Development of innovative simulation teaching for advanced general practice clinical pharmacists.

BACKGROUND: Advanced General Practice Clinical Pharmacists (GPCPs) are expected to manage patients by undertaking clinical assessment then make safe, competent autonomous decisions. Simulation provides a safe learning environment to develop clinical skills, but is rarely used for postgraduate pharmacist development. AIM: Design and deliver innovative simulation teaching to support Advanced GPCPs in Scotland. SETTING: General Practice. DEVELOPMENT: Experienced clinical pharmacy educators designed a simulation day with ten scenarios based on general practice clinical presentations. Learning objectives were mapped to the National Advanced GPCP competency framework. IMPLEMENTATION: Simulation took place at the National Skills Education Hub, Louisa Jordan National Hospital, Glasgow, November 2020. Participants were briefed prior to each immersive simulation. Mannequins were used if clinical signs were expected to be identified on examination. Verbal and written feedback was given after each simulation. EVALUATION: Pre and post simulation questionnaires were developed. Increase in confidence and competence were reported in all areas pertaining to application of consultation and clinical skills. Qualitative comments from the participants regarding the training course were also favourable with respondents highlighting the value of the training, especially in terms of developing confidence via the real-time feedback. CONCLUSION: This innovative simulation evaluated as being of value to GPCPs in developing clinical confidence and competence when dealing with a variety of typical General Practice scenarios. Plans are underway to establish a Scottish Pharmacy Simulation Faculty which could support this training in each health board.

A unique case of penile necrotizing fasciitis secondary to spontaneous corpus cavernosal abscess.

Corpus cavernosal abscess and necrotizing fasciitis occur rarely, and precipitating factors can usually be elicited with careful history and examination. Whilst both conditions share common risk factors such as diabetes mellitus, this is the first reported case of penile necrotizing fasciitis secondary to spontaneous corpus cavernosal abscess in an otherwise healthy patient. A 32-year-old man presented with 4-day history of swollen, painful penis, with ultrasound confirming corpus cavernosal abscess. Biopsies were taken and the cavity aspirated, but, despite intravenous antibiotics, he developed penile necrotizing fasciitis necessitating open cavernostomy and debridement. The overlying skin defect healed by secondary intention, but the patient experienced persistent postoperative erectile dysfunction, so he was referred for penile prosthesis insertion.

Early immune responses in Atlantic salmon (Salmo salar L.) after immunization with PLGA nanoparticles loaded with a model antigen and ß-glucan.

Polymeric nanoparticles (NPs) of poly (lactic-co-glycolic) acid (PLGA) possess adjuvant properties. To date, there are few studies exploring their application as antigen carriers for vaccination of fish. This study presents a preclinical assessment of the early innate and adaptive immune responses in Atlantic salmon following immunization with PLGA NPs. A model antigen (TNP-LPH) and an immunostimulant (ß-glucan) were entrapped in NPs of 300-400nm either alone or in combination. Both the antigen and the ß-glucan were efficiently entrapped (>50%) in particles and an antigen release study indicated particle stability up to 50 days at 8°C. Spleen and head kidney were analyzed for pro-inflammatory markers (TNF-α, IL-1ß, IL-8, C3a) and T cell cytokines, effector molecules and transcription factors (IFN-γ, T-bet, GATA-3, granzyme A, IL-10, Foxp3) at mRNA transcription levels 2, 4 and 8 days post i.p. immunization. NPs alone were able to moderately up-regulate pro-inflammatory immune responses. Addition of immunogenic cargo, either an antigen or ß-glucan generally increased the gene expression of pro-inflammatory markers, while administering both resulted in the highest gene expression. These findings were also reflected by concurrently increased levels of IL-10. Comparing the treatment groups injected with antigen and ß-glucan co-administered either in NPs or FCA demonstrated that the magnitude of the acute pro-inflammatory responses was equal between the treatments or highest in the NP injected group. Although elevated expression of granzyme A in the NP injected groups (carrying antigen and/or ß-glucan) was observed, PLGA NPs were unable to induce T cell differentiation on mRNA gene expression levels, as increased levels of the indicating cytokines and transcriptions factors failed to occur. In conclusion, this study demonstrates that PLGA NPs have potential as an adjuvant in salmon vaccines as they enhance the early pro-inflammatory responses to immunization.

