New, azide-free transformation of epoxides into 1,2-diamino compounds: synthesis of the anti-influenza neuraminidase inhibitor oseltamivir phosphate (Tamiflu).

A new, azide-free transformation of the key precursor epoxide 6 to the influenza neuraminidase inhibitor prodrug oseltamivir phosphate (1, Tamiflu) is described. This sequence represents a new and efficient transformation of an epoxide into a 1,2-diamino compound devoid of potentially toxic and hazardous azide reagents and intermediates and avoids reduction and hydrogenation conditions. Using catalytic MgBr(2).OEt(2) as a new, inexpensive Lewis acid, the introduction of the first amino function was accomplished by opening of the oxirane ring with allylamine followed by Pd/C-catalyzed deallylation to the amino alcohol 16. The introduction of the second amino group was then accomplished via an efficient reaction cascade involving a domino sequence preferably utilizing a transient imino protection. Selective acetylation of the resulting diamine 17 was achieved under acidic conditions providing the crystalline 4-acetamido-5-N-allylamino-derivative 18, which upon deallylation over Pd/C and phosphate salt formation afforded drug substance 1. The overall yield of this route from 6 of 35-38% exceeds the yield of the azide-based process (27-29%) and does not require any chromatographic purification.

The decade of the nineties at the UCLA Medical Center: responses to dramatic marketplace changes.

The evolution of the health care marketplace in the nineties in Southern California is described, including the dominance of managed care at the decade's end. The marketplace, especially in Los Angeles, is now one of the most complex, competitive, and challenging medical marketplaces in the country. The University of California, Los Angeles (UCLA) Medical Center and the academic health center of which it is a part have had to respond appropriately and vigorously to survive and to position themselves for the future. This article focuses on the responses of the medical center to these marketplace pressures. The center has recognized single-signature contracting, cost containment, and an emphasis on ambulatory care as fundamental success factors for survival in a complex, organized managed care environment. Data on the medical, financial, and educational performances of the medical center are presented in terms of its responses to the marketplace. Preliminary information about quality of care is presented for three patient-population groups that have been heavily affected by managed care. The need for emphasis on quality and service for future success and the attendant need for emphasis on information systems are discussed. The importance of fundamental understanding of markets is also reviewed. The concomitant approaches to securing the center's academic missions are described, including changes in institutional governance for the entire health sciences center of which the medical center is a part and the establishment of priorities in research, clinical care, and teaching programs, especially teaching programs in primary care.

[Effectiveness of epicondylitis bandages from the biomechanical viewpoint--an experimental study]. / Die Wirkung von Epikondylitisbandagen aus biomechanischer Sicht--eine experimentelle Versuchsanordnung.

QUESTIONS: During extension of the elbow joint (test measurement) and extension of the wrist (control measurement), maximal bandage pressure is desired on the extensor group of the forearm, especially of the M. extensor carpl radialis brevis (ECRB). Do the various commercial epicondylitis bandages produce a mechanical effect on the extensor group of the forearm and how do the maximal pressures of these bandages behave in direct comparison? Are the pressures produced clinically relevant? METHODS: Eleven different epicondylitis bandage constructions were examined for their biomechanical effects. The exerted pressure was measured continously during the above-mentioned movements. A fist-closing strength of ca. 30 N was maintained for the necessary pre-stressing of the forearm muscles. RESULTS: Strap-type bandages were the only bandages to produce adequately high pressures. Bands applied at pressures which approach those of the straps led to obstruction in bloodflow. Stocking designs showed no effect in respect to our study. CONCLUSION: Bandages which apply pressure to relieve the tendon insertion of the extensor muscles must, from a technical standpoint, be of a strap construction in order to build up adequate pressures to be effective.

The hospital admission decision for patients with community-acquired pneumonia. Results from the pneumonia Patient Outcomes Research Team cohort study.

