice. These lesions were similar to those observed in the 3-month study. Elmiron was not mutagenic in S. typhimurium strains TA97, TA98, TA100, or TA1535 with or without induced hamster or rat liver S9 enzymes. No increases in the frequency of micronucleated polychromatic erythrocytes were seen in bone marrow cells of rats or mice administered Elmiron by gavage three times at 24-hour intervals. No significant alterations in the frequency of micronucleated normochromatic erythrocytes were seen in peripheral blood samples from male or female mice administered Elmiron for 3 months by gavage. Under the conditions of these 2-year gavage studies, there was no evidence of carcinogenic activity of Elmiron in male F344/N rats administered 14, 42, or 126 mg/kg or in female F344/N rats administered 28, 84, or 252 mg/kg. There was some evidence of carcinogenic activity of Elmiron in male B6C3F1 mice based on increased incidences of liver hemangiosarcoma. The increased incidences of hepatocellular neoplasms in male mice may have been related to Elmiron administration. There was some evidence of carcinogenic activity of Elmiron in female B6C3F1 mice based on the increased incidences of liver hemangiosarcoma and hepatocellular neoplasms. The increased incidences of malignant lymphomas in female mice may have been related to Elmiron administration. Elmiron administration caused increased incidences of nonneoplastic lesions (presence of vacuolated histiocytes) of the rectum, lung, mesenteric lymph node, and spleen (males) in rats and of the liver, rectum, mesenteric lymph node, and spleen in mice.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Research in scientific, public health, and policy disciplines relating to the environment increasingly makes use of high-dimensional remote sensing and the output of numerical models in conjunction with traditional observations. Given the public health and resultant public policy implications of the potential health effects of particulate matter (PM*) air pollution, specifically fine PM with an aerodynamic diameter < or = 2.5 pm (PM2.5), there has been substantial recent interest in the use of remote-sensing information, in particular aerosol optical depth (AOD) retrieved from satellites, to help characterize variability in ground-level PM2.5 concentrations in space and time. While the United States and some other developed countries have extensive PM monitoring networks, gaps in data across space and time necessarily occur; the hope is that remote sensing can help fill these gaps. In this report, we are particularly interested in using remote-sensing data to inform estimates of spatial patterns in ambient PM2.5 concentrations at monthly and longer time scales for use in epidemiologic analyses. However, we also analyzed daily data to better disentangle spatial and temporal relationships. For AOD to be helpful, it needs to add information beyond that available from the monitoring network. For analyses of chronic health effects, it needs to add information about the concentrations of long-term average PM2.5; therefore, filling the spatial gaps is key. Much recent evidence has shown that AOD is correlated with PM2.5 in the eastern United States, but the use of AOD in exposure analysis for epidemiologic work has been rare, in part because discrepancies necessarily exist between satellite-retrieved estimates of AOD, which is an atmospheric-column average, and ground-level PM2.5. In this report, we summarize the results of a number of empirical analyses and of the development of statistical models for the use of proxy information, in particular satellite AOD, in predicting PM2.5 concentrations in the eastern United States. We analyzed the spatiotemporal structure of the relationship between PM2.5 and AOD, first using simple correlations both before and after calibration based on meteorology, as well as large-scale spatial and temporal calibration to account for discrepancies between AOD and PM2.5. We then used both raw and calibrated AOD retrievals in statistical models to predict PM2.5 concentrations, accounting for AOD in two ways: primarily as a separate data source contributing a second likelihood to a Bayesian statistical model, as well as a data source on which we could directly regress. Previous consideration of satellite AOD has largely focused on the National Aeronautics and Space Administration (NASA) moderate resolution imaging spectroradiometer (MODIS) and multiangle imaging spectroradiometer (MISR) instruments. One contribution of our work is more extensive consideration of AOD derived from the Geostationary Operational Environmental Satellite East Aerosol/Smoke Product (GOES GASP) AOD and its relationship with PM2.5. In addition to empirically assessing the spatiotemporal relationship between GASP AOD and PM2.5, we considered new statistical techniques to screen anomalous GOES reflectance measurements and account for background surface reflectance. In our statistical work, we developed a new model structure that allowed for more flexible modeling of the proxy discrepancy than previous statistical efforts have had, with a computationally efficient implementation. We also suggested a diagnostic for assessing the scales of the spatial relationship between the proxy and the spatial process of interest (e.g., PM2.5). In brief, we had little success in improving predictions in our eastern-United States domain for use in epidemiologic applications. We found positive correlations of AOD with PM2.5 over time, but less correlation for long-term averages over space, unless we used calibration that adjusted for large-scale discrepancy between AOD and PM2.5 (see sections 3, 4, and 5). Statistical models that combined AOD, PM2.5 observations, and land-use and meteorologic variables were highly predictive of PM2.5 observations held out of the modeling, but AOD added little information beyond that provided by the other sources (see sections 5 and 6). When we used PM2.5 data estimates from the Community Multiscale Air Quality model (CMAQ) as the proxy instead of using AOD, we similarly found little improvement in predicting held-out observations of PM2.5, but when we regressed on CMAQ PM2.5 estimates, the predictions improved moderately in some cases. These results appeared to be caused in part by the fact that large-scale spatial patterns in PM2.5 could be predicted well by smoothing the monitor values, while small-scale spatial patterns in AOD appeared to weakly reflect the variation in PM2.5 inferred from the observations. Using a statistical model that allowed for potential proxy discrepancy at both large and small spatial scales was an important component of our modeling. In particular, when our models did not include a component to account for small-scale discrepancy, predictive performance decreased substantially. Even long-term averages of MISR AOD, considered the best, albeit most sparse, of the AOD products, were only weakly correlated with measured PM2.5 (see section 4). This might have been partly related to the fact that our analysis did not account for spatial variation in the vertical profile of the aerosol. Furthermore, we found evidence that some of the correlation between raw AOD and PM2.5 might have been a function of surface brightness related to land use, rather than having been driven by the detection of aerosol in the AOD retrieval algorithms (see sections 4 and 7). Difficulties in estimating the background surface reflectance in the retrieval algorithms likely explain this finding. With regard to GOES, we found moderate correlations of GASP AOD and PM2.5. The higher correlations of monthly and yearly averages after calibration reflected primarily the improved large-scale correlation, a necessary result of the calibration procedure (see section 3). While the results of this study's GOES reflectance screening and surface reflection correction appeared sensible, correlations of our proposed reflectance-based proxy with PM2.5 were no better than GASP AOD correlations with PM2.5 (see section 7). We had difficulty improving spatial prediction of monthly and yearly average PM2.5 using AOD in the eastern United States, which we attribute to the spatial discrepancy between AOD and measured PM2.5, particularly at smaller scales. This points to the importance of paying attention to the discrepancy structure of proxy information, both from remote-sensing and deterministic models. In particular, important statistical challenges arise in accounting for the discrepancy, given the difficulty in the face of sparse observations of distinguishing the discrepancy from the component of the proxy that is informative about the process of interest. Associations between adverse health outcomes and large-scale variation in PM2.5 (e.g., across regions) may be confounded by unmeasured spatial variation in factors such as diet. Therefore, one important goal was to use AOD to improve predictions of PM2.5 for use in epidemiologic analyses at small-to-moderate spatial scales (within urban areas and within regions). In addition, large-scale PM2.5 variation is well estimated from the monitoring data, at least in the United States. We found little evidence that current AOD products are helpful for improving prediction at small-to-moderate scales in the eastern United States and believe more evidence for the reliability of AOD as a proxy at such scales is needed before making use of AOD for PM2.5 prediction in epidemiologic contexts. While our results relied in part on relatively complicated statistical models, which may be sensitive to modeling assumptions, our exploratory correlation analyses (see sections 3 and 5) and relatively simple regression-style modeling of MISR AOD (see section 4) were consistent with the more complicated modeling results. When assessing the usefulness of AOD in the context of studying chronic health effects, we believe efforts need to focus on disentangling the temporal from the spatial correlations of AOD and PM2.5 and on understanding the spatial scale of correlation and of the discrepancy structure. While our results are discouraging, it is important to note that we attempted to make use of smaller-scale spatial variation in AOD to distinguish spatial variations of relatively small magnitude in long-term concentrations of ambient PM2.5. Our efforts pushed the limits of current technology in a spatial domain with relatively low PM2.5 levels and limited spatial variability. AOD may hold more promise in areas with higher aerosol levels, as the AOD signal would be stronger there relative to the background surface reflectance. Furthermore, for developing countries with high aerosol levels, it is difficult to build statistical models based on PM2.5 measurements and land-use covariates, so AOD may add more incremental information in those contexts. More generally, researchers in remote sensing are involved in ongoing efforts to improve AOD products and develop new approaches to using AOD, such as calibration with model-estimated vertical profiles and the use of speciation information in MISR AOD; these efforts warrant continued investigation of the usefulness of remotely sensed AOD for public health research.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. 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BACKGROUND Improving quality and effectiveness of healthcare is one of the priorities of health policies. Hospital or physician volume represents a measurable variable with an impact on effectiveness of healthcare. An Italian law calls for the definition of «qualitative, structural, technological, and quantitative standards of hospital care». There is a need for an evaluation of the available scientific evidence in order to identify qualitative, structural, technological, and quantitative standards of hospital care, including the volume of care above or below which the public and private hospitals may be accredited (or not) to provide specific healthcare interventions. OBJECTIVES To identify conditions/interventions for which an association between volume and outcome has been investigated. To identify conditions/interventions for which an association between volume and outcome has been proved. To analyze the distribution of Italian health providers by volume of activity. To measure the association between volume of care and outcomes of the health providers of the Italian National Health Service (NHS). METHODS Systematic review An overview of systematic reviews was performed searching PubMed, EMBASE, and The Cochrane Library up to November 2016. Studies were evaluated by 2 researchers independently; quality assessment was performed using the AMSTAR checklist. For each health condition and outcome, if available, total number of studies, participants, high volume cut-off values, and metanalysis have been reported. According to the considered outcomes, health topics were classified into 3 groups: positive association: a positive association was demonstrated in the majority of studies/participants and/or a pooled measure (metanalysis) with positive results was reported; lack of association: both studies and/or metanalysis showed no association; no sufficient evidence of association: both results of single studies and metanalysis do not allow to draw firm conclusions on the association between volume and outcome. Analysis of the distribution of Italian hospitals by volume of activity and the association between volume of activity and outcomes: the Italian National Outcome evaluation Programme 2016 The analyses were performed using the Hospital Information System and the National Tax Register (year 2015). For each condition, the number of hospitals by volume of activity was calculated. Hospitals with a volume lower than 3-5 cases/year were excluded. For conditions with more than 1,500 cases/year and frequency of outcome ≥1%, the association between volume of care and outcome was analyzed estimating risk-adjusted outcomes. RESULTS Bibliographic searches identified 80 reviews, evaluating 48 different clinical areas. The main outcome considered was intrahospital/30-day mortality. The other outcomes vary depending on the type of condition or intervention in study. The relationship between hospital volume and outcomes was considered in 47 out of 48 conditions: 34 conditions showed evidence of a positive association; • 14 conditions consider cancer surgery for bladder, breast, colon, rectum, colon rectum, oesophagus, kidney, liver, lung, ovaries, pancreas, prostate, stomach, head and neck; • 11 conditions consider cardiocerebrovascular area: nonruptured and ruptured abdominal aortic aneurysm, acute myocardial infarction, brain aneurysm, carotid endarterectomy, coronary angioplasty, coronary artery bypass, paediatric heart surgery, revascularization of lower limbs, stroke, subarachnoid haemorrhage; • 2 conditions consider orthopaedic area: knee arthroplasty, hip fracture; • 7 conditions consider other areas: AIDS, bariatric surgery, cholecystectomy, intensive care unit, neonatal intensive care unit, sepsis, and traumas; for 3 conditions, no association was demonstrated: hip arthroplasty, dialysis, and thyroidectomy. for the remaining 10 conditions, the available evidence does not allow to draw firm conclusions about the association between hospital volume and considered outcomes: surgery for testicular cancer and intracranial tumours, paediatric oncology, aortofemoral bypass, cardiac catheterization, appendectomy, colectomy, inguinal hernia, respiratory failure, and hysterectomy. The relationship between volume of clinician/surgeon and outcomes was assessed only through the literature re view; to date, it is not possible to analyze this association for Italian health provider hospitals, since information on the clinician/surgeon on the hospital discharge chart is missing. The literature found a positive association for 21 conditions: 9 consider surgery for cancer: bladder, breast, colon, colon rectum, pancreas, prostate, rectum, stomach, and head and neck; 5 consider the cardiocerebrovascular area: ruptured and nonruptured abdominal aortic aneurysm, carotid endarterectomy, paediatric heart surgery, and revascularization of the lower limbs; 2 consider the orthopaedic area: knee and hip arthroplasty; 5 consider other areas: AIDS, bariatric surgery, hysterectomy, intensive care unit, and thyroidectomy. The analysis of the distribution of Italian hospitals concerned the 34 conditions for which the systematic review has shown a positive volume-outcome association. For the following, it was possible to conduct the analysis of the association using national data: unruptured abdominal aortic aneurysm, coronary angioplasty, hip arthroplasty, knee arthroplasty, coronary artery bypass, cancer surgery (colon, liver, breast, pancreas, lung, prostate, kidney, and stomach), laparoscopic cholecystectomy, hip fracture, stroke, acute myocardial infarction. For these conditions, the association between volume and outcome of care was observed. For laparoscopic cholecystectomy and surgery of the breast and stomach cancer, the association between the volume of the discharge (o dismissal) operating unit and the outcome was analyzed. The outcomes differ depending on the condition studied. The shape of the relationship is variable among different conditions, with heterogeneous slope of the curves. DISCUSSION For many conditions, the overview of systematic reviews has shown a strong evidence of association between higher volumes and better outcomes. The quality of the available reviews can be considered good for the consistency of the results between the studies and for the strength of the association; however, this does not mean that the included studies are of good quality. Analyzing national data, potential confounders, including age and comorbidities, have been considered. The systematic review of the literature does not permit to identify predefined volume thresholds. The analysis of national data shows a strong improvement in outcomes in the first part of the curve (from very low to higher volumes) for most conditions. In some cases, the improvement in outcomes remains gradual or constant with the increasing volume of care; in other, the analysis could allow the identification of threshold values beyond which the outcome does not further improve. However, a good knowledge of the relationship between effectiveness of treatments and costs, the geographical distribution and the accessibility to healthcare services are necessary to choose the minimum volumes of care, under which specific health procedures could not been provided in the NHS. Some potential biases due to the use of information systems data should also be considered. The different way of coding among hospitals could lead to a different selection of cases for some conditions. Regarding the definition of the exposure (volume of care), a possible bias could result from misclassification of health providers with high volume of activity. Performing the intervention in different departments/ units of the same hospital would result in an overestimation of the volume of care measured for hospital rather than for department/unit. For the conditions with a further fragmentation within the same structure, the association between volumes of discharge department and outcomes has also been evaluated. In this case, the two curves were different. The limit is to attribute the outcome to the discharge unit, which in case of surgery may not be the intervention unit. A similar bias could occur if the main determinant of the outcome of treatment was the caseload of each surgeon. The results of the analysis may be biased when different operators in the same hospital/unit carried out the same procedure. In any case, the observed association between volumes and outcome is very strong, and it is unlikely to be attributable to biases of the study design. Another aspect on which there is still little evidence is the interaction between volume of the hospital and of the surgeon. A MEDICARE study suggests that in some conditions, especially for specialized surgery, the effect of the surgeon's volume of activity is different depending on the structure volume, whereas it would not differ for some less specialized surgery conditions. The data here presented still show extremely fragmented volumes of both clinical and surgical areas, with a predominance of very low volume structures. Health systems operate, by definition, in a context of limited resources, especially when the amount of resources to allocate to the health system is reduced. In such conditions, the rationalization of the organization of health services based on the volume of care may make resources available to improve the effectiveness of interventions. The identification and certification of services and providers with high volume of activity can help to reduce differences in the access to non-effective procedures. To produce additional evidence to guide the reorganization of the national healthcare system, it will be necessary to design further primary studies to evaluate the effectiveness and safety of policies aimed at concentrating interventions in structures with high volumes of activity.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
This study describes up-to-date cancer incidence and survival in Italian paediatric and adolescent patients, based on data collected by the network of Italian cancer registries (AIRTUM). It updates the monograph published on the same topic in 2008. The main objective of this monograph is to present the statistics according to standard rigorous epidemiological methods and disseminate them to a wide range of readers, including the lay public. Given the deep impact of the 2008 monograph on the general public, in this update we complement descriptive statistics with additional data and commentaries on issues of importance for public health, in order to provide unambiguous criteria on how to interpret the statistics. The study is the result of the collaboration between AIRTUM and AIEOP (Italian Association of Paediatric Haematology and Oncology) with contributions from interested parties, including representatives of parent associations. The monograph is divided into three parts. The first part presents incidence rates, survival probabilities, and time trends, by sex, age, geographical area, and cancer site or type, by means of tables and graphs as in the previous monograph, to facilitate direct comparisons. Four articles summarize and comment the results. The second part uses data from AIRTUM and AIEOP to outline patient management and health care issues; it includes estimates of the number of new cases in the next decade and of young adults living after a paediatric cancer diagnosis. Health organizational aspects of treatment services for paediatric patients, based on the AIEOP database, are also discussed, along with long-term complications in cured patients. The third section describes the changes in mortality trends due to improving therapies and healthcare services, and discusses risk factors and prevention of childhood cancer, late adverse events in cured patients, and other related issues. Data herein presented were provided by AIRTUM population-based cancer registries, covering 47%of the Italian population below age 20 years, in the period 2003-2008. Quality of cancer registration in Italy is elevated, with high proportions of microscopically verified diagnoses (91%in the 0-14 years age group and 96% between 15 and 19 years of age) and a very small proportion of cases collected through death certificate only (0.1%).The proportion of cases in diagnostic groups XI (other malignant epithelial neoplasms) and XII (other and unspecified neoplasms) of the International Classification for Childhood Cancer (ICCC), based on the third revision of the International Classification of Diseases for Oncology (ICD-O-3), were 7.0% in the 0-14 years age group and 26.0%in the 15-19 years age group.The ratio between mortality and incidence was 17.7% in both children and adolescents. Detailed results are presented in 24 fact sheets for the 12 major ICCC-3 diagnostic groups and 10 sub-groups of special interest; the series is completed by a sheet on all malignant tumours and one on all tumours including non-malignant neoplasms of the central nervous system. All sheets include results for three age groups (0-14, 15-19, and 0-19 years) and are followed by two commentaries on incidence in the recent period, one on trends and the other on survival. Incidence rates were age-standardized on the European population and presented per million children. Incidence rates are also presented by age group, sex, and geographical area. Incidence trends were evaluated for two periods, 1988-2008 and 1998-2008, using estimated annual percent changes, and survival estimates were calculated by age and period. Indicators and corresponding 95% confidence intervals are shown in forms of graphics and tables at the end of the monograph and online at http://www.registri-tumori.it. Geographical analyses were conducted rearranging cancer registries into four macroareas (North-West, North-East, Centre, and South and Islands). Age groups were the same used in descriptive studies on children worldwide (0, 1-4, 5-9, 10- 14 years for paediatric tumours and 15-19 years for adolescents). Incidence trend analyses included cancer registries with three or more years of registration in the 5-year period, using Poisson regression models. Observed survival was computed according to the Kaplan-Meier method. The estimate of expected cases in the next decade was based on observed incidence rates in the most recent period, extended to the Italian estimated population of children and adolescents in the periods 2011-2015 and 2016-2020. The AIEOP database (Modello 1.01) allowed us to compare the number of patients treated and followed-up in specialized centres with expected cases based on AIRTUM estimates. The AIEOP database also provided information regarding health care migration throughout Italian regions and the number of foreign (immigrated) children treated in Italian AIEOP centres. In the period 2003-2008, 31 cancer registries reported 4,473 incident malignant neoplasms, 2,855 in children and 1,618 in adolescents. Cancer incidence rates were 164 cases per million in children aged 14 years or below and 269 cases per million in patients aged 15-19 years. Limited geographical variations emerged. In children (0-14 years) a significant increase in malignant cancer incidence was observed until 1997 (APC: +3.2%), followed by a plateau (APC: -1.1%not statistically significant).Until the late Nineties, a statistically significant increase was also observed in the incidence of all leukaemias in males (APC: +5.7%), lymphoid leukaemias (APC: +5.6%), representing 80% of all leukaemias, Hodgkin and non- Hodgkin lymphomas (APC: +6.3%). A significant decrease emerged for lymphoid leukaemia starting in 1995 (APC: -1.9%), while no substantial change in cancer incidence rates was observed in the last decade of observation for all malignant neoplasms and lymphomas. In addition, no variation emerged for malignant (according to the most recent classification) central nervous system (CNS) neoplasms, while an annual increase of 1.8% (significant) was observed in the period 1988-2008, when non-malignant tumours were included. Increases in cancer incidence were observed throughout the study period for neuroblastoma (APC: +1.9%) and epithelial tumours or melanoma (APC: +4.1%). In the period 1998-2008, in addition to lymphoid leukaemias, a significant decrease was observed for all malignant neoplasms, lymphomas in girls, CNS tumours (males and females), and renal tumours in girls, while no increases were observed in this age group. In adolescents (15-19 years) between 1988 and 2008, a significant increase in incidence rates was observed (APC: +2.0%) for all malignant neoplasms, all lymphomas (APC: +2.9%; in particular Hodgkin lymphoma, APC: +3.6%), thyroid cancer (APC: +6.1%), and melanoma (APC: +8.1%). Conversely, lymphoid leukaemia is the only neoplasm showing a long-term decrease in adolescents. Recent trends (1998-2008) confirm the long-term increases only for all malignant neoplasms in girls and thyroid cancer (APC: +7.9%, boys and girls), while a decrease in bone tumour incidence emerged in girls, albeit based only on 46 cases. Cancer mortality in children showed a persistent decrease for all neoplasms and even for more frequent cancer sites or types, and mortality rates for cancer were three-fold higher in the early Seventies than in 2008. In addition, five-year survival after cancer diagnosis increased in the last three decades and was still increasing in the period 2003- 2008, reaching 82% in children and 86% in adolescents. In the period 2008-2010, 4,488 children (0-14 years) were treated in one of the AIEOP clinical centres and we estimate, based on the above-presented incidence rates, that they represented 92% of all cancer cases in Italy. However, in adolescents, the proportion of patients treated in AIEOP centres was only 25%. A migration of patients living in the South of Italy to Central and Northern Italy emerged from AIEOP information. The expected number of cancer cases in children aged between 0 and 14 years of age is approximately 7,000 in the period 2016- 2020, while the corresponding figure for adolescents between 15 and 19 years of age is 4,000, with no relevant variation in comparison with the previous five-year period. The present findings update descriptive cancer epidemiology in children and adolescents in Italy based on data provided by an extensive network of general and specialized population-based cancer registries. Data obtained from cancer registries are supplemented by additional information collected by specialized clinical AIEOP centres and mortality reports collected by the National Institute of Statistics (ISTAT). Incidence rates reported in Italy were slightly higher in comparison to other developed Countries, but relatively consistent between different Italian areas. Our results also showed that the significant increase in cancer incidence observed until the end of Nineties has halted, with the exception solely of thyroid cancer in adolescents. Efficacy of therapeutic protocols has improved constantly since the Seventies, and recent findings confirm this trend in all age groups and, in particular, for rarer tumours and cancer types that have very poor prognosis. Findings derived from cross-analysis with AIEOP data suggest that it is possible to further improve the efficiency of our healthcare system, in particular for adolescents; migration can be reduced with a more rational use of hospitals throughout Italy.