Inhaled insulin in diabetes mellitus.

BACKGROUND: Insulin therapy often relies on multiple daily injections of insulin. However this is a considerable burden to many people with diabetes and adherence to such an insulin regimen can be difficult to maintain, hence compromising optimal glycaemic control. Also, short acting injected insulin is absorbed more slowly than insulin released by the normal pancreas in response to a meal. Inhaled insulin has the potential to reduce the number of injections to perhaps one long-acting insulin per day, and provide a closer match to the natural state, by more rapid absorption from the lung. OBJECTIVES: To compare the efficacy, adverse effects and patient acceptability of inhaled versus injected insulin. SEARCH STRATEGY: A sensitive search strategy for randomised controlled or cross-over trials was combined with key terms for inhaled insulins. Databases searched were: The Cochrane Library, MEDLINE, PubMed, EMBASE, Science Citation Index, BIOSIS, Web of Science Proceedings, National Research Register UK, Current Controlled Trials, ClinicalTrials.gov, Conference Papers Index, LexisNexis, and web sites of the ADA and EASD were searched for recent meeting abstracts. Reference lists and journals were handsearched. There were no language restrictions on searching. Manufacturers of inhaled insulin were also contacted. Date of last search October 2002. SELECTION CRITERIA: Only randomised controlled trials with parallel groups or controlled cross-over trials, including type 1 or type 2 diabetic patients of any age treated with insulin, were considered eligible. The minimum trial duration considered was 10 weeks, as this is the time taken for glycated haemoglobin to reliably reflect changes in glycaemic control. DATA COLLECTION AND ANALYSIS: Trial selection and evaluation of study quality was performed independently by two reviewers. The quality of reporting of each trial was assessed according to a modification of the criteria outlined in Centre for Reviews and Dissemination (CRD) Report 4, Spitzer; and Jadad. MAIN RESULTS: Six randomised controlled trials were found and the overall number of participants was 1191. Three trials included patients with type 1 diabetes and three with type 2 diabetes. Three trials had a duration of 24 weeks, and three of 12 weeks. All were open label. There was insufficient information to determine the study quality. Results for HbA1c were similar for all trials, in that all showed comparable glycaemic control for inhaled insulin compared to an entirely subcutaneous regimen. All trials that reported patient satisfaction and quality of life showed that these were significantly greater in the inhaled insulin group. Overall there was no difference in total hypoglycaemic episodes between the groups, but one trial showed a statistically significant increase in severe hypoglycaemic episodes for the inhaled insulin group. No adverse pulmonary effects were observed in any of the studies, but longer follow-up will be required to be sure that there are no adverse side-effects. Cavets include: few studies published in full (so quality could not be assessed), and only two studies used the same basal regimen in both the inhaled and injected groups. REVIEWERS' CONCLUSIONS: Inhaled insulin taken before meals, in conjunction with an injected basal insulin, has been shown to maintain glycaemic control comparable to that of patients taking multiple daily injections. The key benefit appears to be that patient satisfaction and quality of life are significantly improved, presumably due to the reduced number of daily injections required. However, the patient satisfaction data is based on five trials, of which only two have been published in full; also the three trials containing quality of life data are all only published in abstract form at present. In addition, longer term pulmonary safety data are still needed. Also, the lower bioavailability, and hence higher doses of inhaled insulin required, may make it less cost-effective than injected insulin.

Systematic reviews of the effectiveness of quality improvement strategies and programmes.