BACKGROUND: The hospital admission decision directly influences the magnitude of resource use in patients with community-acquired pneumonia, yet little information exists on how medical practitioners make this decision. OBJECTIVES: To determine which factors medical practitioners consider in making the hospital admission decision and which health care services they believe would allow ambulatory treatment of low-risk hospitalized patients with community-acquired pneumonia. METHODS: Medical practitioners responsible for the hospital admission decision for low-risk patients with community-acquired pneumonia were asked to describe patient characteristics at initial examination that influenced the hospitalization decision, and to identify the health care services that would have allowed initial outpatient treatment of hospitalized patients. RESULTS: A total of 292 medical practitioners completed questionnaires for 472 (76%) of the 624 low-risk patients eligible for this study. Although all patients had a predicted probability of death of less than 4%, practitioners estimated that 5% of outpatients and 41% of inpatients had an expected 30-day risk of death of more than 5%. Univariate analyses identified 3 practitioner-rated factors that were nearly universally associated with hospitalization: hypoxemia (odds ratio, 173.3; 95% confidence interval, 23.8-1265.0), inability to maintain oral intake (odds ratio, 53.3; 95% confidence interval, 12.8-222.5), and lack of patient home care support (odds ratio, 54.4; 95% confidence interval, 7.3-402.6). In patients without these 3 factors, logistic regression analysis demonstrated that practitioner-estimated risk of death of more than 5% had a strong independent association with hospitalization (odds ratio, 18.4; 95% confidence interval, 6.1-55.7). Practitioners identified home intravenous antibiotic therapy and home nursing observation as services that would have allowed outpatient treatment of more than half (68% and 59%, respectively) of the patients initially hospitalized for treatment. CONCLUSIONS: Practitioners' survey responses suggest that the availability of outpatient intravenous antimicrobial therapy and home nursing care would allow outpatient care for a large proportion of low-risk patients who are hospitalized for community-acquired pneumonia. These data also suggest that methods to improve practitioners' identification of low-risk patients with community-acquired pneumonia could decrease the hospitalization of such patients. Future studies are required to help physicians identify which low-risk patients could safely be treated in the outpatient setting on the basis of clinical information readily available at presentation.

Occupational exposures and diseases among medical inpatients. Prevalence, association, and recognition.

The purpose of this study was to identify the prevalence of occupational exposures, their potential contribution to the development of chronic diseases among medical inpatients, and their recognition by house officers. Occupational histories were obtained from 101 medical inpatients and their charts were reviewed. Sixty-six percent of patients had diseases for which an occupational etiology merited consideration. A relevant occupational exposure was discovered in 68% of patients with a disease potentially attributable to occupation. Specific disease/exposure pairs were associated with each other (P = .001). Senior house staff recognized fewer relevant exposures (17%) than did interns (55%) (P < .001). Relevant occupational exposures are common among medical inpatients, but frequently go unrecognized because of an inadequate fund of knowledge in occupational medicine among physicians.

The inter-rater reliability and internal consistency of a clinical evaluation exercise.

OBJECTIVE: To assess the internal consistency and inter-rater reliability of a clinical evaluation exercise (CEX) format that was designed to be easily utilized, but sufficiently detailed, to achieve uniform recording of the observed examination. DESIGN: A comparison of 128 CEXs conducted for 32 internal medicine interns by full-time faculty. This paper reports alpha coefficients as measures of internal consistency and several measures of inter-rater reliability. SETTING: A university internal medicine program. Observations were conducted at the end of the internship year. PARTICIPANTS: Participants were 32 interns and observers were 12 full-time faculty in the department of medicine. The entire intern group was chosen in order to optimize the spectrum of abilities represented. Patients used for the study were recruited by the chief resident from the inpatient medical service based on their ability and willingness to participate. INTERVENTION: Each intern was observed twice and there were two examiners during each CEX. The examiners were given a standardized preparation and used a format developed over five years of previous pilot studies. MEASUREMENTS AND MAIN RESULTS: The format appeared to have excellent internal consistency; alpha coefficients ranged from 0.79 to 0.99. However, multiple methods of determining inter-rater reliability yielded similar results; intraclass correlations ranged from 0.23 to 0.50 and generalizability coefficients from a low of 0.00 for the overall rating of the CEX to a high of 0.61 for the physical examination section. Transforming scores to eliminate rater effects and dichotomizing results into pass-fail did not appear to enhance the reliability results. CONCLUSIONS: Although the CEX is a valuable didactic tool, its psychometric properties preclude reliable assessment of clinical skills as a one-time observation.

Symptoms and microenvironmental measures in nonproblem buildings.