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Long working hours and sleep deprivation have been a facet of physician training in the US since the advent of the modern residency system. However, the scientific evidence linking fatigue with deficits in human performance, accidents and errors in industries from aeronautics to medicine, nuclear power, and transportation has mounted over the last 40 years. This evidence has also spawned regulations to help ensure public safety across safety-sensitive industries, with the notable exception of medicine. In late 2007, at the behest of the US Congress, the Institute of Medicine embarked on a year-long examination of the scientific evidence linking resident physician sleep deprivation with clinical performance deficits and medical errors. The Institute of Medicine's report, entitled "Resident duty hours: Enhancing sleep, supervision and safety", published in January 2009, recommended new limits on resident physician work hours and workload, increased supervision, a heightened focus on resident physician safety, training in structured handovers and quality improvement, more rigorous external oversight of work hours and other aspects of residency training, and the identification of expanded funding sources necessary to implement the recommended reforms successfully and protect the public and resident physicians themselves from preventable harm. Given that resident physicians comprise almost a quarter of all physicians who work in hospitals, and that taxpayers, through Medicare and Medicaid, fund graduate medical education, the public has a deep investment in physician training. Patients expect to receive safe, high-quality care in the nation's teaching hospitals. Because it is their safety that is at issue, their voices should be central in policy decisions affecting patient safety. It is likewise important to integrate the perspectives of resident physicians, policy makers, and other constituencies in designing new policies. However, since its release, discussion of the Institute of Medicine report has been largely confined to the medical education community, led by the Accreditation Council for Graduate Medical Education (ACGME). To begin gathering these perspectives and developing a plan to implement safer work hours for resident physicians, a conference entitled "Enhancing sleep, supervision and safety: What will it take to implement the Institute of Medicine recommendations?" was held at Harvard Medical School on June 17-18, 2010. This White Paper is a product of a diverse group of 26 representative stakeholders bringing relevant new information and innovative practices to bear on a critical patient safety problem. Given that our conference included experts from across disciplines with diverse perspectives and interests, not every recommendation was endorsed by each invited conference participant. However, every recommendation made here was endorsed by the majority of the group, and many were endorsed unanimously. Conference members participated in the process, reviewed the final product, and provided input before publication. Participants provided their individual perspectives, which do not necessarily represent the formal views of any organization. In September 2010 the ACGME issued new rules to go into effect on July 1, 2011. Unfortunately, they stop considerably short of the Institute of Medicine's recommendations and those endorsed by this conference. In particular, the ACGME only applied the limitation of 16 hours to first-year resident physicans. Thus, it is clear that policymakers, hospital administrators, and residency program directors who wish to implement safer health care systems must go far beyond what the ACGME will require. We hope this White Paper will serve as a guide and provide encouragement for that effort. RESIDENT PHYSICIAN WORKLOAD AND SUPERVISION: By the end of training, a resident physician should be able to practice independently. Yet much of resident physicians' time is dominated by tasks with little educational value. The caseload can be so great that inadequate reflective time is left for learning based on clinical experiences. In addition, supervision is often vaguely defined and discontinuous. Medical malpractice data indicate that resident physicians are frequently named in lawsuits, most often for lack of supervision. The recommendations are: The ACGME should adjust resident physicians workload requirements to optimize educational value. Resident physicians as well as faculty should be involved in work redesign that eliminates nonessential and noneducational activity from resident physician dutiesMechanisms should be developed for identifying in real time when a resident physician's workload is excessive, and processes developed to activate additional providersTeamwork should be actively encouraged in delivery of patient care. Historically, much of medical training has focused on individual knowledge, skills, and responsibility. As health care delivery has become more complex, it will be essential to train resident and attending physicians in effective teamwork that emphasizes collective responsibility for patient care and recognizes the signs, both individual and systemic, of a schedule and working conditions that are too demanding to be safeHospitals should embrace the opportunities that resident physician training redesign offers. Hospitals should recognize and act on the potential benefits of work redesign, eg, increased efficiency, reduced costs, improved quality of care, and resident physician and attending job satisfactionAttending physicians should supervise all hospital admissions. Resident physicians should directly discuss all admissions with attending physicians. Attending physicians should be both cognizant of and have input into the care patients are to receive upon admission to the hospitalInhouse supervision should be required for all critical care services, including emergency rooms, intensive care units, and trauma services. Resident physicians should not be left unsupervised to care for critically ill patients. In settings in which the acuity is high, physicians who have completed residency should provide direct supervision for resident physicians. Supervising physicians should always be physically in the hospital for supervision of resident physicians who care for critically ill patientsThe ACGME should explicitly define "good" supervision by specialty and by year of training. Explicit requirements for intensity and level of training for supervision of specific clinical scenarios should be providedCenters for Medicare and Medicaid Services (CMS) should use graduate medical education funding to provide incentives to programs with proven, effective levels of supervision. Although this action would require federal legislation, reimbursement rules would help to ensure that hospitals pay attention to the importance of good supervision and require it from their training programs. RESIDENT PHYSICIAN WORK HOURS: Although the IOM "Sleep, supervision and safety" report provides a comprehensive review and discussion of all aspects of graduate medical education training, the report's focal point is its recommendations regarding the hours that resident physicians are currently required to work. A considerable body of scientific evidence, much of it cited by the Institute of Medicine report, describes deteriorating performance in fatigued humans, as well as specific studies on resident physician fatigue and preventable medical errors. The question before this conference was what work redesign and cultural changes are needed to reform work hours as recommended by the Institute of Medicine's evidence-based report? Extensive scientific data demonstrate that shifts exceeding 12-16 hours without sleep are unsafe. Several principles should be followed in efforts to reduce consecutive hours below this level and achieve safer work schedules. The recommendations are: Limit resident physician work hours to 12-16 hour maximum shiftsA minimum of 10 hours off duty should be scheduled between shiftsResident physician input into work redesign should be actively solicitedSchedules should be designed that adhere to principles of sleep and circadian science; this includes careful consideration of the effects of multiple consecutive night shifts, and provision of adequate time off after night work, as specified in the IOM reportResident physicians should not be scheduled up to the maximum permissible limits; emergencies frequently occur that require resident physicians to stay longer than their scheduled shifts, and this should be anticipated in scheduling resident physicians' work shiftsHospitals should anticipate the need for iterative improvement as new schedules are initiated; be prepared to learn from the initial phase-in, and change the plan as neededAs resident physician work hours are redesigned, attending physicians should also be considered; a potential consequence of resident physician work hour reduction and increased supervisory requirements may be an increase in work for attending physicians; this should be carefully monitored, and adjustments to attending physician work schedules made as needed to prevent unsafe work hours or working conditions for this group"Home call" should be brought under the overall limits of working hours; work load and hours should be monitored in each residency program to ensure that resident physicians and fellows on home call are getting sufficient sleepMedicare funding for graduate medical education in each hospital should be linked with adherence to the Institute of Medicine limits on resident physician work hours. MOONLIGHTING BY RESIDENT PHYSICIANS: The Institute of Medicine report recommended including external as well as internal moonlighting in working hour limits. The recommendation is: All moonlighting work hours should be included in the ACGME working hour limits and actively monitored. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
In January 2010, the Medical Advisory Secretariat received an application from University Health Network to provide an evidentiary platform on stenting as a treatment management for peripheral artery disease. The purpose of this health technology assessment is to examine the effectiveness of primary stenting as a treatment management for peripheral artery disease of the lower extremities. CONDITION AND TARGET POPULATION Peripheral artery disease (PAD) is a progressive disease occurring as a result of plaque accumulation (atherosclerosis) in the arterial system that carries blood to the extremities (arms and legs) as well as vital organs. The vessels that are most affected by PAD are the arteries of the lower extremities, the aorta, the visceral arterial branches, the carotid arteries and the arteries of the upper limbs. In the lower extremities, PAD affects three major arterial segments i) aortic-iliac, ii) femoro-popliteal (FP) and iii) infra-popliteal (primarily tibial) arteries. The disease is commonly classified clinically as asymptomatic claudication, rest pain and critical ischemia. Although the prevalence of PAD in Canada is not known, it is estimated that 800,000 Canadians have PAD. The 2007 Trans Atlantic Intersociety Consensus (TASC) II Working Group for the Management of Peripheral Disease estimated that the prevalence of PAD in Europe and North America to be 27 million, of whom 88,000 are hospitalizations involving lower extremities. A higher prevalence of PAD among elderly individuals has been reported to range from 12% to 29%. The National Health and Nutrition Examination Survey (NHANES) estimated that the prevalence of PAD is 14.5% among individuals 70 years of age and over. Modifiable and non-modifiable risk factors associated with PAD include advanced age, male gender, family history, smoking, diabetes, hypertension and hyperlipidemia. PAD is a strong predictor of myocardial infarction (MI), stroke and cardiovascular death. Annually, approximately 10% of ischemic cardiovascular and cerebrovascular events can be attributed to the progression of PAD. Compared with patients without PAD, the 10-year risk of all-cause mortality is 3-fold higher in patients with PAD with 4-5 times greater risk of dying from cardiovascular event. The risk of coronary heart disease is 6 times greater and increases 15-fold in patients with advanced or severe PAD. Among subjects with diabetes, the risk of PAD is often severe and associated with extensive arterial calcification. In these patients the risk of PAD increases two to four fold. The results of the Canadian public survey of knowledge of PAD demonstrated that Canadians are unaware of the morbidity and mortality associated with PAD. Despite its prevalence and cardiovascular risk implications, only 25% of PAD patients are undergoing treatment. The diagnosis of PAD is difficult as most patients remain asymptomatic for many years. Symptoms do not present until there is at least 50% narrowing of an artery. In the general population, only 10% of persons with PAD have classic symptoms of claudication, 40% do not complain of leg pain, while the remaining 50% have a variety of leg symptoms different from classic claudication. The severity of symptoms depends on the degree of stenosis. The need to intervene is more urgent in patients with limb threatening ischemia as manifested by night pain, rest pain, ischemic ulcers or gangrene. Without successful revascularization those with critical ischemia have a limb loss (amputation) rate of 80-90% in one year. Diagnosis of PAD is generally non-invasive and can be performed in the physician offices or on an outpatient basis in a hospital. Most common diagnostic procedure include: 1) Ankle Brachial Index (ABI), a ratio of the blood pressure readings between the highest ankle pressure and the highest brachial (arm) pressure; and 2) Doppler ultrasonography, a diagnostic imaging procedure that uses a combination of ultrasound and wave form recordings to evaluate arterial flow in blood vessels. The value of the ABI can provide an assessment of the severity of the disease. Other non invasive imaging techniques include: Computed Tomography (CT) and Magnetic Resonance Angiography (MRA). Definitive diagnosis of PAD can be made by an invasive catheter based angiography procedure which shows the roadmap of the arteries, depicting the exact location and length of the stenosis / occlusion. Angiography is the standard method against which all other imaging procedures are compared for accuracy. More than 70% of the patients diagnosed with PAD remain stable or improve with conservative management of pharmacologic agents and life style modifications. Significant PAD symptoms are well known to negatively influence an individual quality of life. For those who do not improve, revascularization methods either invasive or non-invasive can be used to restore peripheral circulation. TECHNOLOGY UNDER REVIEW: A Stent is a wire mesh "scaffold" that is permanently implanted in the artery to keep the artery open and can be combined with angioplasty to treat PAD. There are two types of stents: i) balloon-expandable and ii) self expandable stents and are available in varying length. The former uses an angioplasty balloon to expand and set the stent within the arterial segment. Recently, drug-eluting stents have been developed and these types of stents release small amounts of medication intended to reduce neointimal hyperplasia, which can cause re-stenosis at the stent site. Endovascular stenting avoids the problem of early elastic recoil, residual stenosis and flow limiting dissection after balloon angioplasty. In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), is primary stenting more effective than percutaneous transluminal angioplasty (PTA) in improving patency?In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), does primary stenting provide immediate success compared to PTA?In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), is primary stenting associated with less complications compared to PTA?In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), does primary stenting compared to PTA reduce the rate of re-intervention?In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion) is primary stenting more effective than PTA in improving clinical and hemodynamic success?Are drug eluting stents more effective than bare stents in improving patency, reducing rates of re-interventions or complications? A literature search was performed on February 2, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA). Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology. English language full-reports from 1950 to January Week 3, 2010Comparative randomized controlled trials (RCTs), systematic reviews and meta-analyses of RCTsProven diagnosis of PAD of the lower extremities in all patients.Adult patients at least 18 years of age.Stent as at least one treatment arm.Patency, re-stenosis, re-intervention, technical success, hemodynamic (ABI) and clinical improvement and complications as at least an outcome. Non-randomized studiesObservational studies (cohort or retrospective studies) and case reportFeasibility studiesStudies that have evaluated stent but not as a primary intervention The primary outcome measure was patency. Secondary measures included technical success, re-intervention, complications, hemodynamic (ankle brachial pressure index, treadmill walking distance) and clinical success or improvement according to Rutherford scale. It was anticipated, a priori, that there would be substantial differences among trials regarding the method of examination and definitions of patency or re-stenosis. Where studies reported only re-stenosis rates, patency rates were calculated as 1 minus re-stenosis rates. Odds ratios (for binary outcomes) or mean difference (for continuous outcomes) with 95% confidence intervals (CI) were calculated for each endpoint. An intention to treat principle (ITT) was used, with the total number of patients randomized to each study arm as the denominator for each proportion. Sensitivity analysis was performed using per protocol approach. A pooled odds ratio (POR) or mean difference for each endpoint was then calculated for all trials reporting that endpoint using a fixed effects model. PORs were calculated for comparisons of primary stenting versus PTA or other alternative procedures. Level of significance was set at alpha=0.05. Homogeneity was assessed using the chi-square test, I(2) and by visual inspection of forest plots. If heterogeneity was encountered within groups (P < 0.10), a random effects model was used. All statistical analyses were performed using RevMan 5. Where sufficient data were available, these analyses were repeated within subgroups of patients defined by time of outcome assessment to evaluate sustainability of treatment benefit. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
What are the effects of weight management interventions that include a diet component on weight-related outcomes in pregnant and postpartum women?The primary objective of this systematic review is to evaluate the effectiveness of weight management interventions which include a diet component and are aimed at limiting gestational weight gain and postpartum weight retention in women.The second objective of this systematic review is to investigate included intervention components with respect to effect on weight-related outcomes. This may include, but is not limited to: length of intervention, use of face-to-face counselling, group or individual consultations, use of other interventions components including exercise, use of goals and use of support tools like food diaries, coaching, including email or text message support. Around half of all women of reproductive age are either overweight or obese, with women aged 25-34 years having a greater risk of substantial weight gain compared with men of all ages. Excessive gestational weight gain (GWG) and postpartum weight retention (PPWR) may play a significant role in long term obesity. Having one child doubles the five- and 10-year obesity incidence for women, with many women who gain excessive weight during pregnancy remaining obese permanently. Excessive GWG and/or PPWR can also significantly contribute to short- and long-term adverse health outcomes for mother, baby and future pregnancies.Maternal obesity increases the risk of pregnancy related complications such as pre-eclampsia, gestational diabetes mellitus, stillbirth and the rate of caesarean section. Childhood obesity is a further long term complication of maternal obesity for offspring, which may persist in to adulthood. Excess GWG is also a risk factor for PPWR both in the short and long-term. Nehring et al. conducted a meta-analysis with over 65,000 women showing that, compared to women who gained weight within recommendations during pregnancy, women with GWG above Institute of Medicine weight gain recommendations, retained an additional 3.1 kg and 4.7kg after three and greater than or equal to 15 years postpartum, respectively. The health risk associated with PPWR is highlighted in a study of 151,025 Swedish women followed between 1992 and 2001.The study identified the risk of adverse pregnancy outcomes for those who gained three or more units of Body Mass Index (kg/m2) between consecutive pregnancies (an average of two years) was much higher compared with women whose BMI changed from -1.0 and 0.9 units. Long-term chronic disease risk may also be affected by PPWR as weight retention at the end of the first year post-partum has been found to be a predictor of maternal overweight 15 years later.With around 14-20% of women retaining 5kg or more 12 months postpartum, the risk of developing conditions like diabetes, metabolic syndrome and cardiovascular disease may be increased. It becomes evident that interventions which aim to support attainment of healthy weight both in the antenatal and postpartum periods are key health priorities for women during this life stage.Lifestyle factors of overweight, having poor diet quality, and not undertaking enough moderate-to-vigorous physical activity are amongst the top five predictors of mortality in women. Additionally it is noted that, for many women, pregnancy and the postpartum period are associated with a reduction in physical activity. It is known that a combination of poor dietary choices, an increase in sedentary time and reduction in physical activity are all contributors to the development of overweight and obesity. With this in mind, current research has focused on lifestyle interventions to limit GWG and PPWR. Thangaratinam et al. reviewed 44 randomized controlled trials (7278 women) where interventions including diet, physical activity or both were evaluated for their influence on maternal weight during pregnancy. Results indicate that all were significantly effective in reducing GWG compared with the control group. More specifically, dietary interventions were the most effective in reducing weight gain, with a mean weight loss of -3.84kg compared with -0.72kg and -1.06kg for physical activity and the mixed (diet plus physical activity) approach, respectively. This finding is supported by Hill and colleagues' recent systematic review of theory based interventions to limit GWG. Included studies in this review reported an underpinning theory base and were classified as adopting a dietary, physical activity or mixed approach. Hill et al. concluded that studies which included a diet intervention were significantly more effective at limiting GWG.In 2011 Tanentsapf et al. reviewed the effect of dietary interventions alone for reducing GWG in normal weight, overweight and obese pregnant women. This review analysed 13 randomized controlled trials and quasi-randomized controlled trials with a dietary intervention to prevent excessive GWG in women. The review concluded that dietary interventions during pregnancy were effective in reducing GWG with an effect of -1.92kg (n=1434) compared with the control group.Tanentsapf et al. identified that trials differed in the conduct of the interventions with various diet and non-diet related components utilised. Dietary approaches were highly variable with some trials focusing only on calorie restriction and others included additional target macronutrient distribution for intake. Some trials further provided feedback based on maternal weight gain guidelines. Interventions also varied in delivery method with a variety of modes used, including face-to-face, individual or group consultations and/or written correspondence. The frequency of communication, despite the type or mix, also changed from trial to trial with additional methods via telephone, posted materials, feedback or food diaries utilised. The inclusion of physical activity in addition to diet intervention was also common. Whilst the recent review by Tanentsapf et al. identified that dietary interventions are effective in reducing GWG, the review did not investigate the impact that different intervention components, delivery methods or dietary counselling approaches had on gestational weight management. It remains unclear as to which intervention components optimize GWG in women.The impact of lifestyle interventions has also been investigated in the postpartum period. The recent systematic review from van der Pligt et al. reported seven of 11 studies reviewed were successful in limiting PPWR. As with studies aimed at limiting GWG, interventions included in van der Pligt et al.'s review differed greatly in their conduct. Six of these seven studies included both dietary and physical activity components for the intervention, with the final successful study including a diet only intervention. Five of the successful studies recruited overweight or obese women only. Intervention time varied considerably in successful studies with some running for as little at ten days, and others up to six months.Bertz et al. demonstrated that their 12-week behavior modification intervention which targeted diet alone or diet and exercise, including two individual sessions with a dietitian and physical therapist, provision of scales for weight self-monitoring and bi-weekly text messages was successful in achieving significant weight loss following the intervention, and sustained at one year. The diet intervention and the diet and exercise intervention yielded significant weight loss compared to the control. Following 12 weeks a reduction of -8.3 +/- 4.2kg for diet intervention and -6.9 +/- 3.0kg for diet and exercise was observed. Additionally after one year, the diet intervention showed -10.2 +/- 5.7kg reduction and -7.3 +/- 6.3kg for the diet and exercise intervention (p<0.001). Colleran et al. also found significant weight change results by implementing a 16-week intervention which consisted of weekly individual sessions with a dietitian regarding calorie restriction, two additional home visits regarding exercise, weekly food diary completion and email support. The intervention group had greater weight loss compared to the control group (-5.8kg +/- 3.5kg vs -1.6kg +/- 5.4kg). It can be seen that various methods have been utilized in investigating the impact of diet and physical activity interventions on PPWR. The review by van der Pligt et al. highlights the impact successful lifestyle interventions can have on postpartum weight change. However, this review did not investigate the different intervention strategies utilized. It remains unclear as to the optimal setting, delivery method, diet strategy, contact frequency or intervention length to limit PPWR.Previous systematic reviews for both GWG and PPWR have focused on the effectiveness of lifestyle interventions as a whole for weight management in pregnant and postpartum women. And despite Tanentsapf et al.'s focus on dietary interventions for GWG, much is still unknown about the effectiveness of differing diet interventions over the antenatal and postpartum period. Specifically, the impact of differing diet intervention strategies on maternal weight gain is not known. Firstly, this systematic review will focus on whether weight management interventions which include a dietary component are effective in pregnant and postpartum women. In addition to this, this review will investigate the different intervention strategies utilized and their effectiveness in maternal weight management. A search of systematic review protocol databases has shown that there is no current review underway for this topic.