Systematic reviews provide the best evidence on the effectiveness of healthcare interventions including quality improvement strategies. The methods of systematic review of individual patient randomised trials of healthcare interventions are well developed. We discuss methodological and practice issues that need to be considered when undertaking systematic reviews of quality improvement strategies including developing a review protocol, identifying and screening evidence sources, quality assessment and data abstraction, analytical methods, reporting systematic reviews, and appraising systematic reviews. This paper builds on our experiences within the Cochrane Effective Practice and Organisation of Care (EPOC) review group.

Inhaled insulin in diabetes mellitus.

BACKGROUND: Insulin therapy often relies on multiple daily injections of insulin. However this is a considerable burden to many people with diabetes and adherence to such an insulin regimen can be difficult to maintain, hence compromising optimal glycaemic control. Also, short acting injected insulin is absorbed more slowly than insulin released by the normal pancreas in response to a meal. Inhaled insulin has the potential to reduce the number of injections to perhaps one long-acting insulin per day, and provide a closer match to the natural state, by more rapid absorption from the lung. OBJECTIVES: To compare the efficacy, adverse effects and patient acceptability of inhaled versus injected insulin. SEARCH STRATEGY: A sensitive search strategy for randomised controlled or cross-over trials was combined with key terms for inhaled insulins. Databases searched were: The Cochrane Library, MEDLINE, PubMed, EMBASE, Science Citation Index, BIOSIS, Web of Science Proceedings, National Research Register UK, Current Controlled Trials, ClinicalTrials.gov, Conference Papers Index, LexisNexis, and web sites of the ADA and EASD were searched for recent meeting abstracts. Reference lists and journals were handsearched. There were no language restrictions on searching. Manufacturers of inhaled insulin were also contacted. Date of last search October 2002. SELECTION CRITERIA: Only randomised controlled trials with parallel groups or controlled cross-over trials, including type 1 or type 2 diabetic patients of any age treated with insulin, were considered eligible. The minimum trial duration considered was 10 weeks, as this is the time taken for glycated haemoglobin to reliably reflect changes in glycaemic control. DATA COLLECTION AND ANALYSIS: Trial selection and evaluation of study quality was performed independently by two reviewers. The quality of reporting of each trial was assessed according to a modification of the criteria outlined in Centre for Reviews and Dissemination (CRD) Report 4, Spitzer; and Jadad. MAIN RESULTS: Six randomised controlled trials were found and the overall number of participants was 1191. Three trials included patients with type 1 diabetes and three with type 2 diabetes. Three trials had a duration of 24 weeks, and three of 12 weeks. All were open label. There was insufficient information to determine the study quality. Results for HbA1c were similar for all trials, in that all showed comparable glycaemic control for inhaled insulin compared to an entirely subcutaneous regimen. All trials that reported patient satisfaction and quality of life showed that these were significantly greater in the inhaled insulin group. Overall there was no difference in total hypoglycaemic episodes between the groups, but one trial showed a statistically significant increase in severe hypoglycaemic episodes for the inhaled insulin group. No adverse pulmonary effects were observed in any of the studies, but longer follow-up will be required to be sure that there are no adverse side-effects. Cavets include: few studies published in full (so quality could not be assessed), and only two studies used the same basal regimen in both the inhaled and injected groups. REVIEWER'S CONCLUSIONS: Inhaled insulin taken before meals, in conjunction with an injected basal insulin, has been shown to maintain glycaemic control comparable to that of patients taking multiple daily injections. The key benefit appears to be that patient satisfaction and quality of life are significantly improved, presumably due to the reduced number of daily injections required. However, the patient satisfaction data is based on five trials, of which only two have been published in full; also the three trials containing quality of life data are all only published in abstract form at present. In addition, longer term pulmonary safety data are still needed. Also, the lower bioavailability, and hence higher doses of inhaled insulin required, may make it less cost-effective than injected insulin.

Is there a "best" way to detect and minimize publication bias? An empirical evaluation.