Symptoms commonly defined as the sick building syndrome were studied in a cross-sectional investigation of 147 office workers in five building areas using a linear-analog self-assessment scale questionnaire to define symptoms at a specific point in time. At the same time, the environment in the breathing zone was characterized by measuring thermal parameters (dry-bulb temperature, relative humidity, air speed, and radiant temperature), volatile organic compounds, respirable suspended particulates, noise and light intensity, and carbon dioxide and carbon monoxide levels. Demographic characteristics of the occupants and building characteristics were recorded. Up to 25% of the variance in regression models could be explained for mucous membrane irritation and central nervous system symptoms. These two symptom groups were related to the concentrations of volatile organic compounds, to crowding, to layers of clothing, and to measured levels of lighting intensity. Chest tightness was also related to lighting intensity. Skin complaints were related only to gender. Gender, age, and education failed to demonstrate a consistent relationship with symptom categories. This study suggests that the sick building syndrome may have specific environmental causes, including lighting and volatile organic compounds.

The duration of Holter monitoring in patients with syncope. Is 24 hours enough?

To determine the incremental yield of ambulatory monitoring in the evaluation of syncope, three serial 24-hour Holter recordings were obtained in a consecutive series of 95 patients with syncope, the cause of which was not explained by history, physical examination, or 12-lead electrocardiogram. The mean age of patients was 61 years and 41% were men. Major electrocardiographic abnormalities were found in 26 patients (27%), including unsustained ventricular tachycardia (19 patients), pauses of at least 2 seconds (8 patients), profound bradycardia (1 patient), and complete heart block (1 patient). The first 24-hour Holter recording had at least one major abnormality in 14 patients (15%) (95% confidence interval, 8.3% to 23.4%). Of the 81 patients without a major abnormality on the first Holter recording, the second Holter recording had major abnormalities in 9 (11%) (95% confidence interval, 5.1% to 20.0%). Of the 72 patients without a major abnormality on the first two Holter recordings, only 3 patients (4.2%) had a major abnormality on the third Holter recording (95% confidence interval, 0.8% to 11.7%). Four factors were significantly associated with an increased likelihood of a major abnormality on 72 hours of monitoring: age above 65 years (relative risk, 2.2), male gender (relative risk, 2.0), history of heart disease (relative risk, 2.2), and an initial nonsinus rhythm (relative risk, 3.5). These results suggest that 24 hours of Holter monitoring is not enough to identify all potentially important arrhythmias in patients with syncope. Monitoring may need to be extended to 48 hours if the first 24-hour Holter recording is normal.

Health care cost containment: how Pittsburgh is addressing the challenge.

Rapidly escalating health care costs have the public and private sectors searching for methods to provide health care benefits in a more efficient manner. Efforts have also been underway at the community level with the development of health care coalitions created to build consensus toward a fair solution for all parties affected. With the assistance of the Robert Wood Johnson Foundation and many local co-sponsors, the Pittsburgh Program for Affordable Health Care (PPAHC) was organized to address health care cost containment issues in the greater Pittsburgh area. One of the means by which PPAHC chose to achieve this was through the development of a Model Utilization Management Program. This is a document containing community-sanctioned administrative and clinical standards for utilization review which take into consideration the needs and concerns of providers, purchasers, and consumers, and which have a goal of reducing medically unnecessary inpatient hospitalization while concurrently maintaining quality of and access to care. This article describes both the process and the product of PPAHC's efforts toward health care cost containment in Pittsburgh, specifically focusing on its utilization management component.

Development of a central division of general internal medicine.

A division of general internal medicine was, by design, developed to be central to many of the activities of the department of medicine. Since 1979 the division has grown from five faculty members to 29 members and has the potential for substantial additional growth. The division provides approximately 70% of all inpatient teaching by attending physicians, provides all of the general medicine outpatient teaching, and has substantial impact on medical student training programs. The division is responsible for more than $1.5 million of clinical services and approximately 10% of hospital admissions, and it is responsible for approximately 40% of all patients on the general medicine service. Research activities are divided into several distinct modules, including medical informatics, clinical epidemiology, occupational medicine, geriatrics, medical competency testing, and ethics. The division receives approximately $1.2 million from external sources, including the federal government and foundations, for its research activities. Because of its success, it may serve as a potential model for similar divisions in other departments of medicine.