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Tiotropium bromide (Spiriva) is a long-acting anticholinergic bronchodilator that maintains bronchodilation for at least 24 hours, allowing once-daily administration. The active moiety is the tiotropium cation (tiotropium); tiotropium bromide 22.5 micrograms is equivalent to 18 micrograms of tiotropium cation. Greater improvements in lung function from baseline (primary endpoint mean trough FEV(1)) were observed with inhaled tiotropium 18 micrograms once daily than with placebo in 6-month and 1-year randomized, double-blind trials in patients with COPD. Tiotropium improved lung function (trough FEV(1) response) more effectively than ipratropium bromide (ipratropium) 40 micrograms four times daily in 1-year clinical trials, and was at least as effective as salmeterol 50 micrograms 12-hourly in 6-month trials. Preliminary data suggest that tiotropium alone or in combination with once-daily formoterol has a greater bronchodilator effect than twice-daily formoterol in patients with COPD. Improvements in patients' perception of health-related quality of life (HR-QOL) or dyspnea were greater with tiotropium than with placebo or ipratropium, and were similar to those with salmeterol. Reductions in the frequency and severity of acute exacerbations and in the use of rescue medication were also greater with tiotropium than with ipratropium or placebo. There was no evidence of tachyphylaxis with tiotropium during 1-year clinical trials. Inhaled tiotropium was generally well tolerated in clinical trials. Apart from dry mouth, the type and incidence of adverse events with tiotropium were similar to those with ipratropium, salmeterol or placebo in patients with COPD. In conclusion, inhaled tiotropium 18 micrograms once daily improved lung function, dyspnea, and HR-QOL, and decreased the incidence of acute COPD exacerbations and the use of rescue medication relative to placebo or ipratropium in clinical trials in patients with COPD. Tiotropium was at least as effective as salmeterol in terms of bronchodilator efficacy and improvements in dyspnea or HR-QOL. With the exception of dry mouth, the tolerability profile of tiotropium was similar to that with placebo, ipratropium, or salmeterol. Consequently, inhaled tiotropium is likely to be a valuable option for first-line, long-term maintenance therapy in the management of bronchoconstriction in patients with symptomatic COPD. Tiotropium bromide has a quaternary ammonium structure and acts as an anticholinergic bronchodilator; the active moiety is the tiotropium cation (tiotropium). A 22.5 micrograms dose of tiotropium bromide provides 18 micrograms of tiotropium. Orally inhaled tiotropium bromide antagonizes the muscarinic M(1), M(2), and M(3) receptors located in airway smooth muscle, reversing vagally mediated bronchoconstriction. Receptor binding assays and in vitro tests indicate that tiotropium bromide is kinetically selective for M(1) and M(3) receptors over the M(2) receptor, unlike ipratropium bromide, which is nonselective. Animal and in vitro studies showed that tiotropium bromide was more potent ( approximate, equals 20-fold) than ipratropium bromide in displacing [(3)H]N-methylscopolamine (NMS) from muscarinic receptors, and had a more sustained protective effect (>70% inhibition) against NMS binding. Tiotropium bromide was a more potent inhibitor of bronchial contraction than atropine ( approximate, equals 23-fold), and had a slower onset and markedly longer duration of action than atropine or an equipotent dose of ipratropium bromide. Aerosol particle penetration is improved with tiotropium, without delaying mucus clearance from the lungs. Tiotropium 4.5-36 micrograms once daily for 4 weeks increased mean trough and average FEV(1) and FVC and mean PEFR values from baseline compared with placebo, with no evidence of tachyphylaxis. Improvements in trough FEV(1) from baseline with tiotropium 4.5-36 micrograms were not dose dependent. Based on a lack of dose response, the optimal once-daily tiotropium dosage is 18 micrograms. Steady-state trough FEV(1) values are achieved within 48 hours of commencing tiotrochodilation (for >/=24 hours) and an attenuation of the nocturnal decline in FEV(1) that were unaffected by timing of the daily tiotropium dose were seen in randomized, double-blind, placebo-controlled studies in patients with stable COPD. The drug improved static and dynamic lung hyperinflation (evidenced by reduced trapped air volume and increased tidal volume and end-of-exercise inspiratory capacity), and improved exertional dyspnea (during activities of daily living and exertion) and exercise tolerance compared with placebo in randomized, double-blind studies. In patients with stable COPD, improved sleep-related oxygen desaturation that was unaffected by the timing of the daily dose was seen with tiotropium but not with placebo. Clinically significant treatment-related disorders of conduction or rhythm, or changes in heart rate were not observed with tiotropium in this patient group. Mean maximal plasma concentrations (C(max)) were observed within 5 minutes of inhalation of a single dose of tiotropium 18 micrograms in patients with COPD. Plasma drug levels declined to minimum concentrations (C(min)) within 1 hour of treatment in healthy volunteers. Mean steady-state C(max) concentrations (16 ng/L) were achieved after 2-3 weeks of once-daily inhaled tiotropium 18 micrograms in elderly patients with COPD; tiotropium does not appear to accumulate once steady-state has been achieved.The estimated absolute bioavailability of tiotropium at steady state in healthy volunteers was approximately 20-25%, and approximately 72% of the drug is bound to plasma proteins. Excretion of tiotropium is predominantly renal (through active secretion by the kidneys), although in vitro studies suggest that cytochrome P450 (CYP) oxidation (possibly involving CYP2D6 and CYP3A4 enzymes) may have a minor role. In patients with COPD, renal excretion of the unchanged drug at 24 hours (Ae(24)) was approximately 7%. The mean plasma elimination half-life after single or multiple doses in healthy volunteers and elderly patients with COPD was approximately 5-6 days. The renal clearance and urinary excretion of tiotropium decrease with increasing age; however, these changes are not considered to be clinically significant. Because of altered steady-state C(max), C(min), area under the concentration-time curve, and Ae(24) values, caution is required with tiotropium administration in patients with moderate-to-severe renal impairment. The pharmacokinetics of tiotropium in patients with severe renal or hepatic impairment have not been studied. Tiotropium does not interact with drugs such as cimetidine or ranitidine, which are also eliminated by active renal secretion. Orally inhaled tiotropium bromide has been evaluated as a bronchodilator for the management of patients with COPD in randomized, double-blind 6-month and 1-year trials, and in several shorter studies. In clinical trials, COPD was diagnosed according to the American Thoracic Society guidelines. The bronchodilator effect was expressed as the trough FEV(1) response (the mean change in FEV(1) from baseline measured 1 hour prior to and immediately before a scheduled dose), and was the primary endpoint in all but two clinical trials. The bronchodilator effect with tiotropium 18 micrograms once daily was superior to that with placebo in several well designed trials in patients with COPD. Moreover, greater improvements in mean peak and average FEV(1) responses occurred with tiotropium but not with placebo. Mean trough, peak, and average FVC responses, and weekly mean morning and evening PEFR values were also improved to a greater extent with tiotropium than with placebo. Tiotropium demonstrated a greater bronchodilator effect than ipratropium bromide (hereafter referred to as ipratropium when used at approved dosages) 40 micrograms four times daily in two 1-year trials in patients with COPD. Mean peak and average FEV(1), mean trough FVC responses, and weekly mean morning and evening PEFR values were also increased to a greater extent with tiotropium than with ipratropium. In one of the two 6-month trials that compared the efficacy of tiotropium with that of inhaled salmeterol 50 micrograms twice daily, greater improvements from baseline in mean trough, peak, and average FEV(1) and FVC responses were seen with tiotropium than with salmeterol. Increases in weekly mean evening, but not morning, PEFR values were generally greater with tiotropium than salmeterol. In the second trial, improvement in the primary endpoint (mean trough FEV(1) response from baseline) with tiotropium or salmeterol was similar, although peak and average responses were superior with tiotropium. Preliminary results from a 6-week crossover study in patients with COPD suggested that tiotropium alone or in combination with once-daily formoterol improved mean trough and average FEV(1) and trough FVC values from baseline to a greater extent than twice-daily formoterol. More patients achieved a clinically important improvement (increase of >/=1 unit) in the transitional dyspnea index focal score (a measure of dyspnea-related impairment) with tiotropium than with placebo in the 1-year trials. Tiotropium was superior to ipratropium in 1-year trials, and was at least as effective as salmeterol in 6-month trials, in achieving a clinically important improvement in focal scores. Tiotropium recipients experienced fewer COPD exacerbations than placebo or ipratropium recipients and had fewer and shorter COPD-related hospitalizations compared with placebo recipients. Unlike salmeterol, tiotropium lengthened the time to onset of the first exacerbation and decreased the number of exacerbations compared with placebo in two 6-month trials. Similar proportions of tiotropium, salmeterol, and placebo recipients required COPD-related hospitalizations. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The objective of this health technology policy analysis was to determine, where, how, and when physiotherapy services are best delivered to optimize functional outcomes for patients after they undergo primary (first-time) total hip replacement or total knee replacement, and to determine the Ontario-specific economic impact of the best delivery strategy. The objectives of the systematic review were as follows: To determine the effectiveness of inpatient physiotherapy after discharge from an acute care hospital compared with outpatient physiotherapy delivered in either a clinic-based or home-based setting for primary total joint replacement patientsTo determine the effectiveness of outpatient physiotherapy delivered by a physiotherapist in either a clinic-based or home-based setting in addition to a home exercise program compared with a home exercise program alone for primary total joint replacement patientsTo determine the effectiveness of preoperative exercise for people who are scheduled to receive primary total knee or hip replacement surgery Total hip replacements and total knee replacements are among the most commonly performed surgical procedures in Ontario. Physiotherapy rehabilitation after first-time total hip or knee replacement surgery is accepted as the standard and essential treatment. The aim is to maximize a person's functionality and independence and minimize complications such as hip dislocation (for hip replacements), wound infection, deep vein thrombosis, and pulmonary embolism. THE THERAPY: The physiotherapy rehabilitation routine has 4 components: therapeutic exercise, transfer training, gait training, and instruction in the activities of daily living. Physiotherapy rehabilitation for people who have had total joint replacement surgery varies in where, how, and when it is delivered. In Ontario, after discharge from an acute care hospital, people who have had a primary total knee or hip replacement may receive inpatient or outpatient physiotherapy. Inpatient physiotherapy is delivered in a rehabilitation hospital or specialized hospital unit. Outpatient physiotherapy is done either in an outpatient clinic (clinic-based) or in the person's home (home-based). Home-based physiotherapy may include practising an exercise program at home with or without supplemental support from a physiotherapist. Finally, physiotherapy rehabilitation may be administered at several points after surgery, including immediately postoperatively (within the first 5 days) and in the early recovery period (within the first 3 months) after discharge. There is a growing interest in whether physiotherapy should start before surgery. A variety of practises exist, and evidence regarding the optimal pre- and post-acute course of rehabilitation to obtain the best outcomes is needed. The Medical Advisory Secretariat used its standard search strategy, which included searching the databases of Ovid MEDLINE, CINHAL, EMBASE, Cochrane Database of Systematic Reviews, and PEDro from 1995 to 2005. English-language articles including systematic reviews, randomized controlled trials (RCTs), non-RCTs, and studies with a sample size of greater than 10 patients were included. Studies had to include patients undergoing primary total hip or total knee replacement, aged 18 years of age or older, and they had to have investigated one of the following comparisons: inpatient rehabilitation versus outpatient (clinic- or home-based therapy) rehabilitation, land-based post-acute care physiotherapy delivered by a physiotherapist compared with patient self-administered exercise and a land-based exercise program before surgery. The primary outcome was postoperative physical functioning. Secondary outcomes included the patient's assessment of therapeutic effect (overall improvement), perceived pain intensity, health services utilization, treatment side effects, and adverse events The quality of the methods of the included studies was assessed using the criteria outlined in the Cochrane Musculoskeletal Injuries Group Quality Assessment Tool. After this, a summary of the biases threatening study validity was determined. Four methodological biases were considered: selection bias, performance bias, attrition bias, and detection bias. A meta-analysis was conducted when adequate data were available from 2 or more studies and where there was no statistical or clinical heterogeneity among studies. The GRADE system was used to summarize the overall quality of evidence. The search yielded 422 citations; of these, 12 were included in the review including 10 primary studies (9 RCTs, 1 non-RCT) and 2 systematic reviews. The Medical Advisory Secretariat review included 2 primary studies (N = 334) that examined the effectiveness of an inpatient physiotherapy rehabilitation program compared with an outpatient home-based physiotherapy program on functional outcomes after total knee or hip replacement surgery. One study, available only as an abstract, found no difference in functional outcome at 1 year after surgery (TKR or THR) between the treatments. The other study was an observational study that found that patients who are younger than 71 years of age on average, who do not live alone, and who do not have comorbid illnesses recover adequate function with outpatient home-based physiotherapy. However results were only measured up to 3 months after surgery, and the outcome measure they used is not considered the best one for physical functioning. Three primary studies (N = 360) were reviewed that tested the effectiveness of outpatient home-based or clinic-based physiotherapy in addition to a self-administered home exercise program, compared with a self-administered exercise program only or in addition to using another therapy (phone calls or continuous passive movement), on postoperative physical functioning after primary TKR surgery. Two of the studies reported no difference in change from baseline in flexion range of motion between those patients receiving outpatient or home-based physiotherapy and doing a home exercise program compared with patients who did a home exercise program only with or without continuous passive movement. The other study reported no difference in the Western Ontario and McMaster Osteoarthritis Index (WOMAC) scores between patients receiving clinic-based physiotherapy and practising a home exercise program and those who received monitoring phone calls and did a home exercise program after TKR surgery. The Medical Advisory Secretariat reviewed two systematic reviews evaluating the effects of preoperative exercise on postoperative physical functioning. One concluded that preoperative exercise is not effective in improving functional recovery or pain after TKR and any effects after THR could not be adequately determined. The other concluded that there was inconclusive evidence to determine the benefits of preoperative exercise on functional recovery after TKR. Because 2 primary studies were added to the published literature since the publication of these systematic reviews the Medical Advisory Secretariat revisited the question of effectiveness of a preoperative exercise program for patients scheduled for TKR ad THR surgery. The Medical Advisory Secretariat also reviewed 3 primary studies (N = 184) that tested the effectiveness of preoperative exercise beginning 4-6 weeks before surgery on postoperative outcomes after primary TKR surgery. All 3 studies reported negative findings with regard to the effectiveness of preoperative exercise to improve physical functioning after TKR surgery. However, 2 failed to show an effect of the preoperative exercise program before surgery in those patients receiving preoperative exercise. The third study did not measure functional outcome immediately before surgery in the preoperative exercise treatment group; therefore the study's authors could not document an effect of the preoperative exercise program before surgery. Regarding health services utilization, 2 of the studies did not find significant differences in either the length of the acute care hospital stay or the inpatient rehabilitation care setting between patients treated with a preoperative exercise program and those not treated. The third study did not measure health services utilization. These results must be interpreted within the limitations and the biases of each study. Negative results do not necessarily support a lack of treatment effect but may be attributed to a type II statistical error. Finally, the Medical Advisory Secretariat reviewed 2 primary studies (N = 136) that examined the effectiveness of preoperative exercise on postoperative functional outcomes after primary THR surgery. One study did not support the effectiveness of an exercise program beginning 8 weeks before surgery. However, results from the other did support the effectiveness of an exercise program 8 weeks before primary THR surgery on pain and functional outcomes 1 week before and 3 weeks after surgery. Based on the evidence, the Medical Advisory Secretariat reached the following conclusions with respect to physiotherapy rehabilitation and physical functioning 1 year after primary TKR or THR surgery: There is high-quality evidence from 1 large RCT to support the use of home-based physiotherapy instead of inpatient physiotherapy after primary THR or TKR surgery.There is low-to-moderate quality evidence from 1 large RCT to support the conclusion that receiving a monitoring phone call from a physiotherapist and practising home exercises is comparable to receiving clinic-based physiotherapy and practising home exercises for people who have had primary TKR surgery. However, results may not be generalizable to those who have had THR surgery.There is moderate evidence to suggest that an exercise program beginning 4 to 6 weeks before primary TKR surgery is not effective. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The United States and Western Europe have seen great improvements in air quality, presumably in response to various regulations curtailing emissions from the broad range of sources that have contributed to local, regional, and global pollution. Such regulations, and the ensuing controls, however, have not come without costs, which are estimated at tens of billions of dollars per year. These costs motivate accountability-related questions such as, to what extent do regulations lead to emissions changes? More important, to what degree have the regulations provided the expected human health benefits? Here, the impacts of specific regulations on both electricity generating unit (EGU) and on-road mobile sources are examined through the classical accountability process laid out in the 2003 Health Effects Institute report linking regulations to emissions to air quality to health effects, with a focus on the 1999-2013 period. This analysis centers on regulatory actions in the southeastern United States and their effects on health outcomes in the 5-county Atlanta metropolitan area. The regulations examined are largely driven by the 1990 Clean Air Act Amendments (C). This work investigates regulatory actions and controls promulgated on EGUs: the Acid Rain Program (ARP), the NO<subx</sub Budget Trading Program (NBP), and the Clean Air Interstate Rule (CAIR) - and mobile sources: Tier 2 Gasoline Vehicle Standards and the 2007 Heavy Duty Diesel Rule. Each step in the classic accountability process was addressed using one or more methods. Linking regulations to emissions was accomplished by identifying major federal regulations and the associated state regulations, along with analysis of individual facility emissions and control technologies and emissions modeling (e.g., using the U.S. Environmental Protection Agency's [U.S. EPA's] MOtor Vehicle Emissions Simulator [MOVES] mobile-source model). Regulators, including those from state environmental and transportation agencies, along with the public service commissions, play an important role in implementing federal rules and were involved along with other regional stakeholders in the study. We used trend analysis, air quality modeling, satellite data, and a ratio-of-ratios technique to investigate a critical current issue, a potential large bias in mobile-source oxides of nitrogen (NO<subx</sub) emissions estimates. The second link, emissions-air quality relationships, was addressed using both empirical analyses as well as chemical transport modeling employing the Community Multiscale Air Quality (CMAQ) model. Kolmogorov-Zurbenko filtering accounting for day of the year was used to separate the air quality signal into long-term, seasonal, weekday-holiday, and short-term meteorological signals. Regression modeling was then used to link emissions and meteorology to ambient concentrations for each of the species examined (ozone [O<sub3</sub], particulate matter ≤ 2.5 μm in aerodynamic diameter [PM<sub2.5</sub], nitrogen dioxide [NO<sub2</sub], sulfur dioxide [SO<sub2</sub], carbon monoxide [CO], sulfate [SO<sub4</sub<sup-2</sup], nitrate [NO<sub3</sub<sup-</sup], ammonium [NH<sub4</sub<sup+</sup], organic carbon [OC], and elemental carbon [EC]). CMAQ modeling was likewise used to link emissions changes to air quality changes, as well as to further establish the relative roles of meteorology versus emissions change impacts on air quality trends. CMAQ and empirical modeling were used to investigate aerosol acidity trends, employing the ISORROPIA II thermodynamic equilibrium model to calculate pH based on aerosol composition. The relationships between emissions and meteorology were then used to construct estimated counterfactual air quality time series of daily pollutant concentrations that would have occurred in the absence of the regulations. Uncertainties in counterfactual air quality were captured by the construction of 5,000 pollutant time series using a Monte Carlo sampling technique, accounting for uncertainties in emissions and model parameters. Health impacts of the regulatory actions were assessed using data on cardiorespiratory emergency department (ED) visits, using patient-level data in the Atlanta area for the 1999-2013 period. Four outcome groups were chosen based on previous studies identifying associations with ambient air pollution: a combined respiratory disease (RD) category; the subgroup of RD presenting with asthma; a combined cardiovascular disease (CVD) category; and the subgroup of CVD presenting with congestive heart failure (CHF). Models were fit to estimate the joint effects of multiple pollutants on ED visits in a time-series framework, using Poisson generalized linear models accounting for overdispersion, with a priori model formulations for temporal and meteorological covariates and lag structures. Several parameterizations were considered for the joint-effects models, including different sets of pollutants and models with nonlinear pollutant terms and first-order interactions among pollutants. Use of different periods for parameter estimates was assessed, as associations between pollutant levels and ED visits varied over the study period. A 7-pollutant, nonlinear model with pollutant interaction terms was chosen as the baseline model and fitted using pollutant and outcome data from 1999-2005 before regulations might have substantially changed the toxicity of pollutant mixtures. In separate analyses, these models were fitted using pollutant and outcome data from the entire 1999-2013 study period. Daily counterfactual time series of pollutant concentrations were then input into the health models, and the differences between the observed and counterfactual concentrations were used to estimate the impacts of the regulations on daily counts of ED visits. To account for the uncertainty in both the estimation of the counterfactual time series of ambient pollutant levels and the estimation of the health model parameters, we simulated 5,000 sets of parameter estimates using a multivariate normal distribution based on the observed variance-covariance matrix, allowing for uncertainty at each step of the chain of accountability. Sensitivity tests were conducted to assess the robustness of the results. EGU NO<subx</sub and SO<sub2</sub emissions in the Southeast decreased by 82% and 83%, respectively, between 1999 and 2013, while mobile-source emissions controls led to estimated decreases in Atlanta-area pollutant emissions of between 61% and 93%, depending on pollutant. While EGU emissions were measured, mobile-source emissions were modeled. Our results are supportive of a potential high bias in mobile-source NO<subx</sub and CO emissions estimates. Air quality benefits from regulatory actions have increased as programs have been fully implemented and have had varying impacts over different seasons. In a scenario that accounted for all emissions reductions across the period, observed Atlanta central monitoring site maximum daily 8-hour (MDA8h) O<sub3</sub was estimated to have been reduced by controls in the summertime and increased in the wintertime, with a change in mean annual MDA8h O<sub3</sub from 39.7 ppb (counterfactual) to 38.4 ppb (observed). PM<sub2.5</sub reductions were observed year-round, with average 2013 values at 8.9 μg/m<sup3</sup (observed) versus 19.1 μg/m<sup3</sup (counterfactual). Empirical and CMAQ analyses found that long-term meteorological trends across the Southeast over the period examined played little role in the distribution of species concentrations, while emissions changes explained the decreases observed. Aerosol pH, which plays a key role in aerosol formation and dynamics and may have health implications, was typically very low (on the order of 1-2, but sometimes much lower), with little trend over time despite the stringent SO<sub2</sub controls and SO<sub4</sub<sup2<sup-</sup</sup reductions. Using health models fit from 1999-2005, emissions reductions from all selected pollution-control policies led to an estimated 55,794 cardiorespiratory disease ED visits prevented (i.e., fewer observed ED visits than would have been expected under counterfactual scenarios) - 52,717 RD visits, of which 38,038 were for asthma, and 3,057 CVD visits, of which 2,104 were for CHF - among the residents of the 5-county area over the 1999-2013 period, an area with approximately 3.5 million people in 2013. During the final two years of the study (2012-2013), when pollution-control policies were most fully implemented and the associated benefits realized, these policies were estimated to prevent 5.9% of the RD ED visits that would have occurred in the absence of the policies (95% interval estimate: -0.4% to 12.3%); 16.5% of the asthma ED visits (95% interval estimate: 7.5% to 25.1%); 2.3% of the CVD ED visits (95% interval estimate: -1.8% to 6.2%); and -.6% of the CHF ED visits (95% interval estimate: 26.3% to 10.4%). Estimates of ED visits prevented were generally lower when using health models fit for the entire 1999-2013 study period. Sensitivity analyses were conducted to show the impact of the choice of parameterization of the health models and to assess alternative definitions of the study area. When impacts were assessed for separate policy interventions, policies affecting emissions from EGUs, especially the ARP and the NBP, appeared to have had the greatest effect on prevention of RD and asthma ED visits. This study demonstrates the effectiveness of regulations on improving air quality and health in the southeastern United States. It also demonstrates the complexities of accountability assessments as uncertainties are introduced in each step of the classic accountability process. While accounting for uncertainties in emissions, air quality-emissions relationships, and health models does lead to relatively large uncertainties in the estimated outcomes due to specific regulations, overall the benefits of regulations have been substantial.