Using 14 meta-analyses that included both published (n = 199) and unpublished (n = 50) randomized trials, we evaluated the utility of different analytical approaches to detect, assess robustness, and minimize publication bias in meta-analysis. The rank correlation and graphical tests indicated funnel plot asymmetry in 3 and 7 of the 14 meta-analyses, respectively. The file drawer number estimates using Iyengar-Greenhouse method were between 1.5 and 4.7 times smaller compared to Rosenthal's estimates. The median difference between the Trim and Fill estimates and the actual number of missing studies was 1 (range -4, 6). Weighted estimation methods adjusted for publication bias and provided estimates of intervention effect close to the reference standard, on average. We showed there are differences in the conclusions one would reach clinically based on the different analytical approaches dealing with publication bias. Our results also suggest that the appropriate use of these methods improves the reliability and accuracy of meta-analysis.

Awareness and use of the Ottawa ankle and knee rules in 5 countries: can publication alone be enough to change practice?

STUDY OBJECTIVES: We evaluate the international diffusion of the Ottawa Ankle and Knee Rules and determine emergency physicians' attitudes toward clinical decision rules in general. METHODS: We conducted a cross-sectional, self-administered mail survey of random samples of 500 members each of the American College of Emergency Physicians, Canadian Association of Emergency Physicians, British Association for Accident and Emergency Medicine, Spanish Society for Emergency Medicine, and all members (n=1,350) of the French Speaking Society of Emergency Physicians, France. Main outcome measures were awareness of the Ottawa Ankle and Knee Rules, reported use of these rules, and attitudes toward clinical decision rules in general. RESULTS: A total of 1,769 (57%) emergency physicians responded, with country-specific response rates between 49% (United States and France) and 79% (Canada). More than 69% of physicians in all countries, except Spain, were aware of the Ottawa Ankle Rules. Use of the Ottawa Ankle Rules differed by country with more than 70% of all responding Canadian and United Kingdom physicians reporting frequent use of the rules compared with fewer than one third of US, French, and Spanish physicians. The Ottawa Knee Rule was less well known and less used by physicians in all countries. Most physicians in all countries viewed decision rules as intended to improve the quality of health care (>78%), a convenient source of advice (>67%), and good educational tools (>61%). Of all physicians, those from the United States held the least positive attitudes toward decision rules. CONCLUSION: This constitutes the largest international survey of emergency physicians' attitudes toward and use of clinical decision rules. Striking differences were apparent among countries with regard to knowledge and use of decision rules. Despite similar awareness in the United States, Canada, and the United Kingdom, US physicians appeared much less likely to use the Ottawa Ankle Rules. Future research should investigate factors leading to differences in rates of diffusion among countries and address strategies to enhance dissemination and implementation of such rules in the emergency department.

Inhaled insulin for the treatment of diabetes mellitus.

(1) Insulin delivery via inhalation, as an alternative to administration by injection, is under development. (2) The available evidence comparing subcutaneous (sc) insulin with inhaled insulin for persons with type 1 and 2 diabetes, shows similar glycosylated hemoglobin (HgA1c) levels after three months of treatment. (3) Clinical trials suggest that insulin delivered by inhalation has a quicker onset of action relative to regular insulin. This means insulin can be taken just prior to a meal rather than the 30 minutes prior to eating required with sc injections of regular insulin. (4) No changes in pulmonary function were noted in the studies, however data is limited to use for three months. Pulmonary thrombosis has subsequently been reported in one patient out of 1000, using Exubera(R) and the Inhale Therapeutic Systems device.

Does the inclusion of grey literature influence estimates of intervention effectiveness reported in meta-analyses?

BACKGROUND: The inclusion of only a subset of all available evidence in a meta-analysis may introduce biases and threaten its validity; this is particularly likely if the subset of included studies differ from those not included, which may be the case for published and grey literature (unpublished studies, with limited distribution). We set out to examine whether exclusion of grey literature, compared with its inclusion in meta-analysis, provides different estimates of the effectiveness of interventions assessed in randomised trials. METHODS: From a random sample of 135 meta-analyses, we identified and retrieved 33 publications that included both grey and published primary studies. The 33 publications contributed 41 separate meta-analyses from several disease areas. General characteristics of the meta-analyses and associated studies and outcome data at the trial level were collected. We explored the effects of the inclusion of grey literature on the quantitative results using logistic-regression analyses. FINDINGS: 33% of the meta-analyses were found to include some form of grey literature. The grey literature, when included, accounts for between 4.5% and 75% of the studies in a meta-analysis. On average, published work, compared with grey literature, yielded significantly larger estimates of the intervention effect by 15% (ratio of odds ratios=1.15 [95% CI 1.04-1.28]). Excluding abstracts from the analysis further compounded the exaggeration (1.33 [1.10-1.60]). INTERPRETATION: The exclusion of grey literature from meta-analyses can lead to exaggerated estimates of intervention effectiveness. In general, meta-analysts should attempt to identify, retrieve, and include all reports, grey and published, that meet predefined inclusion criteria.

Canadian oncologists and clinical practice guidelines: a national survey of attitudes and reported use. Provincial Lung Disease Site Group of Cancer Care Ontario.

PURPOSE: To determine (1) Canadian oncologists' attitudes toward practice guidelines, (2) oncologists' self-reported use of practice guidelines and, (3) physicians' characteristics and attitudes associated with self-reported use of practice guidelines. PARTICIPANTS AND METHODS: A cross-sectional, self-administered postal survey was administered to Canadian oncologists. Main outcome measures were level of agreement with 8 descriptive statements about guidelines, score on the attitudinal scale of the guideline of Tunis et al., and physicians' stated use of guideline. chi(2) and logistic regression procedures were used to explore the relationship between physician characteristics and use of guidelines. RESULTS: Over 80% of respondents agreed that they were good educational tools, convenient sources of advice, intended to improve quality of care; over 40% agreed that they were unbiased syntheses of expert opinion. Conversely, 42, 26, 20 and 16% felt they were intended to cut costs, were oversimplified cookbook medicine, were too rigid to apply to individual patients, and a challenge to physicians' authority, respectively. Forty-one percent reported using practice guidelines routinely or most of the time. Use was associated with positive attitudes about guidelines, receiving medical school training abroad and being a radiation oncologist. CONCLUSION: Canadian oncologists were quite positive about practice guidelines and reported using them frequently. Our results suggest that use of guidelines by oncologists may be related to attitudes about guidelines in general, specialty within oncology and country of medical school training.

The use of technologies to minimize exposure to perioperative allogeneic blood transfusion in elective surgery. A survey of Canadian hospitals.

BACKGROUND: Despite the growing medical and public interest in reducing exposure to allogeneic blood, little is known about the use of alternatives to allogeneic transfusion. This study was conducted to determine the availability of these technologies in Canadian hospitals and was undertaken under the auspices of the International Study of Peri-Operative Transfusion (ISPOT), a 10-country study of the effectiveness of, attitudes toward, and practices related to the use of alternatives to allogeneic transfusion. METHODS: A cross-sectional national mail survey of Canadian hospitals with greater than 50 medical/surgical beds. Chiefs of anesthesia, surgery, and the divisions of cardiac, orthopedic, vascular, and urology were initially mailed a brief postcard asking which of seven technologies were used in their center. This was then followed up with a one-page questionnaire asking how frequently the technologies were used, their thoughts on the appropriateness of the use of the technologies, barriers to their greater use, and reasons for nonuse of the technologies. RESULTS: Response rates to the postcard survey ranged from 70%-98%, depending on the technology and type of surgery, and ranged from 27%-53% for the follow-up questionnaire. All technologies were used most frequently in cardiac surgery. Aprotinin, tranexamic acid, aminocaproic acid, desmopressin, and cell salvage were reported used in over 70% of cardiac surgery centers. Of these, tranexamic acid and cell salvage were the only ones used routinely in some centers. Acute normovolemic hemodilution and erythropoietin were used in 45% and 20% of cardiac centers, respectively. The drugs were used in less than 15% of orthopedic, vascular, and urologic divisions, with the exception of desmopressin in urologic and vascular surgery and aminocaproic acid in urologic surgery. The techniques of cell salvage and acute normovolemic hemodilution were used in 30%-45% of these divisions, with the exception of cell salvage, which was used in less than 15% of urology units. In more than 60% of cases, the technologies were considered to be used "about right," although an important minority felt that they were underused. CONCLUSIONS: In general, alternatives to perioperative allogeneic transfusion were rarely used except in cardiac surgery.