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. 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[structure: see text] o-Nitrotoluene is used to synthesize agricultural and rubber chemicals, azo and sulfur dyes, and dyes for cotton, wool, silk, leather, and paper. o-Nitrotoluene was nominated for study by NIOSH and the NTP based on its considerable human exposure as well as the absence of long-term studies of carcinogenicity in rodents. Male and female F344/N rats and B6C3F1 mice were exposed to o-nitrotoluene (greater than 99% pure) in feed for 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, rat and mouse bone marrow cells, and mouse peripheral blood erythrocytes. 2-YEAR STUDY IN RATS: In the core study, groups of 60 male and 60 female rats were fed diets containing 625, 1,250, or 2,000 ppm o-nitrotoluene (equivalent to average daily doses of approximately 25, 50, or 90 mg o-nitrotoluene/kg body weight to males and 30, 60, or 100 mg/kg to females) for 105 weeks. In a 3-month stop-exposure study, groups of 70 male rats were fed diets containing 2,000 or 5,000 ppm o-nitrotoluene (equivalent to average daily doses of approximately 125 or 315 mg/kg) for 13 weeks followed by undosed feed for the remainder of the study. A group of 70 male rats receiving undosed feed served as a control group for both male rat studies; 60 female rats receiving undosed feed were the control group for the female core study. Ten control males and 10 males from each stop-exposure group were sacrificed at 3 months. Survival, Body Weights, and Feed Consumption: All 2,000 ppm core study, all 5,000 ppm stop-exposure, and all but three core study 1,250 ppm male rats died before the end of the studies. Survival of 625 ppm core study and 2,000 ppm stop-exposure males and of 2,000 ppm females was significantly less than that of the controls. Mean body weights of all exposed groups of males except the 625 ppm group were generally less than those of the controls throughout the study. Mean body weights of 2,000 ppm females were less than those of the controls during year 2 of the study. Feed consumption by exposed groups of rats was similar to that by the controls. Biomarkers of Exposure: Three urinary metabolites were followed during the study as biomarkers of exposure. The ratios of o-nitrobenzoic acid to creatinine and of o-nitrobenzylmercapturic acid to creatinine determined at 2 weeks and at 3, 12, and 18 months were linearly related to exposure concentration in males and females. The ratio of o-aminobenzoic acid to creatinine was not related to exposure concentration. Pathology Findings: The incidences of malignant mesothelioma in male rats occurred with positive trends in both the core and stop-exposure studies and were significantly greater in exposed groups than in the controls. Incidences of subcutaneous skin neoplasms (fibroma, fibrosarcoma, and lipoma) were increased in exposed groups of males, while the incidences of fibroma or fibrosarcoma (combined) were increased in exposed females. In all exposed groups of males and females except 2,000 ppm core study males, the incidences of mammary gland fibroadenoma were significantly increased. The incidences of mammary gland hyperplasia were significantly increased in 625 and 1,250 ppm females. Increased incidences of mesothelioma, skin neoplasms, and mammary gland fibroadenoma in the stop-exposure males indicated that 3 months of dosing were sufficient to produce a carcinogenic effect. Liver weights of 5,000 ppm stop-exposure males were significantly greater than those of the controls at 3 months. The incidences of hepatocellular adenoma in 2,000 ppm core study males and females and of hepatocellular adenoma or carcinoma (combined) in 2,000 ppm core study and 5,000 ppm stop-exposure males were significantly increased. Cholangiocarcinoma occurred in three 5,000 ppm stop-exposure males, and a single hepatocholangiocarcinoma occurred in a 625 ppm male and in a 2,000 ppm core study male. Nonneoplastic lesions of the liver included eosinophilic, mixed cell, and clear cell foci in exposed groups of males and females and mixed cell infiltrate in exposed males and basophilic focus in exposed females. The incidences of alveolar/bronchiolar adenoma and alveolar/bronchiolar adenoma or carcinoma (combined) were significantly increased in 5,000 ppm stop-exposure males, as were alveolar/bronchiolar hyperplasia in most exposed groups of males and females. The incidences of hematopoietic cell proliferation of the spleen and of hyperplasia of the mandibular lymph node (females) and bone marrow were increased in exposed groups of males at 3 months and/or 2 years and in exposed groups of females at 2 years. The incidences of mononuclear cell leukemia were significantly decreased in all groups of males exposed to 1,250 ppm or greater and in all exposed groups of females; the incidence of testicular interstitial cell adenoma was significantly decreased in 5,000 ppm stop-exposure males. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were fed diets containing 0, 1,250, 2,500, or 5,000 ppm o-nitrotoluene (equivalent to average daily doses of approximately 165, 360, or 700 mg/kg to males and 150, 320, or 710 mg/kg to females) for 105 weeks. Survival, Body Weights, and Feed Consumption: All 2,500 and 5,000 ppm males died before the end of the study. Survival of 1,250 ppm males and 5,000 ppm females was significantly less than that of the controls. Mean body weights of exposed males and 5,000 ppm females were generally less than those of the controls throughout the study, and those of 2,500 ppm females were less during the second year of the study. Feed consumption by 5,000 ppm males was less than that by the controls. Biomarkers of Exposure: Three urinary metabolites were followed during the study as biomarkers of exposure. The ratios of o-nitrobenzoic acid to creatinine determined at 2 weeks and at 3, 12, and 18 months were linearly related to exposure concentration in males and females. The concentrations of o-nitrobenzylmercapturic acid and o-aminobenzoic acid were below the limit of quantitation at most time points. Pathology Findings: The incidences of hemangiosarcoma in all exposed groups of males and in 5,000 ppm females were significantly greater than those in the controls. Large intestine (cecum) carcinomas were observed in all exposed groups except 5,000 ppm males. The incidences of hepatocellular neoplasms were significantly increased in 2,500 and 5,000 ppm females. Nonneoplastic liver lesions including eosinophilic and basophilic foci and minimal to mild necrosis were enhanced in exposed males and females. Also present were focal hepatocyte syncytial alteration in exposed males and hepatocyte necrosis and focal hepatocyte cytoplasmic vacuolization in 5,000 ppm females. Renal tubule pigmentation occurred more frequently in exposed groups of males and in 5,000 ppm females than in the controls. Olfactory epithelial degeneration occurred in every male and female mouse exposed to 2,500 or 5,000 ppm, and the severity of this lesion increased with increasing exposure concentration. o-Nitrotoluene was not mutagenic in any of several strains of S. typhimurium, with or without metabolic activation enzymes (S9). Sister chromatid exchanges were significantly increased in cultured Chinese hamster ovary cells following exposure to o-nitrotoluene in the presence of S9; an equivocal response was seen without S9. o-Nitrotoluene did not induce chromosomal aberrations in cultured Chinese hamster ovary cells, with or without S9. o-Nitrotoluene did not induce a significant increase in the frequency of micronuclei in bone marrow polychromatic erythrocytes of male rats or male mice when administered by intraperitoneal injection. Results of a peripheral blood micronucleus test were equivocal for male mice and negative for female mice administered o-nitrotoluene in feed for 13 weeks. Under the conditions of these studies, there was clear evidence of carcinogenic activity* of o-nitrotoluene in male rats based on increased incidences of malignant mesothelioma, subcutaneous skin neoplasms, mammary gland fibroadenoma, and liver neoplasms. The increased incidences of lung neoplasms in male rats were also considered to be exposure related. There was clear evidence of carcinogenic activity of o-nitrotoluene in female rats based on increased incidences of subcutaneous skin neoplasms and mammary gland fibroadenoma. The increased incidence of hepatocellular adenoma in female rats was also considered to be exposure related. There was clear evidence of carcinogenic activity of -o-nitrotoluene in male and female mice based on increased incidences of hemangiosarcoma, carcinoma of the large intestine (cecum), and hepatocellular neoplasms (females only). Exposure to o--nitrotoluene caused increased incidences of nonneoplastic lesions of the mammary gland (females only), liver, bone marrow, spleen, lung, and mandibular lymph node (females only) in male and female rats and of the liver, kidney, and nose in male and female mice. Decreased incidences of mononuclear cell leukemia occurred in exposed groups of rats; the incidence of testicular interstitial cell adenoma was decreased in exposed male rats. [tables: see text]	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The Ontario Health Technology Advisory Committee asked the Medical Advisory Secretariat (MAS) to conduct a health technology assessment on energy delivery systems for the treatment of benign prostatic hyperplasia (BPH). TARGET POPULATION AND CONDITION BPH is a noncancerous enlargement of the prostate gland and the most common benign tumour in aging men. (1) It is the most common cause of lower urinary tract symptoms (LUTS) and bladder outlet obstruction (BOO) and is an important cause of diminished quality of life among aging men. (2) The primary goal in the management of BPH for most patients is a subjective improvement in urinary symptoms and quality of life. Until the 1930s, open prostatectomy, though invasive, was the most effective form of surgical treatment for BPH. Today, the benchmark surgical treatment for BPH is transurethral resection of the prostate (TURP), which produces significant changes of all subjective and objective outcome parameters. Complications after TURP include hemorrhage during or after the procedure, which often necessitates blood transfusion; transurethral resection (TUR) syndrome; urinary incontinence; bladder neck stricture; and sexual dysfunction. A retrospective review of 4,031 TURP procedures performed by one surgeon between 1979 and 2003 showed that the incidence of complications was 2.4% for blood transfusion, 0.3% for TUR syndrome, 1.5% for hemostatic procedures, 2.8% for bladder neck contracture, and 1% for urinary stricture. However, the incidence of blood transfusion and TUR syndrome decreased as the surgeon's skills improved. During the 1990s, a variety of endoscopic techniques using a range of energy sources have been developed as alternative treatments for BPH. These techniques include the use of light amplification by stimulated emission of radiation (laser), radiofrequency, microwave, and ultrasound, to heat prostate tissue and cause coagulation or vaporization. In addition, new electrosurgical techniques that use higher amounts of energy to cut, coagulate, and vaporize prostatic tissue have entered the market as competitors to TURP. The driving force behind these new treatment modalities is the potential of producing good hemostasis, thereby reducing catheterization time and length of hospital stay. Some have the potential to be used in an office environment and performed under local anesthesia. Therefore, these new procedures have the potential to rival TURP if their effectiveness is proven over the long term. The following energy-based techniques were considered for assessment: transurethral electrovaporization of the prostate (TUVP)transurethral electrovapor resection of the prostate (TUVRP)transurethral electrovaporization of the prostate using bipolar energy (plasmakinetic vaporization of the prostate [PKVP])visual laser ablation of the prostate (VLAP)transurethral ultrasound guided laser incision prostatectomy (TULIP)contact laser vaporization of the prostate (CLV)interstitial laser coagulation (ILC)holmium laser resection of the prostate (HoLRP)holmium laser enucleation of the prostate (HoLEP)holmium laser ablation of the prostate (HoLAP)potassium titanyl phosphate (KTP) lasertransurethral microwave thermotherapy (TUMT)transurethral needle ablation (TUNA) REVIEW STRATEGY: A search of electronic databases (OVID MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library, and the International Agency for Health Technology Assessment [INAHTA] database) was undertaken to identify evidence published from January 1, 2000 to June 21, 2006. The search was limited to English-language articles and human studies. The literature search identified 284 citations, of which 38 randomized controlled trials (RCTs) met the inclusion criteria. Since the application of high-power (80 W) KTP laser (photoselective vaporization of the prostate [PVP]) has been supported in the United States and has resulted in a rapid diffusion of this technology in the absence of any RCTs, the MAS decided that any comparative studies on PVP should be identified and evaluated. Hence, the literature was searched and one prospective cohort study (3) was identified but evaluated separately. Meta-analysis of the results of RCTs shows that monopolar electrovaporization is as clinically effective as TURP for the relief of urinary symptoms caused by BPH (based on 5-year follow-up data). Meta-analysis of the results of RCTs shows that bipolar electrovaporization (PKVP) is clinically as effective as TURP for the relief of urinary symptoms caused by BPH (based on 1-year follow-up data). Two of the three RCTs on VLAP have shown that patients undergoing VLAP had a significantly lesser improvement in urinary symptom scores compared with patients undergoing TURP.RCTs showed that the time to catheter removal was significantly longer in patients undergoing VLAP compared with patients undergoing TURP.Meta-analysis of the rate of reoperation showed that patients undergoing VLAP had a significantly higher rate of reoperation compared with patients undergoing TURP.Meta-analysis showed that patients undergoing CLV had a significantly lesser improvement in urinary symptom scores compared with TURP at 2 years and at 3 or more years of follow-up.Two RCTs with 6-month and 2-year follow-up showed similar improvement in symptom scores for ILC and TURP.Time to catheter removal was significantly longer in patients undergoing ILC compared with patients undergoing TURP.The results of RCTs on HoLEP with 1-year follow-up showed excellent clinical outcomes with regard to the urinary symptom score and peak urinary flow.Meta-analysis showed that at 1-year follow-up, patients undergoing HoLEP had a significantly greater improvement in urinary symptom scores and peak flow rate compared with patients undergoing TURP.Procedural time is significantly longer in HoLEP compared with TURP.The results of one RCT with 4-year follow-up showed that HoLRP and TURP provided equivalent improvement in urinary symptom scores.The results of one RCT with 1-year follow-up showed that patients undergoing KTP had a lesser improvement in urinary symptom scores than did patients undergoing TURP. However, the results were not significant at longer-term follow-up periods.Two RCTs that provided 3-year follow-up data reported that patients undergoing TUMT had a significantly lesser improvement in symptom score compared with patients undergoing TURP.RCTs reported a longer duration of catheterization for TUMT compared with TURP (P values are not reported).The results of a large RCT with 5-year follow-up showed a significantly lesser improvement in symptom scores in patients undergoing TUNA compared with patients undergoing TURP.Meta-analysis of the rate of reoperation showed that patients undergoing TUNA had a significantly higher rate of reoperation compared with patients undergoing TURP.Based on the results of RCTs, TURP is associated with a 0.5% risk of TUR syndrome, while no cases of TUR syndrome have been reported in patients undergoing monopolar or bipolar electrovaporization, laser-based procedures, TUMT, or TUNA.Based on the results of RCTs, the rate of blood transfusion ranges from 0% to 8.3% in patients undergoing TURP. The rate is about 1.7% in monopolar electrovaporization, 1.4% in bipolar electrovaporization, and 0.4% in the VLAP procedure. No patients undergoing CLV, ILC, HoLEP, HoLRP, KTP, TUMT, and TUNA required blood transfusion.The mean length of hospital stay is between 2 and 5 days for patients undergoing TURP, about 3 days for electrovaporization, about 2 to 4 days for Nd:YAG laser procedures, and about 1 to 2 days for holmium laser procedures. TUMT and TUNA can each be performed as a day procedure in an outpatient setting (0.5 and 1 day respectively).Based on a prospective cohort study, PVP is clinically as effective as TURP for the relief of urinary symptoms caused by BPH (based on 6-month follow-up data). Time to catheter removal was significantly shorter in patients undergoing PVP than in those undergoing TURP. Operating room time was significantly longer in PVP than in TURP. PVP has the potential to reduce health care expenses due to shorter hospital stays. In the three most recent fiscal years (FY) reported, an average of approximately 5,000 TURP procedures per year were performed in Ontario. From FY 2002 to FY 2004, the total number of surgical interventions decreased by approximately 500 procedures. During this time, the increase in costs of drugs to the government was estimated at approximately $10 million (Cdn); however, there was a concurrent decrease in costs due to a decline in the total number of surgical procedures, estimated at approximately $1.9 million (Cdn). From FY 2002 to FY 2004, the increase in costs associated with the increase in utilization of drugs for the treatment of BPH translates into $353 (Cdn) per patient while the cost savings associated with a decrease in the total number of surgical procedures translates into a savings of $3,906 (Cdn) per patient. The following table summarizes the change in the current budget, depending on various estimates of the total percentage of the 5,000 TURP procedures that might be replaced by other energy-based interventions for the treatment of BPH in the future. Executive Summary Table 1:Budget Impact With Various Estimates of the Percentage of TURP Procedures Captured by Energy-based Interventions for the Treatment of BPHTechnologyCost perprocedure, $Budget Impact of 25% diffusion, $MBudget Impact of 50% diffusion, $MBudget Impact of 75% diffusion, $MBudget Impact of 100% diffusion, $MIncremental Budget Impact, $MTURP3,88719.4Bipolar Electrovaporization4,01119.619.719.920.00.6Monopolar Electrovaporization4,13019.720.020.320.61.2TUMT1,52916.513.510.67.6(11.8) TUNA4,80420.621.722.924.04.6PVP1,18416.012.79.35. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. 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In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry's newly released Diabetes Strategy.After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,DIABETES STRATEGY EVIDENCE PLATFORM: Summary of Evidence-Based AnalysesContinuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis BARIATRIC SURGERY FOR PEOPLE WITH DIABETES AND MORBID OBESITY: An Evidence-Based Summary Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario The objective of this report is to determine whether behavioural interventions are effective in improving glycemic control in adults with type 2 diabetes. Diabetes is a serious chronic condition affecting millions of people worldwide and is the sixth leading cause of death in Canada. In 2005, an estimated 8.8% of Ontario's population had diabetes, representing more than 816,000 Ontarians. The direct health care cost of diabetes was $1.76 billion in the year 2000 and is projected to rise to a total cost of $3.14 billion by 2016. Much of this cost arises from the serious long-term complications associated with the disease including: coronary heart disease, stroke, adult blindness, limb amputations and kidney disease. Type 2 diabetes accounts for 90-95% of diabetes and while type 2 diabetes is more prevalent in people aged 40 years and older, prevalence in younger populations is increasing due to a rise in obesity and physical inactivity in children. Data from the United Kingdom Prospective Diabetes Study (UKPDS) has shown that tight glycemic control can significantly reduce the risk of developing serious complications in type 2 diabetics. Despite physicians' and patients' knowledge of the importance of glycemic control, Canadian data has shown that only 38% of patients with diabetes have HbA1C levels in the optimal range of 7% or less. This statistic highlights the complexities involved in the management of diabetes, which is characterized by extensive patient involvement in addition to the support provided by physicians. An enormous demand is, therefore, placed on patients to self-manage the physical, emotional and psychological aspects of living with a chronic illness. Despite differences in individual needs to cope with diabetes, there is general agreement for the necessity of supportive programs for patient self-management. While traditional programs were didactic models with the goal of improving patients' knowledge of their disease, current models focus on behavioural approaches aimed at providing patients with the skills and strategies required to promote and change their behaviour. Several meta-analyses and systematic reviews have demonstrated improved health outcomes with self-management support programs in type 2 diabetics. They have all, however, either looked at a specific component of self-management support programs (i.e. self-management education) or have been conducted in specific populations. Most reviews are also qualitative and do not clearly define the interventions of interest, making findings difficult to interpret. Moreover, heterogeneity in the interventions has led to conflicting evidence on the components of effective programs. There is thus much uncertainty regarding the optimal design and delivery of these programs by policymakers. EVIDENCE-BASED ANALYSIS OF EFFECTIVENESS: Are behavioural interventions effective in improving glycemic control in adults with type 2 diabetes?Is the effectiveness of the intervention impacted by intervention characteristics (e.g. delivery of intervention, length of intervention, mode of instruction, interventionist etc.)? English Language Published between January 1996 to August 2008 Type 2 diabetic adult population (>18 years)Randomized controlled trials (RCTs)Systematic reviews, or meta-analyses Describing a multi-faceted self-management support intervention as defined by the 2007 Self-Management Mapping Guide (1)Reporting outcomes of glycemic control (HbA1c) with extractable data Studies with a minimum of 6-month follow up Studies with a control group other than usual care Studies with a sample size <30 Studies without a clearly defined intervention glycemic control (HbA1c) systolic blood pressure (SBP) control, lipid control, change in smoking status, weight change, quality of life, knowledge, self-efficacy, managing psychosocial aspects of diabetes, assessing dissatisfaction and readiness to change, and setting and achieving diabetes goals. A search was performed in OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1996 and August 2008. Abstracts were reviewed by a single author and studies meeting the inclusion criteria outlined above were obtained. Data on population characteristics, glycemic control outcomes, and study design were extracted. Reference lists were also checked for relevant studies. The quality of the evidence was assessed as being either high, moderate, low, or very low according to the GRADE methodology. The search identified 638 citations published between 1996 and August 2008, of which 12 met the inclusion criteria and one was a meta-analysis (Gary et al. 2003). The remaining 11 studies were RCTs (9 were used in the meta-analysis) and only one was defined as small (total sample size N=47). SUMMARY OF PARTICIPANT DEMOGRAPHICS ACROSS STUDIES: A total of 2,549 participants were included in the 11 identified studies. The mean age of participants reported was approximately 58 years and the mean duration of diabetes was approximately 6 years. Most studies reported gender with a mean percentage of females of approximately 67%. Of the eleven studies, two focused only on women and four included only Hispanic individuals. All studies evaluated type 2 diabetes patients exclusively. STUDY CHARACTERISTICS: The studies were conducted between 2002 and 2008. Approximately six of 11 studies were carried out within the USA, with the remaining studies conducted in the UK, Sweden, and Israel (sample size ranged from 47 to 824 participants). The quality of the studies ranged from moderate to low with four of the studies being of moderate quality and the remaining seven of low quality (based on the Consort Checklist). Differences in quality were mainly due to methodological issues such as inadequate description of randomization, sample size calculation allocation concealment, blinding and uncertainty of the use of intention-to-treat (ITT) analysis. Patients were recruited from several settings: six studies from primary or general medical practices, three studies from the community (e.g. via advertisements), and two from outpatient diabetes clinics. A usual care control group was reported in nine of 11 of the studies and two studies reported some type of minimal diabetes care in addition to usual care for the control group. INTERVENTION CHARACTERISTICS: All of the interventions examined in the studies were mapped to the 2007 Self-management Mapping Guide. The interventions most often focused on problem solving, goal setting and encouraging participants to engage in activities that protect and promote health (e.g. modifying behaviour, change in diet, and increase physical activity). All of the studies examined comprehensive interventions targeted at least two self-care topics (e.g. diet, physical activity, blood glucose monitoring, foot care, etc.). Despite the homogeneity in the aims of the interventions, there was substantial clinical heterogeneity in other intervention characteristics such as duration, intensity, setting, mode of delivery (group vs. individual), interventionist, and outcomes of interest (discussed below). DURATION, INTENSITY AND MODE OF DELIVERY: Intervention durations ranged from 2 days to 1 year, with many falling into the range of 6 to 10 weeks. The rest of the interventions fell into categories of ≤ 2 weeks (2 studies), 6 months (2 studies), or 1 year (3 studies). Intensity of the interventions varied widely from 6 hours over 2 days, to 52 hours over 1 year; however, the majority consisted of interventions of 6 to 15 hours. Both individual and group sessions were used to deliver interventions. Group counselling was used in five studies as a mode of instruction, three studies used both individual and group sessions, and one study used individual sessions as its sole mode of instruction. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