Autologous versus allogeneic transfusion: patients' perceptions and experiences.

BACKGROUND: Preoperative autologous donation is one way to decrease a patient's exposure to allogeneic blood transfusion. This study was designed to determine patients' perceptions about the autologous blood donation process and their experiences with transfusion. METHODS: To assess patient perception, a questionnaire was administered a few days before surgery to patients undergoing elective cardiac and orthopedic surgery in a Canadian teaching hospital. All patients attending the preoperative autologous donation clinic during a 10-month period were eligible. A convenience sample of patients undergoing the same types of surgery who had not predonated blood were selected from preadmission clinics. Patient charts were reviewed retrospectively to assess actual transfusion practice in all cases. RESULTS: A total of 80 patients underwent cardiac surgery (40 autologous donors, 40 nondonors) and 73 underwent orthopedic surgery (38 autologous donors, 35 nondonors). Of the autologous donors, 75 (96%) attended all scheduled donation appointments, 73 (93%) said that they were "very likely" or "likely" to predonate again, and 75 (96%) said that they would recommend autologous donation to others. There was little difference in preoperative symptoms between the autologous donors and the nondonors, although the former were more likely than the latter to report that their overall health had remained the same during the month before surgery (30 [75%] v. 21 [52%] for the cardiac surgery patients and 30 [79%] v. 18 [51%] for the orthopedic surgery patients). When the autologous donors were asked what they felt their chances would have been of receiving at least one allogeneic blood transfusion had they not predonated, the median response was 80%. When they were asked what their chances were after predonating their own blood, the median response was 0%. The autologous donors were significantly less likely to receive allogeneic blood transfusions (6 [15%] for cardiac surgery and 3 [8%] for orthopedic surgery) than were the nondonors (14 [35%] for cardiac surgery and 16 [46%] for orthopaedic surgery). They were, however, more likely to receive any transfusion (autologous or allogeneic) than were the nondonors (25 [63%] v. 14 [35%] for cardiac surgery and 31 [81%] v. 16 [46%] for orthopedic surgery). INTERPRETATION: Patients who underwent preoperative autologous blood donation were positive about the experience and did not report more symptoms than patients who did not donate blood preoperatively. Autologous donors overestimated their chances of receiving allogeneic blood transfusions had they not predonated and underestimated their chances after they had predonated. They were less likely to receive allogeneic transfusions, but more likely to receive any type of transfusion, than were patients who did not predonate.

How interested is the public in genetic testing for colon cancer susceptibility? Report of a cross-sectional population survey.