1,2-Dihydro-2,2,4-trimethylquinoline (monomer) is used as an antioxidant in styrene-butadiene and nitrile-butadiene rubbers and latexes. It was nominated by the National Cancer Institute as part of a review of chemicals used in the manufacture and processing of rubber, during which potential occupational and consumer exposure to this compound can occur. It was selected for evaluation because it is a derivative of quinoline, a known rodent carcinogen, and was regarded as having potential carcinogenic activity. Because of the pattern of use and exposure, dermal administration was considered most appropriate. Male and female F344/N rats and B6C3F1 mice received topical applications of 1,2-dihydro-2,2,4-trimethylquinoline in acetone (greater than 90% pure) for 13 weeks or 2 years. Groups of female SENCAR mice received 1,2-dihydro-2,2,4-trimethylquinoline (greater than 90% pure) during a 1-year dermal initiation/promotion study to determine the tumor initiation or promotion potential of the chemical. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood cells. 13-WEEK STUDY IN RATS: Groups of 10 male and 10 female F344/N rats were topically administered 0, 5, 20, 50, 100, or 200 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 13 weeks. In addition, there were 10 male and 10 female untreated controls. All rats survived to the end of the study. Final mean body weights and mean body weight gains of treated male and female rats were similar to those of the vehicle controls except those of 200 mg/kg males, which were significantly lower than those of the vehicle controls. The only notable clinical observation was skin discoloration of treated rats. In the 200 mg/kg groups, absolute and relative liver weights of males and absolute liver weights of females were significantly greater than those of the vehicle controls. There were no significant differences in hematology or clinical chemistry parameters, reproductive tissue parameters, or estrous cycle characterization between treated and control groups. Histopathologic lesions of the skin at the site of application included acanthosis and hyperkeratosis in 100 and 200 mg/kg males and 200 mg/kg females. Cytoplasmic vacuolization of hepatocytes of mild to moderate severity was observed in the livers of all 200 mg/kg males and was considered treatment related. Based on the incidence and severity of skin and liver lesions observed in 200 mg/kg rats in the 13-week study, 100 mg/kg was selected as the high dose for the 2-year rat study. 13-WEEK STUDY IN MICE: Groups of 10 male and 10 female B6C3F1 mice were topically administered 0, 2.5, 5, 10, 20, or 50 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 13 weeks. In addition, there were 10 male and 10 female untreated controls. All mice except one 2.5 mg/kg female survived to the end of the study. Final mean body weights and mean body weight gains of male and female mice were similar to those of the vehicle controls. There were no treatment-related clinical observations. There were no significant differences between treated and control groups in organ weights, hematology and clinical chemistry parameters, reproductive tissue parameters, or estrous cycle characterization. Histopathologic lesions of the skin at the site of application included acanthosis (epidermal hyperplasia), hyperkeratosis, and parakeratosis, all ranging from minimal to mild in severity. Minimal to mild fibrosis and subchronic inflammation were observed in the dermis. Based on the incidences and severities of skin lesions observed in 20 and 50 mg/kg mice in the 13-week study, 10 mg/kg was selected as the high dose for the 2-year mouse study. 2-YEAR STUDY IN RATS: Groups of 60 male and 60 female F344/N rats were topically administered 0, 36, 60, or 100 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 103 (males) or 104 (females) weeks. Ten rats per group were evaluated after 15 moed after 15 months of treatment. Survival and Body Weights Survival of treated rats was similar to that of controls. Mean body weights of 60 mg/kg males and 100 mg/kg males and females were slightly lower than those of the controls after week 21. Mean body weights of 36 mg/kg males and females and 60 mg/kg females were generally similar to those of the controls throughout the study. Pathology Findings: No skin neoplasms were attributed to treatment with 1,2-dihydro-2,2,4-trimethylquinoline. Several nonneoplastic skin lesions were determined to be treatment related. Incidences of acanthosis at the site of application in all treated groups of males and in 100 mg/kg females at the 15-month interim evaluation were significantly greater than those in the controls. At the end of the 2-year study, incidences of acanthosis at the site of application in 60 and 100 mg/kg males and females and hyperkeratosis at the site of application in 60 mg/kg females were significantly greater than those in the controls. Absolute and relative right kidney weights of 60 and 100 mg/kg male rats were significantly greater than those of the controls at the 15-month interim evaluation. Incidences of renal tubule adenoma and adenoma or carcinoma (combined) in all treated groups of males were significantly greater than those in the controls. These incidences exceeded the range from the historical controls in 2-year NTP feed studies. An extended (step section) evaluation of the kidneys of male rats did not reveal an additional increase in neoplastic response because additional adenomas and hyperplasias were observed in the controls as well as in treated groups. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female B6C3F1 mice were topically administered 0, 3.6, 6, or 10 mg 1,2-dihydro-2,2,4-trimethylquinoline/kg body weight in acetone, 5 days per week for 103 (males) or 104 (females) weeks. Nine or ten mice per group were evaluated after 15 months of treatment. Survival and Body Weights: Survival of treated mice was similar to that of controls. Mean body weights of treated male and female mice were similar to those of the controls throughout the study. Pathology Findings: No neoplasms or nonneoplastic lesions were attributed to treatment with 1,2-dihydro-2,2,4-trimethylquinoline. 1-YEAR INITIATION/PROMOTION STUDY IN FEMALE SENCAR MICE: Groups of 30 female SENCAR mice were topically administered varying initiation/promotion treatments as outlined in the table below. Survival, Body Weights, and Clinical Findings: Survival in all treated groups was similar to that of the respective controls, except in the 2.5 mg 7,12-dimethylbenz(a)anthracene (DMBA)/0.5 mg 12-O-tetradecanoylphorbol-13-acetate (TPA) group in which survival was significantly lower than that of the controls. Mean body weights of all treated groups were similar to those of the respective controls throughout the study. No clinical observations were associated with 1,2-dihydro-2,2,4-trimethylquinoline treatment; however, mice promoted with TPA showed signs of irritation and papilloma at the site of application. Pathology Findings: Initiation and promotion with acetone alone was not associated with any skin lesions at the site of application. The incidences of acanthosis and chronic inflammation were increased in all groups promoted with TPA regardless of the initiator treatment; however, the incidences of nonneoplastic lesions were low in all other groups. Incidences of squamous cell papillomas and squamous cell carcinomas were markedly increased in the DMBA/TPA positive control group; however, no response was observed in groups initiated with DMBA and promoted with 5, 10, or 25 mg/kg 1,2-dihydro-2,2,4-trimethylquinoline or in the group initiated with 1,2-dihydro-2,2,4-trimethylquinoline and promoted with TPA. GENETIC TOXICOLOGY: 1,2-Dihydro-2,2,4-trimethylquinoline was not mutagenic in any of several strains of Salmonella typhimurium, with or without S9 metabolic activation. 1,2-Dihydro-2,2,4-trimethylquinoline induced sister chromatid exchanges in cultured Chinese hamster ovary cells in the absence of S9, but not in the presence of S9. However, no increase in the frequency of chromosomal aberrations was observed in cultured Chinese hamster ovary cells treated with 1,2-dihydro-2,2,4-trimethylquinoline, with or without S9. No increase in the frequency of micronucleated erythrocytes was noted in peripheral blood of male or female mice exposed topically to 1,2-dihydro-2,2,4-trimethylquinoline for 13 weeks. CONCLUSIONS: Under the conditions of these 2-year dermal studies, there was some evidence of carcinogenic activity of 1,2-dihydro-2,2,4-trimethylquinoline in male F344/N rats, based on increased incidences of renal tubule adenoma and adenoma or carcinoma (combined). There was no evidence of carcinogenic activity of 1,2-dihydro-2,2,4-trimethylquinoline in female F344/N rats receiving 36, 60, or 100 mg/kg, or in male or female B6C3F1 mice receiving 3.6, 6, or 10 mg/kg. Exposure of rats to 1,2-dihydro-2,2,4-trimethylquinoline by dermal application in acetone for 2 years resulted in acanthosis in males and females and hyperkeratosis in females at the site of application. No nonneoplastic lesions in male or female mice were attributed to treatment with 1,2-dihydro-2,2,4-trimethylquinoline. Synonyms: 2,2,4-Trimethyl-1,2-dihydroquinoline; acetone anil; methylquinoline Trade names: Agerite Resin D; Flectol A; Flectol H; Flectol Pastilles; Vulkanox HS/LG; Vulkanox HS/Powder	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
One advantage of advanced computer technology is the high throughput with which the retinal and the choroidal circulation can be evaluated from new aspects. To study the choroidal circulation, we first reevaluated indocyanine green video angiography to improve the visualization of indocyanine green (ICG) images, then applied computer technology to analyze images obtained by an ICG video camera system. We also developed a new instrument to measure oxygen saturation levels in the fundus using spectral retinal imaging technology. I. Choroidal circulation. 1. Reevaluation of ICG video camera system: For this purpose, the bio-chemical nature of ICG was studied. 1) Spectral absorption of ICG: The peak absorption of ICG in distilled water was 780 nm as measured with a spectrophotometer. Its maximum absorption shifted from 780 nm to 805 nm after gradually mixing ICG with human serum protein. Conjugation time of ICG as well as fluorescein sodium with human serum protein was then measured by a stopped flowmeter. It was found that fluorescein sodium conjugated with human serum protein within a few milliseconds, while ICG required more than 600 seconds before equilibrium of the binding was reached. From these observations, we developed a new ICG video system with dual light sources; one, a 780 nm diode laser for the early dye filling phase, and the other, a 805 nm diode laser for the later phase of ICG angiography. 2) Binding properties of ICG in human blood: Blood samples were obtained from three healthy volunteers after intravenous administration of ICG. The resulting plasma samples were fractionated by agarose gel immunoelectrophoresis and polyacrylamide gel DISC electrophoresis. The electrophoretic pattern obtained by each method was observed with an ICG fundus video system. We also studied the affinity of ICG for lipids that are common molecular components of lipoproteins such as high-density lipoprotein (HDL) and low-density lipoprotein (LDL). Four kinds of ICG solutions mixed with phospholipid, free cholesterol, esterified cholesterol, and triacrylglycerol were observed with the ICG fundus video system. Both electrophoretic studies showed that ICG bound intensely to HDL and moderately to LDL, and only the solution with phospholipid fluoresced brightly when observed with the ICG fundus video system. 2. Residual fundus ICG fluorescence: Residual fundus fluorescence observed in the late phase of ICG angiography may be delineated differently in normal subjects and in patients with age-related macular degeneration (ARMD). We performed ICG angiography on 8 normal subjects aged below 36 years (8 eyes), 9 normal subjects aged above 62 years (9 eyes), and 21 patients with ARMD aged 50 to 88 years (37 eyes). The intensity and pattern of fluorescence from angiograms obtained in the ultra-late phase, 24 hours after dye injection, was recorded and analyzed. In the ultra-late phase, 95% of ARMD eyes with choroidal neovascularization (CNV) showed geographic hypofluorescent lesions. These hypofluorescent lesions occurred in 73% of ARMD eyes without CN, while age-matched normal subjects had no hypofluorescent lesions. The mean intensity of fluorescence in the normal elder subject group was significantly higher than that seen in the normal younger subject group. These findings may reflect aging change and bio-distribution of lipid on the Bruch-RPE complex. 3. The early dye filling pattern of the choroid: We performed ICG angiography on 10 healthy young volunteers aged 22 to 26 years (23.4+/-1.3; mean+/-standard deviation) using an improved ICG video camera system. ICG (50 mg) dissolved in 2 ml in distilled water was injected through the antecubital vein. Although the choroidal dye filling varied among subjects, it always began in the macular area. In the 10 subjects, initial dye filling had two patterns: reticular (n=8) and flush (n=2). The choroidal circulation filled completely before the retinal circulation did. Bright fluorescence in the macula and fast blood flow may be correlated with ample blood volume and abundant blood vessels in the macular area. 4. The spreading pattern of ICG fluorescence in the choroid: The ICG images obtained for observing the early dye filling pattern of the choroid were further processed with a computer-assisted image analyzer. Subtracted images were made using the early ICG frames with a time interval of 0.12 second. Ninety frames of time-sequential images for 3 seconds starting from the initial dye appearance in the choroid were prepared to construct an animated image. In the initial phase of eye filling, patchy fluorescence appeared in the fovea. The fluorescence then spread centrifugally in all directions in a wave-like pulsatile manner towards the peripheral fundus with increasing brightness. Thus an animated video of subtracted images allowed us to evaluate flow dynamics at the level of the choriocapillaris. Using this new approach, pathogenic involvement of choroidal circulation in varied chorioretinal diseases such as central serous chorioretinopathy can be studied with precision. II. Retinal circulation. We developed a new device to study the oxygen saturation (OS) levels in a wider fundus area. We call this device a spectral retinal image (SRI) system. We are pursuing the possibility of this instrument being in clinics to evaluate chorioretinal diseases. 1. Introduction of the device: The instrument consists of a Sagnac interferometer that has been mounted on top of a fundus camera, and a software module which consists of an acquisition module and an analysis module. The image acquisition process takes 6 seconds during which the fundus is illuminated by the white incandescent light of the fundus camera at the regular power settings. OS values in each pixel of the fundus image with a 35-degree view can then be estimated from the respective spectrum that is obtained by Fourier-transforming the interferometer signals. Each OS value is represented by a specific color, and each pixel of the fundus image is painted accordingly. 2. Clinical applications. 1) Control study: OS levels of both retinal arteries and veins within a 1 disc diameter (DD) area around the disc were measured from 20 SRIs obtained from 10 healthy volunteers, and were 96.65+/-3.30% and 56.05+/-4.69%, respectively. Then 30 healthy volunteers were recruited for further study in which the OS values were calculated in five retinal regions: (1) juxta-papillary area within 1.75 DD, (2) fovea within 1.0 DD, (3) papillomacular region within 1.0 DD, (4) superior area of the posterior fundus within 1.0 DD, and (5) inferior posterior area of the posterior fundus within 1.0 DD. The OS level of the juxta-papillary area was the highest, while that of the fovea was the lowest and the other three posterior retinal regions were in the middle. Thus OS levels differed at various areas in the retina with statistical significance. In spite of abundant choroidal circulation in the fovea, the overlying retina may have a relative by low oxygen level. As the retinal pigment epithelium may be efficient enough to block the effect of the choroid optically, our results may indicate that the OS levels represent the OS of the retina. 2) Measurement of OS levels in eyes with retinal circulatory disturbances: Eleven eyes of 10 patients with central retinal vein occlusion (CRVO), which showed various degrees of severity, and 4 fellow unaffected eyes of selected patients were examined by both fluorescein angiography (FAG) and the new SRI system. The fluroescein angiograms were correlated with OS maps that were calculated from the SRI. OS grading demonstrated by OS maps correlated well with severity of CRVO, as estimated by FAG. Thus our SRI system is noninvasive with reproducible results, and may prove to be a useful clinical tool to evaluate the degree of retinal ischemia. 3) Measurement of OS levels in eyes with glaucoma: Forty-seven eyes with open angle glaucoma (OAG) of 47 patients and 21 eyes of 21 age-matched normal subjects were recuited for the study. Twelve eyes with low-tension glaucoma (LTG) were included in the OAG eyes and the rest of the OAG eyes had primary OAG. All patients and normal subjects were examined by SRI. Visual field tests for OAG eyes were done with a Humphrey Field Analyzer using the 30-2 program, Swedish interactive threshold argorithm (SITA). OS levels in the retina at 5 different points: superior, inferior, superio- and inferio-temporal, and nasal region within a juxta-papillary area of 200 microm in diameter were calculated from the SRI. OS levels of retinal arteries were also measured and there were no significant differences between OAG and the control group. OAG eyes showed reduced OS levels in the inferio-temporal retina with statistical significance. This observation was more prominent in LTG eyes. The reduced OS levels observed in OAG eyes correlated well with mean deviation (MD) and the sum of total deviation of the 17 points in corresponding areas in the visual field analysis.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The limited scientific knowledge on relationship between exposure and health effects in relation to geothermal activity motivated an epidemiologic investigation in Tuscan geothermal area. The study aims to describe the health status of populations living in Tuscany municipalities where concessions for exploitation of geothermal resources were granted. This is an ecological study, so it is not useful to produce evidence to sustain a judgment on the cause-effect link. The major limits of this type of study are the use of the residence at municipal level as a proxy of exposure to both environmental and socioeconomic factors and the use of aggregated data of health outcomes that can lead to the well-known ecological fallacy. Sixteen municipalities were included in the study area: eight are part of the so-called "traditional" geothermal area, defined as Northern Geothermal Area (NGA) and eight located in the Amiata Mountain defined as Southern Geothermal Area (SGA). In 2000-2006, the average resident population in the overall area was approximately 43,000 inhabitants. Thirty-one geothermal power plants were active, with a production capacity of 811 MW, 5 of them with 88 MW located in the SGA. Statistical analyses on the entire geothermal area, NGA and SGA subareas, and the sixteen municipalities were performed. Mortality data were obtained from Tuscany Regional Mortality Registry for the 1971-2006 period, analysing 60 causes of death, of interest for population health status or consistent with "Project SENTIERI" criteria. Hospital discharge records of residents in Tuscany Region in 2004-2006, anywhere admitted to hospital, were analyzed considering only the main diagnosis, excluding repeated admissions for the same cause. The causes taken into account are the same analysed for mortality were considered. Age-standardized mortality rates (TSDM) and the temporal trends of TSDM for four periods (1971-1979, 1980-1989, 1990-1999, 2000-2006) were computed. Age-standardized mortality/hospitalization ratios (SMR/SHR), with and without adjustment for the deprivation index based on 2001 census data, were calculated: mortality in the years 2000-2006 and hospitalization in 2004-2006. The expected number of events were computed using rates of residents in neighbouring municipalities (municipalities included in 50 km radius circle centred on the study area). Bayesian estimates of mortality/hospitalization ratios (BMR/BHR) at municipal level only and relating maps of the Bayesian risk estimators were elaborated. Congenital malformations (MC) were analysed using data from Tuscan Registry of Birth Defect in 1992-2006 period, relative to outcomes of pregnancies in women resident in the municipalities of study area, wherever the birth or termination of pregnancy occurred. The ratio between observed and expected cases (O/A), with expected defined according to regional rate, were calculated and O/A Bayesian estimates (BMR) are showed only at municipal level. The low weight and the males/females ratio at birth were analysed using data from Tuscany Birth Certificates, covering period 2001-2007, excluding births occurred in facilities outside Tuscany Region. For Low birth weight (< 2,500 grams), very low birth weight (< 1,500 grams), low birth weight in women with normal gestational age or greater than 36 weeks, gestational age less than 36 weeks, and the frequency of males, the observed/expected ratio was calculated, with the expected number defined according to regional rate. ENVIRONMENTAL BACKGROUND: High levels of arsenic in drinking water distribution emerges as a critical element, so that several municipalities resorted to granting exemptions for the parameters laid down by the Legislative Decree in force (D.Lgs 31/01). However, during the final phase of the study, new blast systems activated in the SGA decreased the arsenic levels in the water supply, reaching values not requiring derogations, which, instead, are still effective in some NGA municipalities. Air quality data, from Tuscany Regional Agency for Environmental Protection-ARPAT, show that geothermal activities are able to affect air quality, especially with hydrogen sulphide in NGA, and hydrogen sulphide and mercury in SGA. A significant contribution to the presence of mercury in air is due to previous metallurgical sites. Although mercury levels are below WHO guideline values, in SGA nearby Siena, values were significantly higher than in other geothermal areas, because of power plant PC2 (turned off in July 2011) in Piancastagnaio municipality. The hydrogen sulphide concentration levels were generally lower than WHO reference values, with occasional excesses over guideline value for health protection (150 µg/m3 as average of the 24 hours). Olfactory pollution was more critic with values exceeding 7-10 µg/m3 range even in areas without geothermal plants. POPULATION'S HEALTH STATUS: This study evaluated health status of resident population in geothermal areas analysing geographic and temporal distribution of mortality, hospitalization and reproductive health outcomes (congenital malformations, low birth weight, sex ratio among newborns). In both geothermal areas mortality rates steadily declined from 1971 to 2006, in males and females, in line with the regional trends. In 2000-2006 period, in the overall geothermal area a significant mortality excess was observed for all causes among males (2,312 deaths, 2,146 expected), but not among females, using as reference residents in neighbouring municipalities. The mortality excess among males was more evident for infectious diseases (25 deaths, 10 expected), especially tuberculosis (8 deaths, 2 expected), for respiratory diseases (218 deaths, 170 expected), in particular pneumoconiosis, including deaths from silicosis (51 deaths, 14 expected), and for nervous system diseases (72 deaths, 56 expected). Among females significant mortality excess for liver cirrhosis (35 deaths, 25 expected) emerged, while mortality from cardiovascular diseases and ischemic heart diseases were significantly lower than expected. In the NGA, mortality among men was lower than expected for all cancers (-15%), in particular for lung cancer (- 25%), while values significantly in excesses were observed for infectious diseases (11 observed, 4 expected) and respiratory diseases (90 observed, 73 expected), expecially pneumoconiosis (20 observed, 6 expected). Among females, significant mortality excesses for ovarian cancer (17 observed, 10 expected) and for circulatory disorders of brain (170 observed, 140 expected) resulted. In the SGA, mortality was more critical, accounting for majority of the excesses detected in overall Geothermal Area. In fact, only infectious diseases and pneumoconiosis were detected in excess in both the geothermal areas. In the SGA, excess of general mortality among males (1,431 deaths; 1,245 expected) but not among females emerged. Even for all cancers, an excess among males (505 deaths, 419 expected) was observed, in particular for cancer of stomach (53 deaths, 44 expected, not statistically significant after adjusting for DI), liver (39 deaths, 23 expected) and lung (124 deaths, 102 expected) cancer. Mortality in SGA was also in excess for respiratory diseases only among men (128 deaths, 97 expected), mostly due to silicosis (31 deaths, 8 expected), although steadily decreasing since 1971 as observed at regional level. Also tuberculosis resulted in excess in SGA (7 deaths, 1 expected). Among females acute respiratory disease mortality was significantly in excess (41 observed, 29 expected). Temporal trend showed a decline from the 70s to the 90s, with a rising trend in recent years in line with Tuscany region. It should be considered that pneumonia was the commonest cause of death of acute respiratory diseases, which allow for lower reliability of death certificate, especially among the elderly (> 64 years). Among females resident in SGA a mortality excess from digestive system diseases was observed (72 observed, 55 expected). The hospitalization in the overall Geothermal Area did not show any excess for all causes and all tumours in both genders. Statistically significant excesses for hospital admission from stomach cancer among males (49 observed, 38 expected) and females (42 observed, 28 expected), and from lymphohematopoietic tumours among females, particularly from lymphatic leukaemia (15 observed, 5 expected), were observed. As mortality analysis highlighted, also hospital admissions by geothermal areas and gender showed a worst picture in SGA than in NGA. In the latter, a significant excess of hospital admissions from all causes among females (1,357 observed, 1,284 expected) but not among males (1,193 observed, 1,141 expected) and an excess - close to statistical significance - from all tumours only among females (297 observed; 272 expected) were observed. Furthermore, statistically significant excesses of hospital admissions from digestive system diseases in both genders (M: 392 observed, 350 expected; F: 300 observed, 268 expected), from dementias (16 observed, 8 expected) and from lympho hematopoietic cancers among females, particularly from lymphatic leukaemia (9 observed, 2 expected), were observed. In the SGA, statistically significant excesses of hospital admissions for stomach cancer (M: 32 observed, 21 expected, not significant after adjusting by DI; F: 29 observed, 18 expected), for respiratory diseases (M: 408 observed, 351 expected; F: 339 observed, 277 expected) and for renal failure (M: 61 observed, 41 expected; F: 52 observed, 34 expected) were observed in both genders. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Cellulose insulation (CI) is a type of thermal insulation produced primarily from recycled newspapers. The newspapers are shredded, milled, and treated with fire-retardant chemicals. The blowing process for installing CI generates a significant quantity of airborne material that presents a potential inhalation hazard to workers. CI was selected for study based upon the high production volume, the potential for widespread human exposure, and a lack of toxicity data; insufficient information was available to determine whether inhalation studies in laboratory animals were technically feasible or necessary. Studies were conducted to characterize the chemical and physical properties of CI aerosols, to evaluate the potential acute pulmonary toxicity of CI, and to assess occupational exposure of CI installers. Workplace exposure assessments were conducted in collaboration with the National Institute for Occupational Safety and Health (NIOSH, 2001). Chemical analyses were performed on samples of bulk CI from four major United States manufacturers. All samples of the bulk CI were found to contain primarily amorphous cellulose (60% to 65%) with a smaller crystalline component (35% to 40%). The crystalline phase was primarily native cellulose (75% to 85%) with a minor amount of cellulose nitrate (15% to 25%). Elemental analyses of acid digests of CI materials indicated that the major components (>0.1% by weight) included aluminum, boron, calcium, sodium, and sulfur. An acid-insoluble residue present in all four materials (3% to 5% of original sample weight) was found to consist primarily of aluminum silicate hydroxide (kaolinite; approximately 85%) with minor amounts (<5% each) of magnesium silicate hydroxide (talc), potassium aluminum silicate hydroxide (muscovite), and titanium oxide (rutile). Solvent extracts of the bulk materials were analyzed for organic components by gas chromatography with flame ionization detection. Analyses revealed a mass of poorly resolved peaks. Because of the very low concentrations, further quantitative and qualitative analyses were not performed. An aerosol generation system was designed to separate CI particles based upon aerodynamic size and to simulate the process used during CI installation at work sites. Less than 0.1% of each of the CI samples was collected as the small respirable particle fraction. The mean equivalent diameter of respirable particles ranged from 0.6 to 0.7 mum. The numbers of fibers in the respirable fractions ranged from 9.7 x 103 to 1.4 x 106 fibers/g of CI. The respirable particle fractions did not contain cellulose material and consisted mainly of fire retardants and small quantities of clays. The respirable fraction from one CI sample was administered by intratracheal instillation to male Fischer 344 rats at doses of 0, 0.625, 1.25, 2.5, 5, or 10 mg/kg body weight; the bronchoalveolar lavage (BAL) fluid cellularity was evaluated 3 days later. Based upon the relatively mild severity of the inflammatory response, a dose of 5 mg/kg body weight was selected for use in a subsequent 28-day study. Rats received CI, titanium dioxide (particle controls), or sterile saline (controls). BAL fluid was evaluated 1, 3, 7, 14, and 28 days after instillation, and lung histopathology was evaluated 14 and 28 days after treatment. CI caused a greater influx of inflammatory cells than titanium dioxide and caused significant increases in BAL fluid protein and lactate dehydrogenase. These CI-induced changes in BAL fluid parameters were transient and by day 14 were not significantly different than those observed in rats treated with titanium dioxide or phosphate-buffered saline. Unlike titanium dioxide, CI treatment caused a minimal to mild nonprogressive, minimally fibrosing granulomatous pneumonitis characterized by nodular foci of macrophages and giant cells. These results indicated that few respirable particles or fibers are likely generated during the CI application and that the acute pulmonary toxicity is minimal. The CI exposure assessment was conducted with 10 contractors located across the United States. Air samples of total dust and respirable dust were collected for scanning electron microscopy (SEM) to characterize any fibers in the dust. Two SEM air samples for each day of CI activities were collected from the installer and hopper operator. Bulk CI samples were collected and analyzed for metal, boron, and sulfate content. Real-time and video exposure monitoring was conducted to further characterize the CI dust and workers' exposures. The exposure assessment also included a medical component. Investigators collected 175 personal breathing zone (PBZ) total dust, 106 area total dust, and 90 area respirable dust air samples during CI-related activities at the 10 contractor sites. Twenty-six employees' total dust 8-hour time-weighted averages (TWAs) exceeded the Occupational Safety and Health Administration (OSHA) permissible exposure limit (PEL) of 15 mg/m3, and 42 exceeded the American Conference of Governmental Industrial Hygienists (ACGIH) threshold-limit value (TLV) of 10 mg/m3. Respirable dust air sampling and real-time monitoring with particle size discrimination indicated low levels of respirable dust generation. The SEM analyses revealed that fibers were an average 28 mum in length and ranged from 5 mum to 150 mum. CI installers' PBZ total dust, area total dust, and area respirable dust air samples were all significantly higher during dry attic applications than wet attic applications (P<0.01). Conversely, the hopper operators' total dust exposures were significantly higher during wet wall and ceiling applications than dry wall and ceiling applications (P=0.02). Analyses of variance tests revealed that exposure concentrations in total dust air samples collected in the PBZ of all CI workers, including installers working in attics, installers during wall applications, hopper operators during attic applications, and hopper operators during wall and ceiling applications, varied significantly during dry applications (P<0.01). The respirable dust air samples collected in attic areas, hopper areas during attic applications, and hopper areas during wall and ceiling applications also differed significantly during dry applications (P=0.03). Twenty-three workers participated in the medical phase of the investigation. The workers completed medical and work history questionnaires, performed serial peak flow tests, and completed multiple acute symptom surveys. The medical questionnaires indicated respiratory, nasal, and skin symptoms that employees attributed to CI exposure. The most common symptoms reported while working with CI included nasal symptoms (35%), eye symptoms (35%), and morning phlegm production (25%). There was a temporal association between CI exposure and eye symptoms, but there was little evidence of lower respiratory system health conditions associated with CI exposure. Chemical analyses of the four bulk CI samples revealed only minor differences in additives. The major elemental components detected were aluminum, boron, calcium, sodium, and sulfur, but they were attributed to the fire retardants aluminum sulfate, boric acid, and sodium sulfate. For all four CI samples, less than 0.1% by weight was collected as the small respirable particle fraction. The fractions consisted mainly of fire retardants and smaller quantities of clays and did not contain cellulose material. Intratracheal instillation of the respirable fraction in rats produced minimal to mild inflammatory responses in the lungs with no increase in severity by 28 days after dosage. Although a significant increase in lung collagen was detected at day 28 in treated rats, microscopic evaluation revealed only a minimal to mild increase in collagen fibrils associated with granulomatous nodules. The results of these studies indicated that few respirable particles or fibers are generated during the aerosolization of CI, and that even at very high doses of respirable CI particles, acute pulmonary toxicity is minimal. These results are supported by the NIOSH workplace exposure assessment conducted on CI workers. Based on the air sample data collected from the 10 contractor site visits, there is a potential for overexposure to CI; however, respirable dust concentrations were typically low. There was increased potential for 8-hour TWAs exceeding the OSHA PEL for total and respirable dust when employees were involved in CI application activities for longer periods of time. There was evidence of work-related eye and mucous membrane irritation among some workers, which were possibly caused by the additives present in CI, such as boric acid. There was little evidence of lower respiratory system health conditions associated with CI exposure. Based upon the results of the CI chemical characterization studies, the pulmonary toxicity study, and the worksite exposure assessment, the NTP concluded that additional studies of CI in laboratory animals are not warranted at this time. However, the animal pulmonary toxicity studies and worker health surveys focused on acute CI exposures and do not preclude the possibility of toxicity resulting from chronic exposure. Although exposure concentrations of respirable CI particulate matter were low, additional information is needed on the biodurability and reactivity of CI particles and fibers in the respiratory tract. CI should continue to be regarded as a nuisance dust, and workers should continue to wear protective masks to prevent inhalation exposure to CI dusts.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
This overview of the Luciolinae addresses the fauna of S. E. Asia including India, Sri Lanka, China, Japan, Malaysia, Thailand, Laos, Cambodia, Vietnam, Indonesia, the Philippines, the Republic of Palau, Federated States of Micronesia, and the Australopacific area of Australia, Papua New Guinea, Solomon Islands, New Caledonia, Vanuatu and Fiji.Of the 28 genera now recognised in the Luciolinae we address 27 genera from the study area as defined above, including three new genera which are described herein, and 222 species including 13 species newly described herein. Photuroluciola Pic from Madagascar is the only Luciolinae genus not addressed here. A key to genera is presented. Keys to species are either included here or referenced in existing literature. Twelve genera have had no new taxonomic decisions made nor are any new species records listed, and are addressed in an abbreviated fashion, with short diagnoses and plates of features of life stages: Aquatica Fu et al. 2010, Australoluciola Ballantyne 2013, Convexa Ballantyne 2009, Emeia Fu et al. 2012a, Inflata Boontop 2015, Lloydiella Ballantyne 2009, Missimia Ballantyne 2009, Pteroptyx Olivier 1902, Pyrophanes Olivier 1885, Sclerotia Ballantyne 2016, Triangulara Pimpasalee 2016, and Trisinuata Ballantyne 2013. Abscondita Ballantyne 2013 contains 8 species, and includes new records for Abs. anceyi (Olivier 1883), Abs. chinensis (L.) (which is newly synonymised with Luciola succincta Bourgeois), Abs. terminalis (Olivier 1883) including a first record from both Laos and Thailand, and Abs. perplexa (Walker 1858). Luciola pallescens Gorham 1880 is transferred to Abscondita and the pronotal colour range is addressed from a wide range of localities. Abs. berembun Nada sp. nov. and Abs. jerangau Nada sp. nov. are described from Malaysia. Hooked bursa plates are described for pallescens and berembun. Aquilonia Ballantyne 2009 is expanded to include 3 species. Gilvainsula Ballantyne 2009, represented by two species from the south eastern coast of New Guinea is synonymised under Aquilonia Ballantyne 2009, which is briefly redescribed and keyed from: Aquil. costata (Lea) from northern Australia, including many new records, Aquil. messoria (Ballantyne) comb. nov. and Aquil. similismessoria (Ballantyne) comb. nov. Asymmetricata Ballantyne 2009 now includes 4 species. As. bicoloripes (Pic 1927) comb. nov. and As. humeralis (Walker 1858) comb. nov. are transferred from Luciola, with L. doriae Olivier 1885, L. impressa Olivier 1910b and L. notatipennis Olivier 1909a newly synonymised with As. humeralis. Luciola aemula Olivier 1891 is synonymised with As. ovalis (Hope 1831). The variation in the extent of the anterior median emargination of the light organ in ventrite 7, and the possibility of a bipartite light organ in males of As. circumdata (Motsch. 1854) is explored. Females of both As. circumdata and As. ovalis (Hope 1831) are without bursa plates and the distinctively shaped median oviduct plate in each is described. Records from Thailand are recorded for both As. circumdata and As. ovalis. Atyphella Olliff 1890 now contains 28 species with 4 transferred from other genera, and one new species: Aty. abdominalis (Olivier 1886) comb. nov. and Aty. striata (Fabricius 1801) comb. nov. are transferred from Luciola, with Aty. carolinae Olivier 1911b and Aty. rennellia (Ballantyne 2009) comb. nov. transferred from Magnalata Ballantyne 2009. Atyphella telokdalam Ballantyne sp. nov. from Indonesia is described herein. Atyphella is now known from records in the Philippines and Indonesia as well as Australia and New Guinea. Colophotia Motschulsky 1853 is considered here from seven species for which intact types can be located for three. An abbreviated revision based on the United States National Museum collection only is presented, with specimens of C. bakeri Pic 1924, C. brevis Olivier 1903a, C. plagiata (Erichson 1834) and C. praeusta (Eschscholtz 1822) redescribed, using where possible features of males, females and larvae. Colophotia particulariventris Pic 1938 is newly synonymised with C. praeusta. Colophotia miranda Olivier 1886 and L. truncata Olivier 1886 are treated as species incertae sedis. Curtos Motschulsky 1845 includes 19 species with suggestions made, but not yet formalised, for the possible transfer of the following seven species from Luciola: Luciola complanata Gorham 1895, L. costata Pic 1929, L. delauneyi Bourgeois 1890, L. deplanata Pic 1929, L. extricans Walker 1858, L. multicostulata Pic 1927 and L. nigripes Gorham 1903. Curtos is not revised here. Emarginata Ballantyne gen nov. is described for E. trilucida (Jeng et al. 2003b) comb. nov., transferred from Luciola and characterised by the emarginated elytral apex. An extended range of specimens from Thailand is listed. Kuantana Ballantyne gen. nov. from Selangor, Malaysia is described from K. menayah gen. et sp. nov. having bipartite light organs in ventrite 7 and an asymmetrical tergite 8 which is not emarginated on its left side. Female has no bursa plates. Luciola Laporte 1833 s. stricto as defined by a population of the type species Luciola italica (L. 1767) from Pisa, Italy, is further expanded and considered to comprise the following19 species: L. antipodum (Bourgeois 1884), L. aquilaclara Ballantyne 2013, L. chapaensis Pic 1923 which is synonymised with L. atripes Pic 1929, L. curtithorax Pic 1928, L. filiformis Olivier 1913c, L. horni Bourgeois 1905, L. hypocrita Olivier 1888, L. italica (L. 1767), L. kagiana Matsumura 1928, L. oculofissa Ballantyne 2013, L. pallidipes Pic 1928 which is synonymised with L. fletcheri Pic 1935, L. parvula Kiesenwetter 1874, L. satoi Jeng Yang 2003, L. tuberculata Yiu 2017, and two species treated as near L. laticollis Gorham 1883, and near L. nicollieri Bugnion 1922. The following are described as new: L. niah Jusoh sp. nov., L. jengai Nada sp. nov. and L. tiomana Ballantyne sp. nov. Luciola niah sp. nov. female has two wide bursa plates on each side of the bursa. Luciola s. lato (as defined here) consists of 36 species. Twenty-seven species formerly standing under Luciola have been assigned to other genera or synonymised. Seven species are recommended for transfer to Curtos, and 32 species now stand under species incertae sedis. Magnalata Ballantyne is reduced to the type species M. limbata and redescribed. Medeopteryx Ballantyne 2013 is expanded to 20 species with the addition of two new combinations, Med. semimarginata (Olivier 1883) comb. nov. and Med. timida (Olivier 1883) comb. nov., both transferred from Luciola, and one new species, Med. fraseri Nada sp. nov. from Malaysia. The range of this genus now extends from Australia and the island of New Guinea to SE Asia. Medeopteryx semimarginata females have wide paired bursa plates. Pygoluciola Wittmer 1939 now includes 19 species with 5 new species: P. bangladeshi Ballantyne sp. nov., P. dunguna Nada 2018, P. matalangao Ballantyne sp. nov. (scored by the code name 'Jeng Matalanga' in Ballantyne Lambkin 2013), P. phupan Ballantyne sp. nov. and P. tamarat Jusoh sp. nov. Six species are transferred from Luciola: P. abscondita (Olivier 1891) comb. nov., P. ambita (Olivier 1896) comb. nov., P. calceata (Olivier 1905) comb. nov., P. insularis (Olivier 1883) comb. nov., P. nitescens (Olivier 1903b) comb. nov. and P. vitalisi (Pic 1934) comb. nov., and redescribed from males, and includes female reproductive anatomy for P. nitescens comb. nov. and P. dunguna, both of which have hooked bursa plates. Serratia Ballantyne gen. nov. is erected for S. subuyania gen. et sp. nov. and characterised by the serrate nature of certain antennal flagellar segments in the male. The following 37 species listed under species incertae sedis are further explored: Colophotia miranda Olivier 1886, Lampyris serraticornis Boisduval 1835, Luciola angusticollis Olivier 1886, L. antennalis Bourgeois 1905, L. antica (Boisduval 1835), L. apicalis (Eschscholtz 1822), L. aurantiaca Pic 1927, L. bicoloriceps Pic 1924, L. binhana Pic 1927, L. bourgeoisi Olivier 1895, L. dilatata Pic 1929, L. exigua (Gyllenhall 1817), L. exstincta Olivier 1886, L. fissicollis Fairmaire 1891, L. flava Pic 1929, L. flavescens (Boisduval 1835), L. fukiensis Pic 1955, L. immarginata Bourgeois 1890, L. incerta (Boisduval 1835), L. infuscata (Erichson 1834), L. intricata (Walker 1858), L. japonica (Thunberg 1784), L. klapperichi Pic 1955, L. lata Olivier 1883, L. limbalis Fairmaire 1889, L. marginipennis (Boisduval 1835), L. melancholica Olivier 1913a, L. robusticeps Pic 1928, L. ruficollis (Boisduval 1835), L. spectralis Gorham 1880, L. stigmaticollis Fairmaire 1887, L. tincticollis Gorham 1895, L. trivandrensis Raj 1947, L. truncata Olivier 1886, L. vittata (Laporte 1833) Pteroptyx atripennis Pic 1923 and P. curticollis Pic 1923. While phylogenetic analyses indicate their distinctiveness, no further taxonomic action is taken with Luciola cruciata Motschulsky 1854 and L. owadai Sâtô et Kimura 1994 from Japan given the importance of the former as a national icon. Analyses also indicate that Lampyroidea syriaca Costa 1875 belongs in Luciola s. str. A much wider taxonomic analysis of this genus including all the species is necessary before any further action can be taken.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Hydroquinone is used an antioxidant in the rubber industry and as a developing agent in photography. It is also an intermediate in the manufacture of rubber and food antioxidants and monomer inhibitors. Hydroquinone and products containing hydroquinone are used as depigmenting agents to lighten skin. NTP Toxicology and Carcinogenesis studies were conducted by administering hydroquinone (greater than 99% pure) in corn oil or water by gavage to groups of F344/N rats and B6C3F1 mice of each sex for 14 days, 13 weeks, or 2 years. Additionally, genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma cells, Chinese hamster ovary (CHO) cells, and Drosophila melanogaster. Preliminary 3-day dermal studies were conducted with rats and mice using sufficient hydroquinone in 95% ethanol to crystallize on the skin (4 or 40 mg per animal); conjugated metabolites of hydroquinone were detected in the urine. Fourteen-day dermal studies were conducted at doses up to 3,840 mg/kg for rats and 4,800 mg/kg for mice. No toxic effects were seen in the 3- or 14-day dermal studies. Therefore, in further evaluations of hydroquinone, the gavage route of administration was used. Results of Fourteen-Day and Thirteen-Week Studies: Fourteen-day gavage studies were conducted by administering hydroquinone in corn oil to rats at doses ranging from 63 to 1,000 mg/kg body weight and to mice at doses ranging from 31 to 500 mg/kg. All rats receiving 1,000 mg/kg and 1/5 male and 4/5 female rats receiving 500 mg/kg died before the end of the 14 days. Compound-related clinical signs in rats included tremors lasting up to 30 minutes after each dosing at 500 and 1,000 mg/kg. In the 14-day gavage studies with mice, 4/5 male mice and 5/5 female mice receiving 500 mg/kg and 3/5 males receiving 250 mg/kg died before the end of the studies. Tremors followed by convulsions were seen at 250 and 500 mg/kg. In the 13-week studies, doses for rats and mice ranged from 25 to 400 mg/kg. All rats receiving 400 mg/kg and 3/10 female rats receiving 200 mg/kg died before the end of the studies. The mean body weight at necropsy of male rats administered 100 or 200 mg/kg was about 8%-9% lower than that of vehicle controls. Mean body weights of vehicle control and dosed female rats at necropsy were similar. Tremors and convulsions were observed after dosing in most rats receiving 400 mg/kg and in several female rats receiving 200 mg/kg. Inflammation and/or epithelial hyperplasia (acanthosis) of the forestomach were seen in 4/10 male rats and 1/10 female rats receiving 200 mg/kg. Toxic nephropathy, characterized by tubular cell degeneration in the renal cortex, was seen in 7/10 male and 6/10 female rats receiving 200 mg/kg and in 1/10 females receiving 100 mg/kg. In the 13-week studies in mice, 8/10 males and 8/10 females receiving 400 mg/kg and 2/10 male mice receiving 200 mg/kg died early. Mean body weights of dosed and vehicle control mice at necropsy were similar. Liver weight to body weight ratios for dosed male mice were significantly greater than for vehicle controls. Ulceration, inflammation, or epithelial hyperplasia of the forestomach was found in 3/10 male and 2/10 female mice receiving 400 mg/kg and 1/10 females receiving 200 mg/kg. Based on these collective results, 2-year studies were conducted by administering 0, 25, or 50 mg/kg hydroquinone in deionized water by gavage to groups of 65 rats of each sex, 5 days per week. Groups of 65 mice of each sex were administered 0, 50, or 100 mg/kg on the same schedule. Ten rats and 10 mice from each group were killed after 15 months for an interim evaluation. Observations at Fifteen Months: In the rats killed at 15 months, the relative kidney weight for high dose male rats was greater than that for vehicle controls. The hematocrit value, hemoglobin concentration, and erythrocyte count for high dose female rats were decreased. Compound-related increased severity of nephropathy was observed in male rats. In mice killed at 15 months, the relative liver weights for high dose male and female mice were signif and female mice were significantly greater than those for vehicle controls. Lesions seen in the liver of male mice included increased syncytial cells and diffuse cytomegaly. Body Weights, Organ Weights, and Survival in the Two-Year Studies: Mean body weights of high dose male rats were 5&percnt;-13&percnt; lower than those of vehicle controls after week 73, and those of low dose male rats were 5&percnt;-9&percnt; lower than those of vehicle controls after week 89. Mean body weights of dosed female rats were similar to those of vehicle controls throughout the study. The relative kidney and liver weights for high dose male rats were higher than those for vehicle controls. Mean body weights of high dose male mice were 5&percnt;-8&percnt; lower than those of vehicle controls after week 93, and those of high dose female mice were 5&percnt;-14&percnt; lower after week 20. Relative liver weights were increased for dosed male and high dose female mice. No significant differences in survival were observed between any groups of rats or mice of either sex after 2 years (male rats: vehicle control, 27/55; low dose, 18/55; high dose, 18/55; female rats: 40/55; 27/55; 32/55; male mice: 33/55; 37/54; 36/55; female mice: 37/55; 39/55; 36/55). Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Nearly all male rats and most female rats in all vehicle control and dosed groups had nephropathy. The severity of this disease was judged to be greater in high dose male rats. Hyperplasia of the renal pelvic transitional epithelium and renal cortical cysts, changes observed with advanced renal disease, were increased in male rats. Renal tubular hyperplasia was seen in 2 high dose male rats, and renal tubular adenomas were seen in 4/55 low dose and 8/55 high dose male rats; none was seen in vehicle controls. Mononuclear cell leukemia in female rats occurred with a positive trend, and the incidences in the dosed groups were greater than that in the vehicle controls (vehicle control, 9/55; low dose, 15/55; high dose, 22/55). The historical incidence of leukemia in water gavage vehicle control female F344/N rats is 25&percnt; &plusmn; 15&percnt; and in untreated controls is 19&percnt; &plusmn; 7&percnt;. Compound-related lesions observed in the liver of high dose male mice included anisokaryosis (0/55; 2/54; 12/55), syncytial alteration (5/55; 3/54; 25/55), and basophilic foci (2/55; 5/54; 11/55). The incidences of hepatocellular adenomas were increased in dosed male mice (9/55; 21/54; 20/55), but these increases were offset by decreases in the incidences of hepatocellular carcinomas (13/55; 11/54; 7/55). The incidences of hepatocellular neoplasms, primarily adenomas, were increased in dosed female mice (3/55; 16/55; 13/55). Follicular cell hyperplasia of the thyroid gland was increased in dosed mice (male: 5/55; 15/53; 19/54; female: 13/55; 47/55; 45/55). Follicular cell adenomas were seen in 2/55 vehicle control, 1/53 low dose, and 2/54 high dose male mice and in 3/55 vehicle control, 5/55 low dose, and 6/55 high dose female mice, a follicular cell carcinoma was seen in a seventh high dose female mouse. The highest observed incidence of follicular cell adenomas or carcinomas(combined) in historical water gavage vehicle control female B6C3F1 mice is 3/48 (6&percnt;). Genetic Toxicology: Hydroquinone was not mutagenic in S. typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. It induced trifluorothymidine (Tft) resistance in mouse L5178Y/TK lymphoma cells in the presence or absence of metabolic activation. An equivocal response was obtained in tests for induction of sex-linked recessive lethal mutations in Drosophila administered hydroquinone by feeding. Hydroquinone induced sister chromatid exchanges (SCEs) in CHO cells both with or without exogenous metabolic activation and caused chromosomal aberrations in the presence of activation. Conclusions: Under the conditions of these 2-year gavage studies, there was some evidence of carcinogenic activity of hydroquinone for male F344/N rats, as shown by marked increases in tubular cell adenomas of the kidney. There was some evidence of carcinogenic activity of hydroquinone for female F344/N rats, as shown by increases in mononuclear cell leukemia. There was no evidence of carcinogenic activity of hydroquinone for male B6C3F1 mice administered 50 or 100 mg/kg in water by gavage. There was some evidence of carcinogenic activity of hydroquinone for female B6C3F1 mice, as shown by increases in hepatocellular neoplasms, mainly adenomas. Administration of hydroquinone was associated with thyroid follicular cell hyperplasia in both male and female mice and anisokaryosis, multinucleated hepatocytes, and basophilic foci of the liver in male mice. Synonyms: 1,4-benzenediol; p-benzenediol; benzohydroquinone; benzoquinol; 1,4-dihydroxybenzene; p-dihydroxybenzene; p-dioxobenzene; p-dioxybenzene; hydroquinol; hydroquinole; a-hydroquinone; p-hydroquinone; p-hydroxyphenol; quinol; b-quinol	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Private investment in biomedical research has increased over the last few decades. At most places it has been welcomed as the next best thing to technology itself. Much of the intellectual talent from academic institutions is getting absorbed in lucrative positions in industry. Applied research finds willing collaborators in venture capital funded industry, so a symbiotic growth is ensured for both.There are significant costs involved too. As academia interacts with industry, major areas of conflict of interest especially applicable to biomedical research have arisen. They are related to disputes over patents and royalty, hostile encounters between academia and industry, as also between public and private enterprise, legal tangles, research misconduct of various types, antagonistic press and patient-advocate lobbies and a general atmosphere in which commercial interest get precedence over patient welfare.Pharma image stinks because of a number of errors of omission and commission. A recent example is suppression of negative findings about Bayer's Trasylol (Aprotinin) and the marketing maneuvers of Eli Lilly's Xigris (rhAPC). Whenever there is a conflict between patient vulnerability and profit motives, pharma often tends to tilt towards the latter. Moreover there are documents that bring to light how companies frequently cross the line between patient welfare and profit seeking behaviour.A voluntary moratorium over pharma spending to pamper drug prescribers is necessary. A code of conduct adopted recently by OPPI in India to limit pharma company expenses over junkets and trinkets is a welcome step.Clinical practice guidelines (CPG) are considered important as they guide the diagnostic/therapeutic regimen of a large number of medical professionals and hospitals and provide recommendations on drugs, their dosages and criteria for selection. Along with clinical trials, they are another area of growing influence by the pharmaceutical industry. For example, in a relatively recent survey of 2002, it was found that about 60% of 192 authors of clinical practice guidelines reported they had financial connections with the companies whose drugs were under consideration. There is a strong case for making CPGs based not just on effectivity but cost effectivity. The various ramifications of this need to be spelt out. Work of bodies like the Appraisal of Guidelines Research and Evaluation (AGREE) Collaboration and Guidelines Advisory Committee (GAC) are also worth a close look.Even the actions of Foundations that work for disease amelioration have come under scrutiny. The process of setting up 'Best Practices' Guidelines for interactions between the pharmaceutical industry and clinicians has already begun and can have important consequences for patient care. Similarly, Good Publication Practice (GPP) for pharmaceutical companies have also been set up aimed at improving the behaviour of drug companies while reporting drug trialsThe rapidly increasing trend toward influence and control by industry has become a concern for many. It is of such importance that the Association of American Medical Colleges has issued two relatively new documents - one, in 2001, on how to deal with individual conflicts of interest; and the other, in 2002, on how to deal with institutional conflicts of interest in the conduct of clinical research. Academic Medical Centers (AMCs), as also medical education and research institutions at other places, have to adopt means that minimize their conflicts of interest.Both medical associations and research journal editors are getting concerned with individual and institutional conflicts of interest in the conduct of clinical research and documents are now available which address these issues. The 2001 ICMJE revision calls for full disclosure of the sponsor's role in research, as well as assurance that the investigators are independent of the sponsor, are fully accountable for the design and conduct of the trial, have independent access to all trial data and control all editorial and publication decisions. However the findings of a 2002 study suggest that academic institutions routinely participate in clinical research that does not adhere to ICMJE standards of accountability, access to data and control of publication.There is an inevitable slant to produce not necessarily useful but marketable products which ensure the profitability of industry and research grants outflow to academia. Industry supports new, not traditional, therapies, irrespective of what is effective. Whatever traditional therapy is supported is most probably because the company concerned has a product with a big stake there, which has remained a 'gold standard' or which that player thinks has still some 'juice' left.Industry sponsorship is mainly for potential medications, not for trying to determine whether there may be non-pharmacological interventions that may be equally good, if not better. In the paradigm shift towards biological psychiatry, the role of industry sponsorship is not overt but probably more pervasive than many have realised, or the right thinking may consider good, for the health of the branch in the long run.An issue of major concern is protection of the interests of research subjects. Patients agree to become research subjects not only for personal medical benefit but, as an extension, to benefit the rest of the patient population and also advance medical research.We all accept that industry profits have to be made, and investment in research and development by the pharma industry is massive. However, we must also accept there is a fundamental difference between marketing strategies for other entities and those for drugs.The ultimate barometer is patient welfare and no drug that compromises it can stand the test of time. So, how does it make even commercial sense in the long term to market substandard products? The greatest mistake long-term players in industry may make is try to adopt the shady techniques of the upstart new entrant. Secrecy of marketing/sales tactics, of the process of manufacture, of other strategies and plans of business expansion, of strategies to tackle competition are fine business tactics. But it is critical that secrecy as a tactic not extend to reporting of research findings, especially those contrary to one's product.Pharma has no option but to make a quality product, do comprehensive adverse reaction profiles, and market it only if it passes both tests.Why does pharma adopt questionable tactics? The reasons are essentially two:What with all the constraints, a drug comes to the pharmacy after huge investments. There are crippling overheads and infrastructure costs to be recovered. And there are massive profit margins to be maintained. If these were to be dependent only on genuine drug discoveries, that would be taking too great a risk.Industry players have to strike the right balance between profit making and credibility. In profit making, the marketing champions play their role. In credibility ratings, researchers and paid spokes-persons play their role. All is hunky dory till marketing is based on credibility. When there is nothing available to make for credibility, something is projected as one and marketing carried out, in the calculated hope that profits can accrue, since profit making must continue endlessly. That is what makes pharma adopt even questionable means to make profits.Essentially, there are four types of drugs. First, drugs that work and have minimal side-effects; second, drugs which work but have serious side-effects; third, drugs that do not work and have minimal side-effects; and fourth, drugs which work minimally but have serious side-effects. It is the second and fourth types that create major hassles for industry. Often, industry may try to project the fourth type as the second to escape censure.The major cat and mouse game being played by conscientious researchers is in exposing the third and fourth for what they are and not allowing industry to palm them off as the first and second type respectively. The other major game is in preventing the second type from being projected as the first. The third type are essentially harmless, so they attract censure all right and some merriment at the antics to market them. But they escape anything more than a light rap on the knuckles, except when they are projected as the first type.What is necessary for industry captains and long-term players is to realise:Their major propelling force can only be producing the first type. 2. They accept the second type only till they can lay their hands on the first. 3. The third type can be occasionally played around with to shore up profits, but never by projecting them as the first type. 4. The fourth type are the laggards, real threat to credibility and therefore do not deserve any market hype or promotion.In finding out why most pharma indulges in questionable tactics, we are lead to some interesting solutions to prevent such tactics with the least amount of hassles for all concerned, even as both profits and credibility are kept intact.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Dichloroacetic acid was nominated for study by the United States Environmental Protection Agency (EPA) and by the National Institute of Environmental Health Sciences because of its widespread occurrence in drinking water as a by-product of water disinfection using chlorination. It was also nominated because dichloroacetic acid is the most studied representative of the class of haloacetic acids and has been shown to cause liver tumors in both rats and mice. Haloacetic acids are second only to trihalomethanes as a family of disinfection by-products found in many drinking water supplies. Dichloroacetic acid is one of several disinfection by-products being evaluated to determine whether genetically modified mouse models can serve as a more rapid and cost-effective means of evaluating and ranking potential hazards of disinfection by-products. The NTP has explored the use of genetically altered mouse models as adjuncts to 2-year rodent cancer assays. These models may prove to be more rapid, use fewer animals, and provide some mechanistic insights into neoplastic responses. As part of the evaluation of new mouse cancer screening models, dichloroacetic acid was tested for potential toxicity and carcinogenicity in two relatively well-studied models, the Tg.AC hemizygous strain and the p53 haploinsufficient strain. Male and female Tg.AC hemizygous and p53 haploinsufficient mice were exposed to dichloroacetic acid in the drinking water (greater than 98% pure) for 26 or 39 weeks. Genetic toxicology studies were conducted in Salmonella typhimurium strains TA98, TA100, and TA1535 and in mouse peripheral blood erythrocytes. 26- AND 39-WEEK DERMAL STUDIES IN Tg.AC HEMIZYGOUS MICE Groups of 15 male and 15 female Tg.AC hemizygous mice were administered 0, 31.25, 125, or 500 mg dichloroacetic acid/kg body weight 5 days per week for 26 weeks with additional groups of 10 males and 10 females continued on treatment for 39 weeks. Survival of dosed males and females was similar to that of the vehicle control groups for both studies. Mean body weights of dosed males and females in the 26-week study were similar to those of the vehicle control groups. Mean body weights of dosed males in the 39-week study were similar to those of the vehicle control groups. Mean body weights of the 500 mg/kg females were greater than those of the vehicle controls in the 39-week study. The absolute liver weights were increased by greater than 50% compared to the vehicle controls for the 500 mg/kg males and females in both studies. At the site of application, the incidences of squamous cell papilloma were significantly increased in 500 mg/kg males and females at 39 weeks. In addition, one 125 mg/kg male, two 500 mg/kg males, and two 500 mg/kg females had squamous cell papillomas at 26 weeks. The incidences of epidermal hyperplasia and hyperkeratosis were significantly increased at the site of application in the 125 and 500 mg/kg males and females at 26 weeks. At 39 weeks, the incidence of epidermal hyperkeratosis was increased in the 31.25 mg/kg males, but in females, increased epidermal hyperkeratosis and hyperplasia occurred only in the 500 mg/kg group. There was a modest increase in pulmonary adenomas at 39 weeks that may have been related to the dichloroacetic acid exposure in males and females exposed to 125 or 500 mg/kg. In both studies, there was a dose-related increase in the mean severity of hepatocyte cytoplasmic vacuolization in males and females, and the incidence of nephropathy was increased in 500 mg/kg males. 26- AND 41-WEEK DRINKING WATER STUDIES IN Tg.AC HEMIZYGOUS MICE: Groups of 15 male and 15 female Tg.AC hemizygous mice were exposed to drinking water containing 0, 500, 1,000, or 2,000 mg/L dichloroacetic acid for 26 weeks with additional groups of 10 males and 10 females exposed for 41 weeks. The equivalent average daily doses were approximately 75, 145, and 235 mg dichloroacetic acid/kg body weight to males and approximately 100, 185, and 285 mg/kg to females. Survival of exposed males was similar in both studies. In the females, survival was decreased in the 26-week but not the 41-week study. While there was some variability, the mean body weights of mice exposed to dichloroacetic acid tended to be similar to those of the control groups. In the 41-week study, mean body weights of exposed males and females tended to be less than those of the control groups. Water consumption by males and females exposed to 1,000 and 2,000 mg/L was less than that by the controls throughout both studies. The incidences and/or severity of hepatocyte cytoplasmic vacuolization were increased in males and females in both studies. The incidence of pulmonary adenoma was increased in the male mice exposed to 1,000 mg/L dichloroacetic acid for 41 weeks. Two pulmonary adenomas were found in the 2,000 mg/L females at 41 weeks. At 26 weeks, a pulmonary carcinoma was found in one 1,000 mg/L male, one 500 mg/L female, and one 2,000 mg/L female. 26- AND 41-WEEK DRINKING WATER STUDIES IN p53 HAPLOINSUFFICIENT MICE: Groups of 15 male and 15 female p53 haploinsufficient mice were exposed to drinking water containing 0, 500, 1,000, or 2,000 mg/L dichloroacetic acid for 26 weeks with additional groups of 10 males and 10 females exposed for 41 weeks. The equivalent average daily doses were approximately 45, 80, and 145 mg/kg to males and approximately 75, 145, and 220 mg/kg to females. Survival of all exposed groups was similar to that of the control groups in both studies. Mean body weights of 1,000 and 2,000 mg/L males and females were generally less than those of the control groups throughout most of both studies; mean body weights of 500 mg/L males and females were less than those of the controls for much of the 41-week study. Water consumption by 1,000 and 2,000 mg/L males and females was less than that by the control groups throughout both studies. The incidences and/or severities of hepatocyte cytoplasmic vacuolization were increased in males in the 26-week study and females in both studies. Dichloroacetic acid was mutagenic in Salmonella typhimurium strains TA100 and TA1535 in tests conducted in the absence of S9 liver activation enzymes; no increase in mutations was observed in either strain in the presence of rat or hamster liver S9. Dichloroacetic acid was not mutagenic in S. typhimurium strain TA98 with or without S9. Dichloroacetic acid was also tested for micronucleus induction in peripheral blood erythrocytes of male and female Tg.AC hemizygous and p53 haploinsufficient mice treated by drinking water or dermal application for 26 weeks. No induction of micronuclei was seen in Tg.AC hemizygous mice treated by either route or in the p53 haploinsufficient mice, which were exposed only by the drinking water route. In another study, analysis of peripheral blood samples for frequency of micronucleated erythrocytes in male and female B6C3F1 mice exposed to dichloroacetic acid in drinking water for 3 months revealed no alteration in micronucleus frequencies in male mice; a small increase seen in females was judged to be equivocal. Under the conditions of these drinking water studies, there was no evidence of carcinogenic activity of dichloroacetic acid in male or female p53 haploinsufficient mice exposed to 0, 500, 1,000, or 2,000 mg/L for 26 or 41 weeks. The incidences and/or severities of cytoplasmic vacuolization of the hepatocyte were increased in males and females exposed to dichloroacetic acid for 26 or 41 weeks. Under the conditions of these dermal studies, there were increased incidences of squamous cell papillomas at the site of application in male and female Tg.AC hemizygous mice exposed to 500 mg/kg for 39 weeks. There were dose-related increased incidences of epidermal hyperkeratosis and hyperplasia at the site of application in both male and female mice exposed to dichloroacetic acid for 26 or 39 weeks. Under the conditions of these drinking water studies, there was an increase in the incidence of alveolar/bronchiolar adenoma in male Tg.AC hemizygous mice exposed to 1,000 mg/L for 41 weeks. There were a few bronchiolar/alveolar carcinomas in males and females exposed to dichloroacetic acid in the drinking water for 26 weeks and a few bronchiolar/alveolar adenomas in females exposed to dichloroacetic acid in the drinking water for 41 weeks. There were increased incidences and/or severities of cytoplasmic vacuolization of the hepatocyte in male and female Tg.AC hemizygous mice exposed to dichloroacetic acid in the drinking water study for 26 or 41 weeks. The marginally increased incidences of pulmonary adenomas and/or carcinomas compared to the unexposed groups found in both the dermal and drinking water studies at 39 or 41 weeks were considered to be related to dichloroacetic acid exposure.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Goldenseal root powder is used in folk medicine for the treatment of gastrointestinal disturbances, urinary disorders, hemorrhage, skin, mouth, and eye infections, and inflammation. The major alkaloids in goldenseal are berberine, hydrastine, and canadine. Goldenseal root powder was nominated for study by the National Institute of Environmental Health Sciences based on the potential for human exposure and the lack of carcinogenicity data, and because it is one of the most widely used herbs in the United States. Male and female F344/N rats and B6C3F1 mice were exposed to ground goldenseal root powder in feed for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, Escherichia coli, mouse bone marrow cells, and mouse peripheral blood erythrocytes. 2-WEEK STUDY IN RATS: Groups of five male and five female rats were fed diets containing 0, 1,560, 3,121, 6,250, 12,500, 25,000, or 50,000 ppm goldenseal root powder (equivalent to average daily doses of approximately 155, 315, 630, 1,190, 2,465, and 4,815 mg goldenseal root powder/kg body weight for males and 150, 290, 640, 1,240, 2,370, and 4,870 mg/kg for females) for 15 days. All rats survived to the end of the study. Mean body weights and feed consumption of all exposed groups of males and females were similar to those of the control groups throughout the study. Liver weights of males exposed to 6,250 ppm or greater and females exposed to 12,500 ppm or greater were significantly greater than those of the controls. Minimal to moderate hepatocellular hypertrophy occurred in three males and all females exposed to 25,000 ppm and in all 50,000 ppm males and females. 2-WEEK STUDY IN MICE: Groups of five male and five female mice were fed diets containing 0, 1,560, 3,121, 6,250, 12,500, 25,000, or 50,000 ppm goldenseal root powder (equivalent to average daily doses of approximately 380, 840, 1,760, 3,435, 6,700, and 15,170 mg/kg body weight for males and 330, 670, 1,240, 2,375, 4,760, and 8,475 mg/kg for females) for 15 days. All mice survived to the end of the study. Mean body weights and feed consumption of all exposed groups of males and females were similar to those of the control groups throughout the study. Significant increases in liver weights occurred in males exposed to 25,000 and 50,000 ppm and in females exposed to 50,000 ppm. Absolute and relative thymus weights of 12,500 and 50,000 ppm males were significantly decreased. Minimal hypertrophy of centrilobular hepatocytes occurred in all males and females exposed to 50,000 ppm. 3-MONTH STUDY IN RATS: Groups of 10 male and 10 female rats were fed diets containing 0, 3,121, 6,250, 12,500, 25,000, or 50,000 ppm goldenseal root powder (equivalent to average daily doses of approximately 255, 500, 1,000, 2,020, and 4,060 mg/kg for males and 260, 500, 1,030, 2,070, and 4,100 mg/kg for females) for 14 weeks. Additional groups of 10 male and 10 female clinical pathology study rats were given the same concentrations for 23 days. All rats survived to the end of the study. None of the body weights or mean body weight gains were significantly different from those of the controls. Feed consumption by exposed groups was generally similar to that by controls throughout the study. Liver weights were significantly increased in males exposed to 6,250 ppm or greater and in all exposed groups of females. The incidences of hepatocyte hypertrophy were significantly increased in the liver of males and females exposed to 12,500 ppm or greater; cytoplasmic vacuolization of hepatocytes occurred in all exposed males. 3-MONTH STUDY IN MICE: Groups of 10 male and 10 female mice were fed diets containing 0, 3,121, 6,250, 12,500, 25,000, or 50,000 ppm goldenseal root powder (equivalent to average daily doses of approximately 680, 1,360, 2,260, 5,370, and 10,550 mg/kg for males and 590, 1,250, 2,345, 4,790, and 10,740 mg/kg for females) for 14 weeks. All mice survived to the end of the study. Mean body weights of males exposed to 50,000 ppm and females exposed to 25,000 or 50,000 ppm were significantly less than those of the controls. Feed consumption by 3,121, 6,250, 12,500, 25,000, and 50,000 ppm males was similar to that by controls. Liver weights were significantly increased in males exposed to 12,500 ppm or greater and in females exposed to 25,000 or 50,000 ppm. The left epidydimal weight in male mice was significantly decreased relative to controls. The incidences of hepatocyte hypertrophy were significantly increased in males and females exposed to 12,500 ppm or greater. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were fed diets containing 0, 3,000, 9,000, or 25,000 ppm goldenseal root powder (equivalent to average daily doses of approximately 135, 400, and 1,175 mg/kg for males and 150, 470, and 1,340 mg/kg for females) for 105 to 106 weeks. Survival of 9,000 ppm females was significantly greater than that of the controls. Mean body weights of females exposed to 9,000 ppm were 6% less than those of the controls after week 37, and those of 25,000 ppm females were 6% less than those of the controls after week 8. Feed consumption by exposed groups of males and females was generally similar to that by the controls throughout the study. The incidences of hepatocellular adenoma were significantly increased in males and females exposed to 25,000 ppm, and the incidence of hepatocellular adenoma or carcinoma (combined) was significantly increased in 25,000 ppm males. All exposed groups of males and females had significantly increased incidences of hepatocyte hypertrophy. The incidences of hepatocyte degeneration were significantly increased in all exposed groups of males and in 9,000 and 25,000 ppm females. The incidences of eosinophilic focus were significantly increased in 9,000 and 25,000 ppm males and all exposed groups of females. The incidences of cardiomyopathy were significantly decreased in all exposed groups of males and in 25,000 ppm females. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were fed diets containing 0, 3,000, 9,000, or 25,000 ppm goldenseal root powder (equivalent to average daily doses of approximately 375, 1,120, and 3,275 mg/kg for males and 330, 1,000, and 2,875 mg/kg for females) for 105 to 106 weeks. Survival of 9,000 ppm females was significantly less than that of the controls. Mean body weights of females exposed to 25,000 ppm were 3% to 9% less than those of the controls after week 13, 6% less for weeks 14 to 52, and 5% less for weeks 53 to 101. Feed consumption by exposed groups of males and females was generally similar to that of the controls throughout the study. The incidences of hepatocellular adenoma occurred with a positive trend in males, and the incidences of multiple hepatocellular adenoma were significantly increased in 9,000 and 25,000 ppm males. The incidences of hepatoblastoma occurred with a positive trend in males with a marginal increase in the 25,000 ppm group. Significantly increased incidences of eosinophilic focus or mixed cell focus occurred in all exposed groups of males. Goldenseal root powder was not mutagenic in Salmonella typhimurium or Escherichia coli tester strains, with or without liver S9 metabolic activation enzymes. In addition, no increases in the frequencies of micronucleated erythrocytes were observed in peripheral blood samples from mice exposed to goldenseal root powder in feed for 3 months. Berberine chloride was also tested for mutagenicity in standard screening assays. No mutagenicity was observed in several tester strains of Salmonella typhimurium, with or without rat or hamster liver S9 metabolic activation enzymes. In an acute exposure assay, no increase in the frequency of micronucleated polychromatic erythrocytes was seen in bone marrow of male mice administered three intraperitoneal injections of berberine chloride at 24-hour intervals. Under the conditions of these 2-year feed studies, there was clear evidence of carcinogenic activity of goldenseal root powder in male F344/N rats based on the increased incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined). There was clear evidence of carcinogenic activity of goldenseal root powder in female F344/N rats based on the increased incidence of hepatocellular adenoma. There was some evidence of carcinogenic activity of goldenseal root powder in male B6C3F1 mice based on the increased incidences of hepatoblastoma and multiple hepatocellular adenoma. There was no evidence of carcinogenic activity of goldenseal root powder in female B6C3F1 mice exposed to 3,000, 9,000, or 25,000 ppm goldenseal root powder in feed for 2 years. Administration of goldenseal root powder resulted in increased incidences of nonneoplastic lesions in the liver of male and female rats and male mice.	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The objective of this analysis is to systematically review limbal stem cell transplantation (LSCT) for the treatment of patients with limbal stem cell deficiency (LSCD). This evidence-based analysis reviews LSCT as a primary treatment for nonpterygium LSCD conditions, and LSCT as an adjuvant therapy to excision for the treatment of pterygium. CONDITION AND TARGET POPULATION The outer surface of the eye is covered by 2 distinct cell layers: the corneal epithelial layer that overlies the cornea, and the conjunctival epithelial layer that overlies the sclera. These cell types are separated by a transitional zone known as the limbus. The corneal epithelial cells are renewed every 3 to 10 days by a population of stem cells located in the limbus. NONPTERYGIUM LIMBAL STEM CELL DEFICIENCY: When the limbal stem cells are depleted or destroyed, LSCD develops. In LSCD, the conjunctival epithelium migrates onto the cornea (a process called conjunctivalization), resulting in a thickened, irregular, unstable corneal surface that is prone to defects, ulceration, corneal scarring, vascularization, and opacity. Patients experience symptoms including severe irritation, discomfort, photophobia, tearing, blepharospasm, chronic inflammation and redness, and severely decreased vision. Depending on the degree of limbal stem cell loss, LSCD may be total (diffuse) or partial (local). In total LSCD, the limbal stem cell population is completed destroyed and conjunctival epithelium covers the entire cornea. In partial LSCD, some areas of the limbus are unharmed, and the corresponding areas on the cornea maintain phenotypically normal corneal epithelium. Confirmation of the presence of conjunctivalization is necessary for LSCD diagnosis as the other characteristics and symptoms are nonspecific and indicate a variety of diseases. The definitive test for LSCD is impression cytology, which detects the presence of conjunctival epithelium and its goblet cells on the cornea. However, in the opinion of a corneal expert, diagnosis is often based on clinical assessment, and in the expert's opinion, it is unclear whether impression cytology is more accurate and reliable than clinical assessment, especially for patients with severe LSCD. The incidence of LSCD is not well understood. A variety of underlying disorders are associated with LSCD including chemical or thermal injuries, ultraviolet and ionizing radiation, Stevens-Johnson syndrome, multiple surgeries or cryotherapies, contact lens wear, extensive microbial infection, advanced ocular cicatricial pemphigoid, and aniridia. In addition, some LSCD cases are idiopathic. These conditions are uncommon (e.g., the prevalence of aniridia ranges from 1 in 40,000 to 1 in 100,000 people). PTERYGIUM: Pterygium is a wing-shaped fibrovascular tissue growth from the conjunctiva onto the cornea. Pterygium is the result of partial LSCD caused by localized ultraviolet damage to limbal stem cells. As the pterygium invades the cornea, it may cause irregular astigmatism, loss of visual acuity, chronic irritation, recurrent inflammation, double vision, and impaired ocular motility. Pterygium occurs worldwide. Incidence and prevalence rates are highest in the "pterygium belt," which ranges from 30 degrees north to 30 degrees south of the equator, and lower prevalence rates are found at latitudes greater than 40 degrees. The prevalence of pterygium for Caucasians residing in urban, temperate climates is estimated at 1.2%. EXISTING TREATMENTS OTHER THAN TECHNOLOGY BEING REVIEWED: NONPTERYGIUM LIMBAL STEM CELL DEFICIENCY: In total LSCD, a patient's limbal stem cells are completely depleted, so any successful treatment must include new stem cells. Autologous oral mucosal epithelium transplantation has been proposed as an alternative to LSCT. However, this procedure is investigational, and there is very limited level 4c evidence() to support this technique (fewer than 20 eyes examined in 4 case series and 1 case report). For patients with partial LSCD, treatment may not be necessary if their visual axis is not affected. However, if the visual axis is conjunctivalized, several disease management options exist including repeated mechanical debridement of the abnormal epithelium; intensive, nonpreserved lubrication; bandage contact lenses; autologous serum eye drops; other investigational medical treatments; and transplantation of an amniotic membrane inlay. However, these are all disease management treatments; LSCT is the only curative option. PTERYGIUM: The primary treatment for pterygium is surgical excision. However, recurrence is a common problem after excision using the bare sclera technique: reported recurrence rates range from 24% to 89%. Thus, a variety of adjuvant therapies have been used to reduce the risk of pterygium recurrence including LSCT, amniotic membrane transplantation (AMT), conjunctival autologous (CAU) transplantation, and mitomycin C (MMC, an antimetabolite drug). NEW TECHNOLOGY BEING REVIEWED: To successfully treat LSCD, the limbal stem cell population must be repopulated. To achieve this, 4 LSCT procedures have been developed: conjunctival-limbal autologous (CLAU) transplantation; living-related conjunctival-limbal allogeneic (lr-CLAL) transplantation; keratolimbal allogeneic (KLAL) transplantation; and ex vivo expansion of limbal stem cells transplantation. Since the ex vivo expansion of limbal stem cells transplantation procedure is considered experimental, it has been excluded from the systematic review. These procedures vary by the source of donor cells and the amount of limbal tissue used. For CLAU transplants, limbal stem cells are obtained from the patient's healthy eye. For lr-CLAL and KLAL transplants, stem cells are obtained from living-related and cadaveric donor eyes, respectively. In CLAU and lr-CLAL transplants, 2 to 4 limbal grafts are removed from the superior and inferior limbus of the donor eye. In KLAL transplants, the entire limbus from the donor eye is used. The recipient eye is prepared by removing the abnormal conjunctival and scar tissue. An incision is made into the conjunctival tissue into which the graft is placed, and the graft is then secured to the neighbouring limbal and scleral tissue with sutures. Some LSCT protocols include concurrent transplantation of an amniotic membrane onto the cornea. Health Canada does not require premarket licensure for stem cells. However, they are subject to Health Canada's clinical trial regulations until the procedure is considered accepted transplantation practice, at which time it will be covered by the Safety of Human Cells, Tissues and Organs for Transplantation Regulations (CTO Regulations). The Medical Advisory Secretariat systematically reviewed the literature to assess the effectiveness and safety of LSCT for the treatment of patients with nonpterygium LSCD and pterygium. A comprehensive search method was used to retrieve English-language journal articles from selected databases. The GRADE approach was used to systematically and explicitly evaluate the quality of evidence and strength of recommendations. NONPTERYGIUM LIMBAL STEM CELL DEFICIENCY: The search identified 873 citations published between January 1, 2000, and March 31, 2008. Nine studies met the inclusion criteria, and 1 additional citation was identified through a bibliography review. The review included 10 case series (3 prospective and 7 retrospective). Patients who received autologous transplants (i.e., CLAU) achieved significantly better long-term corneal surface results compared with patients who received allogeneic transplants (lr-CLAL, P< .001; KLAL, P< .001). There was no significant difference in corneal surface outcomes between the allogeneic transplant options, lr-CLAL and KLAL (P = .328). However, human leukocyte antigen matching and systemic immunosuppression may improve the outcome of lr-CLAL compared with KLAL. Regardless of graft type, patients with Stevens-Johnson syndrome had poorer long-term corneal surface outcomes. Concurrent AMT was associated with poorer long-term corneal surface improvements. When the effect of the AMT was removed, the difference between autologous and allogeneic transplants was much smaller. Patients who received CLAU transplants had a significantly higher rate of visual acuity improvements compared with those who received lr-CLAL transplants (P = .002). However, to achieve adequate improvements in vision, patients with deep corneal scarring will require a corneal transplant several months after the LSCT. No donor eye complications were observed. Epithelial rejection and microbial keratitis were the most common long-term complications associated with LSCT (complications occurred in 6%-15% of transplantations). These complications can result in graft failure, so patients should be monitored regularly following LSCT. PTERYGIUM: The search yielded 152 citations published between January 1, 2000 and May 16, 2008. Six randomized controlled trials (RCTs) that evaluated LSCT as an adjuvant therapy for the treatment of pterygium met the inclusion criteria and were included in the review. Limbal stem cell transplantation was compared with CAU, AMT, and MMC. The results showed that CLAU significantly reduced the risk of pterygium recurrence compared with CAU (relative risk [RR], 0.09; 95% confidence interval [CI], 0.01-0.69; P = .02). CLAU reduced the risk of pterygium recurrence for primary pterygium compared with MMC, but this comparison did not reach statistical significance (RR, 0.48; 95% CI, 0.21-1.10; P = .08). Both AMT and CLAU had similar low rates of recurrence (2 recurrences in 43 patients and 4 in 46, respectively), and the RR was not significant (RR, 1.88; 95% CI, 0.37-9.5; P = .45). (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
Emission sources of volatile organic compounds (VOCs*) are numerous and widespread in both indoor and outdoor environments. Concentrations of VOCs indoors typically exceed outdoor levels, and most people spend nearly 90% of their time indoors. Thus, indoor sources generally contribute the majority of VOC exposures for most people. VOC exposure has been associated with a wide range of acute and chronic health effects; for example, asthma, respiratory diseases, liver and kidney dysfunction, neurologic impairment, and cancer. Although exposures to most VOCs for most persons fall below health-based guidelines, and long-term trends show decreases in ambient emissions and concentrations, a subset of individuals experience much higher exposures that exceed guidelines. Thus, exposure to VOCs remains an important environmental health concern. The present understanding of VOC exposures is incomplete. With the exception of a few compounds, concentration and especially exposure data are limited; and like other environmental data, VOC exposure data can show multiple modes, low and high extreme values, and sometimes a large portion of data below method detection limits (MDLs). Field data also show considerable spatial or interpersonal variability, and although evidence is limited, temporal variability seems high. These characteristics can complicate modeling and other analyses aimed at risk assessment, policy actions, and exposure management. In addition to these analytic and statistical issues, exposure typically occurs as a mixture, and mixture components may interact or jointly contribute to adverse effects. However most pollutant regulations, guidelines, and studies remain focused on single compounds, and thus may underestimate cumulative exposures and risks arising from coexposures. In addition, the composition of VOC mixtures has not been thoroughly investigated, and mixture components show varying and complex dependencies. Finally, although many factors are known to affect VOC exposures, many personal, environmental, and socioeconomic determinants remain to be identified, and the significance and applicability of the determinants reported in the literature are uncertain. To help answer these unresolved questions and overcome limitations of previous analyses, this project used several novel and powerful statistical modeling and analysis techniques and two large data sets. The overall objectives of this project were (1) to identify and characterize exposure distributions (including extreme values), (2) evaluate mixtures (including dependencies), and (3) identify determinants of VOC exposure. METHODS VOC data were drawn from two large data sets: the Relationships of Indoor, Outdoor, and Personal Air (RIOPA) study (1999-2001) and the National Health and Nutrition Examination Survey (NHANES; 1999-2000). The RIOPA study used a convenience sample to collect outdoor, indoor, and personal exposure measurements in three cities (Elizabeth, NJ; Houston, TX; Los Angeles, CA). In each city, approximately 100 households with adults and children who did not smoke were sampled twice for 18 VOCs. In addition, information about 500 variables associated with exposure was collected. The NHANES used a nationally representative sample and included personal VOC measurements for 851 participants. NHANES sampled 10 VOCs in common with RIOPA. Both studies used similar sampling methods and study periods. Specific Aim 1. To estimate and model extreme value exposures, extreme value distribution models were fitted to the top 10% and 5% of VOC exposures. Health risks were estimated for individual VOCs and for three VOC mixtures. Simulated extreme value data sets, generated for each VOC and for fitted extreme value and lognormal distributions, were compared with measured concentrations (RIOPA observations) to evaluate each model's goodness of fit. Mixture distributions were fitted with the conventional finite mixture of normal distributions and the semi-parametric Dirichlet process mixture (DPM) of normal distributions for three individual VOCs (chloroform, 1,4-DCB, and styrene). Goodness of fit for these full distribution models was also evaluated using simulated data. Specific Aim 2. Mixtures in the RIOPA VOC data set were identified using positive matrix factorization (PMF) and by toxicologic mode of action. Dependency structures of a mixture's components were examined using mixture fractions and were modeled using copulas, which address correlations of multiple components across their entire distributions. Five candidate copulas (Gaussian, t, Gumbel, Clayton, and Frank) were evaluated, and the performance of fitted models was evaluated using simulation and mixture fractions. Cumulative cancer risks were calculated for mixtures, and results from copulas and multivariate lognormal models were compared with risks based on RIOPA observations. Specific Aim 3. Exposure determinants were identified using stepwise regressions and linear mixed-effects models (LMMs). Specific Aim 1. Extreme value exposures in RIOPA typically were best fitted by three-parameter generalized extreme value (GEV) distributions, and sometimes by the two-parameter Gumbel distribution. In contrast, lognormal distributions significantly underestimated both the level and likelihood of extreme values. Among the VOCs measured in RIOPA, 1,4-dichlorobenzene (1,4-DCB) was associated with the greatest cancer risks; for example, for the highest 10% of measurements of 1,4-DCB, all individuals had risk levels above 10(-4), and 13% of all participants had risk levels above 10(-2). Of the full-distribution models, the finite mixture of normal distributions with two to four clusters and the DPM of normal distributions had superior performance in comparison with the lognormal models. DPM distributions provided slightly better fit than the finite mixture distributions; the advantages of the DPM model were avoiding certain convergence issues associated with the finite mixture distributions, adaptively selecting the number of needed clusters, and providing uncertainty estimates. Although the results apply to the RIOPA data set, GEV distributions and mixture models appear more broadly applicable. These models can be used to simulate VOC distributions, which are neither normally nor lognormally distributed, and they accurately represent the highest exposures, which may have the greatest health significance. Specific Aim 2. Four VOC mixtures were identified and apportioned by PMF; they represented gasoline vapor, vehicle exhaust, chlorinated solvents and disinfection byproducts, and cleaning products and odorants. The last mixture (cleaning products and odorants) accounted for the largest fraction of an individual's total exposure (average of 42% across RIOPA participants). Often, a single compound dominated a mixture but the mixture fractions were heterogeneous; that is, the fractions of the compounds changed with the concentration of the mixture. Three VOC mixtures were identified by toxicologic mode of action and represented VOCs associated with hematopoietic, liver, and renal tumors. Estimated lifetime cumulative cancer risks exceeded 10(-3) for about 10% of RIOPA participants. The dependency structures of the VOC mixtures in the RIOPA data set fitted Gumbel (two mixtures) and t copulas (four mixtures). These copula types emphasize dependencies found in the upper and lower tails of a distribution. The copulas reproduced both risk predictions and exposure fractions with a high degree of accuracy and performed better than multivariate lognormal distributions. Specific Aim 3. In an analysis focused on the home environment and the outdoor (close to home) environment, home VOC concentrations dominated personal exposures (66% to 78% of the total exposure, depending on VOC); this was largely the result of the amount of time participants spent at home and the fact that indoor concentrations were much higher than outdoor concentrations for most VOCs. In a different analysis focused on the sources inside the home and outside (but close to the home), it was assumed that 100% of VOCs from outside sources would penetrate the home. Outdoor VOC sources accounted for 5% (d-limonene) to 81% (carbon tetrachloride [CTC]) of the total exposure. Personal exposure and indoor measurements had similar determinants depending on the VOC. Gasoline-related VOCs (e.g., benzene and methyl tert-butyl ether [MTBE]) were associated with city, residences with attached garages, pumping gas, wind speed, and home air exchange rate (AER). Odorant and cleaning-related VOCs (e.g., 1,4-DCB and chloroform) also were associated with city, and a residence's AER, size, and family members showering. Dry-cleaning and industry-related VOCs (e.g., tetrachloroethylene [or perchloroethylene, PERC] and trichloroethylene [TCE]) were associated with city, type of water supply to the home, and visits to the dry cleaner. These and other relationships were significant, they explained from 10% to 40% of the variance in the measurements, and are consistent with known emission sources and those reported in the literature. Outdoor concentrations of VOCs had only two determinants in common: city and wind speed. Overall, personal exposure was dominated by the home setting, although a large fraction of indoor VOC concentrations were due to outdoor sources. City of residence, personal activities, household characteristics, and meteorology were significant determinants. Concentrations in RIOPA were considerably lower than levels in the nationally representative NHANES for all VOCs except MTBE and 1,4-DCB. Differences between RIOPA and NHANES results can be explained by contrasts between the sampling designs and staging in the two studies, and by differences in the demographics, smoking, employment, occupations, and home locations. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.
The liver lobule is formed by parenchymal cells, i.e., hepatocytes and nonparenchymal cells. In contrast to hepatocytes that occupy almost 80% of the total liver volume and perform the majority of numerous liver functions, nonparenchymal liver cells, which contribute only 6.5% to the liver volume, but 40% to the total number of liver cells, are localized in the sinusoidal compartment of the tissue. The walls of hepatic sinusoid are lined by three different cell types: sinusoidal endothelial cells (SEC), Kupffer cells (KC), and hepatic stellate cells (HSC, formerly known as fat-storing cells, Ito cells, lipocytes, perisinusoidal cells, or vitamin A-rich cells). Additionally, intrahepatic lymphocytes (IHL), including pit cells, i.e., liver-specific natural killer cells, are often present in the sinusoidal lumen. It has been increasingly recognized that both under normal and pathological conditions, many hepatocyte functions are regulated by substances released from neighboring nonparenchymal cells. Liver sinusoidal endothelial cells constitute the lining or wall of the hepatic sinusoid. They perform important filtration function due to the presence of small fenestrations that allow free diffusion of many substances, but not of particles of the size of chylomicrons, between the blood and the hepatocyte surface. SEC show huge endocytic capacity for many ligands including glycoproteins, components of the extracellular matrix (ECM; such as hyaluronate, collagen fragments, fibronectin, or chondroitin sulphate proteoglycan), immune complexes, transferrin and ceruloplasmin. SEC may function as antigen-presenting cells (APC) in the context of both MHC-I and MHC-II restriction with the resulting development of antigen-specific T-cell tolerance. They are also active in the secretion of cytokines, eicosanoids (i.e., prostanoids and leukotrienes), endothelin-1, nitric oxide, and some ECM components. Kupffer cells are intrasinusoidally located tissue macrophages with a pronounced endocytic and phagocytic capacity. They are in constant contact with gut-derived particulate materials and soluble bacterial products so that a subthreshold level of their activation in the normal liver may be anticipated. Hepatic macrophages secrete potent mediators of the inflammatory response (reactive oxygen species, eicosanoids, nitric oxide, carbon monoxide, TNF-alpha, and other cytokines), and thus control the early phase of liver inflammation, playing an important part in innate immune defense. High exposure of Kupffer cells to bacterial products, especially endotoxin (lipopolysaccharide, LPS), can lead to the intensive production of inflammatory mediators, and ultimately to liver injury. Besides typical macrophage activities, Kupffer cells play an important role in the clearance of senescent and damaged erythrocytes. Liver macrophages modulate immune responses via antigen presentation, suppression of T-cell activation by antigen-presenting sinusoidal endothelial cells via paracrine actions of IL-10, prostanoids, and TNF-alpha, and participation in the development of oral tolerance to bacterial superantigens. Moreover, during liver injury and inflammation, Kupffer cells secrete enzymes and cytokines that may damage hepatocytes, and are active in the remodeling of extracellular matrix. Hepatic stellate cells are present in the perisinusoidal space. They are characterized by abundance of intracytoplasmic fat droplets and the presence of well-branched cytoplasmic processes, which embrace endothelial cells and provide focally a double lining for sinusoid. In the normal liver HSC store vitamin A, control turnover of extracellular matrix, and regulate the contractility of sinusoids. Acute damage to hepatocytes activates transformation of quiescent stellate cells into myofibroblast-like cells that play a key role in the development of inflammatory fibrotic response. Pit cells represent a liver-associated population of large granular lymphocytes, i.e., natural killer (NK) cells. They spontaneously kill a variety of tumor cells in an MHC-unrestricted way, and this antitumor activity may be enhanced by the secretion of interferon-gamma. Besides pit cells, the adult liver contains other subpopulations of lymphocytes such as gamma delta T cells, and both "conventional" and "unconventional" alpha beta T cells, the latter containing liver-specific NK T cells. The development of methods for the isolation and culture of main liver cell types allowed to demonstrate that both nonparenchymal and parenchymal cells secrete tens of mediators that exert multiple paracrine and autocrine actions. Co-culture experiments and analyses of the effects of conditioned media on cultures of another liver cell type have enabled the identification of many substances released from non-parenchymal liver cells that evidently regulate some important functions of neighboring hepatocytes and non-hepatocytes. To the key mediators involved in the intercellular communication in the liver belong prostanoids, nitric oxide, endothelin-1, TNF-alpha, interleukins, and chemokines, many growth factors (TGF-beta, PDGF, IGF-I, HGF), and reactive oxygen species (ROS). Paradoxically, the cooperation of liver cells is better understood under some pathological conditions (i.e., in experimental models of liver injury) than in normal liver due to the possibility of comparing cellular phenotype under in vivo and in vitro conditions with the functions of the injured organ. The regulation of vitamin A metabolism provides an example of the physiological role for cellular cross-talk in the normal liver. The majority (up to 80%) of the total body vitamin A is stored in the liver as long-chain fatty acid esters of retinal, serving as the main source of retinoids that are utilized by all tissues throughout the body. Hepatocytes are directly involved in the uptake from blood of chylomicron remnants, and the synthesis of retinol-binding protein that transfers retinol to other tissues. However, more than 80% of the liver retinoids are stored in lipid droplets of hepatic stellate cells. HSC are capable of both uptake and release of retinol depending on the body's retinol status. The activity of some major enzymes of vitamin A metabolism have been found to be many times higher per protein basis in stellate cells than in hepatocytes. Despite progress in the understanding of the roles played by these two cell types in hepatic retinoid metabolism, the way in which retinoids move between the parenchymal cells, stellate cells, and blood plasma has not been fully elucidated. Sinusoidal blood flow is, to a great extent, regulated by hepatic stellate cells that can contract due to the presence of smooth muscle alpha-actin. The main vasoactive substances that affect constriction or relaxation of HSC derive both from distant sources and from neighboring hepatocytes (carbon monoxide, leukotrienes), endothelial cells (endothelin, nitric oxide, prostaglandins), Kupffer cells (prostaglandins, NO), and stellate cells themselves (endothelin, NO). The cellular cross-talk reflected by the fine-tuned modulation of sinusoidal contraction becomes disturbed under pathological conditions, such as endotoxemia or liver fibrosis, through the excess synthesis of vasoregulatory compounds and the involvement of additional mediators acting in a paracrine way. The liver is an important source of some growth factors and growth factor-binding proteins. Although hepatocytes synthesize the bulk of insulin-like growth factor I (IGF-I), also other types of nonparenchymal liver cells may produce this peptide. Cell-specific expression of distinct IGF-binding proteins observed in the rat and human liver provides the potential for specific regulation of hepatic IGF-I synthesis not only by growth hormone, insulin, and IGF-I, but also by cytokines released from activated Kupffer (IL-1, TNF-alpha, TGF-beta) or stellate cells (TGF-alpha, TGF-beta). Hepatic stellate cells may affect turnover of hepatocytes through the synthesis of potent positive as well as negative signals such as, respectively, hepatocyte-growth-factor or TGF-beta. Although hepatocytes seem not to produce TGF-beta, a pleiotropic cytokine synthesized and secreted in the latent form by Kupffer and stellate cells, they may contribute to its actions in the liver by the intracellular activation of latent TGF-beta, and secretion of the biologically active isoform. Many mediators that reach the liver during inflammatory processes, such as endotoxins, immune-complexes, anaphylatoxins, and PAF, increase glucose output in the perfused liver, but fail to do so in isolated hepatocytes, acting indirectly via prostaglandins released from Kupffer cells. In the liver, prostaglandins synthesized from arachidonic acid mainly in Kupffer cells in a response to various inflammatory stimuli, modulate hepatic glucose metabolism by increasing glycogenolysis in adjacent hepatocytes. The release of glucose from glycogen supports the increased demand for energetic fuel by the inflammatory cells such as leukocytes, and additionally enables enhanced glucose turnover in sinusoidal endothelial cells and Kupffer cells which is necessary for effective defense of these cells against invading microorganisms and oxidative stress in the liver. Leukotrienes, another oxidation product of arachidonic acid, have vasoconstrictive, cholestatic, and metabolic effects in the liver. A transcellular synthesis of cysteinyl leukotrienes (LTC4, LTD4, and LTE4) functions in the liver: LTA4, an important intermediate, is synthesized in Kupffer cells, taken up by hepatocytes, converted into the potent LTC4, and then released into extracellular space, acting in a paracrine way on Kupffer and sinusoidal endothelial cells. Thus, hepatocytes are target cells for the action of eicosanoids and the site of their transformation and degradation, but can not directly oxidate arachidonic acid to eicosanoids. (ABSTRACT TRUNCATED)	Given the following content, create a question whose answer can be found within the content. Then, provide the answer to that question. Ensure the answer is derived directly from the content. Format the question and answer in the following JSON structure: {Question: '', Answer: ''}.

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