OBJECTIVE: To assess the public's interest in genetic testing for colon cancer susceptibility, to determine whether provision of information about the accuracy of the test or the population risk of inheriting the colon cancer gene influences interest, to determine the reasons for wanting to be tested and to identify the factors related to interest in testing. DESIGN: A cross-sectional random digit dialing telephone survey of 501 adults. SETTING: Ontario. MAIN OUTCOME MEASURES: Proportion of the public interested in genetic testing; reasons for interest in testing. RESULTS: Of the sample, 39.9% (95% confidence interval [CI] 35.5 to 44.3) stated that they would be very interested in taking a simple blood test if a positive result suggested they had an 80% chance of getting colon cancer sometime during their lifetime. When it was suggested that the test might be accurate only 90% of the time, 33.1% of the sample (95% CI 28.7 to 37.5) still said they would be very interested in testing. When informed that less than 1% of the population inherits the gene for colon cancer, the proportion of the sample stating they would still be very interested in genetic testing fell to 19.2% (95% CI 14.8 to 23.6). The main reasons given for wanting genetic testing were to take preventive action, for peace of mind and curiosity. For respondents who remained interested in testing after being given information about the population risk of inheriting the gene, 2 factors were identified by logistic regression analysis as being independently related to interest: worry about cancer and perceived risk of getting colon cancer. CONCLUSIONS: If the public's interest in testing for colon cancer susceptibility has any influence on its eventual request to be tested, then demand for genetic testing may be considerable once such tests become widely available and known to the public. This study reveals that the public's interest in genetic testing is substantial, although modifiable by the provision of information about the population risk of inheriting a colon cancer gene. This finding suggests that genetic researchers and others should be careful to provide the population risk of inheriting cancer genes when discussing the discovery of these genes with the media. Furthermore, public health educators will need to ensure that information aids include material on familial risk criteria, genetic counselling and genetic testing, as well as on the implications of genetic testing, the general population risk of developing colon cancer and the general population risk of carrying the colon cancer gene. This information should also be provided to those who seek assessment, to health care professionals and to the public.

Molecular and immunohistochemical identification of p53 alterations in bone and soft tissue sarcomas.

p53 has been shown to suppress tumor growth by regulating the cell cycle and by triggering apoptosis. Acquired somatic mutations of the p53 gene have been observed in a variety of human malignancies, and these result in a loss of its tumor suppressor function. To examine the occurrence of p53 abnormalities in bone and soft tissue sarcomas, 113 tumors were subjected to molecular analysis and mutations were confirmed in 16 tumors. The frequency of p53 alterations varied among the different subtypes of bone and soft tissue sarcomas, being observed predominantly in osteosarcomas (8/34 cases), rhabdomyosarcomas (2/3 cases), Ewing's sarcomas (1/5 cases), and liposarcomas (3/21 cases). In contrast, p53 gene mutations were detected at a lower frequency in malignant fibrous histiocytomas (2/34 cases) and not at all in nine chondrosarcomas and five leiomyosarcomas. Immunohistochemical staining of p53 protein was performed on 69 cases and compared to the DNA results. For 64 cases the results were concordant: 56 sarcomas were considered to have wild-type p53 by both techniques. As well, increased p53 protein expression was observed in eight of the nine tumors with p53 gene mutations. However, positive p53 staining was also seen in four sarcomas which had no detectable p53 mutations in exons 5 through 9. Because some sarcomas exhibit amplification and overexpression of MDM-2, which may interact with p53 and cause stabilization of wild-type p53 protein, we examined these tumors for MDM-2 amplification. None of the tumors with MDM-2 amplification exhibited p53 immunopositivity. Very weak p53 reactivity was detected in four malignant fibrous histiocytomas that had received either chemotherapy or radiotherapy. Of 16 metastatic lesions examined, only one contained a p53 mutation. In addition, for five cases in which both the original lesion and its metastases were analyzed, p53 alterations were not observed in the metastases if the tumor was wild-type at presentation. These data suggest that p53 alterations occur at different frequencies in various subtypes of sarcoma and, although detected in metastatic lesions, are not associated more frequently with progression.

Administrative and operational responsibilities in contract management.

Frequently, chief financial officers or marketing executives negotiate contracts that are difficult if not impossible to implement. In addition, those parties responsible for implementing contracts are often unaware of the terms. Formal verbal and written communications within a health care organization will minimize consumer (payer and patient) displeasure, as well as alleviate internal frustration and stress.