Liver injury tests in hazardous waste workers: the role of obesity.

The prevalence of fatty liver disease at autopsy ranges from 40% to 80% in Europe and North America, and liver injury tests are abnormal in up to 8% of healthy populations. Liver injury tests were therefore examined in a group of 325 workers without exposure to hepatotoxins to identify the influence of obesity and gender. Obesity was a strong predictor of the degree of abnormality for serum levels of arginine and alanine aminotransferase and of alkaline phosphatase, even in the normal range. Women generally demonstrated lower levels of these enzymes. Workers with morbid obesity were substantially more likely to have abnormal liver injury tests. Obesity and gender must be considered in the interpretation of abnormal liver injury tests in hazardous waste workers.

Chest X-rays in hypersensitivity pneumonitis: a metaanalysis of secular trend.

A metaanalysis of published reports of outbreaks of hypersensitivity pneumonitis was undertaken. A statistically significant substantial decline was seen in the sensitivity of chest X-rays (percent of positive in cases of disease) for the diagnosis of hypersensitivity pneumonitis over the years 1950-1980. Chest X-rays were also less likely to be abnormal where a population-based approach to the diagnosis of disease had been undertaken. Such declines in the diagnostic "sensitivity" of a test may be related to secular trends in knowledge and recognition of disease or to changes in the disease itself. Standardization of chest X-ray interpretation alone, even if successful, may not resolve the issue of accurate diagnosis of interstitial lung disease.

The medical evaluation of elderly patients with major depression.

Elderly patients hospitalized for management of major depression frequently have an extensive medical evaluation to determine if physical illness is masquerading as, or serving as the precipitating event for, the depression. The purpose of this study was to determine the incidence of newly discovered medical problems and the yield of various diagnostic modalities in such elderly depressed patients. Of 100 depressed geropsychiatric inpatients, the most frequent new diagnoses included: electrolyte abnormalities (6 patients), bacteriuria (13), medication reactions (7), exacerbation of previous thyroid disease (6), new thyroid function abnormalities (3), and renal failure, Parkinson's Disease, and chronic obstructive lung disease (2 each). One patient had a cerebellar hemangioblastoma, and 4 had acute illnesses. A workup including CBC, blood chemistries, urinalysis, and thyroid function tests frequently yielded abnormal results. When used as screening tests, head CT scanning, electroencephalography, and chest radiography did not affect management. We conclude that elderly depressed patients have a high prevalence of undiscovered physical illnesses, but that history, physical examination, and simple laboratory evaluation may be sufficient to guide their workups.

Diagnostic and prognostic implications of recurrences in patients with syncope.

The incidence and the diagnostic and prognostic implications of recurrences in 433 patients enrolled in a prospective syncope study are reported. Over a mean follow-up of 30 months, 146 patients had recurrent syncope. Patients with an initial diagnosis of a cardiovascular cause of syncope had a recurrence rate of 31 percent, patients with a noncardiovascular cause had a recurrence rate of 36 percent, and patients with syncope of unknown origin had a recurrence rate of 43 percent at three years (these differences were not significant; the minimum for any two-way comparison was p greater than or equal to 0.11). In eight of the 191 patients in whom a cause of syncope could not be found on initial evaluation, a diagnosis was assigned in follow-up after recurrent syncope. Recurrences led to major morbidity in eight of 146 patients (5 percent) and minor trauma in 10 patients (7 percent). Using recurrence as a time-dependent variable in the Cox models, it was found that this variable was not a significant predictor of overall mortality or sudden death. It is concluded that recurrences are common in patients with syncope, but new diagnosis are rarely established on the basis of evaluation of recurrences. Recurrences are not predictors of mortality or sudden death.

Clinical prediction rules for computed tomographic scanning in senile dementia.

The role of computed tomography (CT) of the head in evaluating patients with dementing illnesses remains a controversial issue. Several prediction rules to guide the selective application of CT in the evaluation of dementia have recently been proposed in the medical literature. The present authors examine the value of four such rules through a validation study performed in an outpatient geriatric assessment unit. The rules were assessed in terms of their diagnostic sensitivities, specificities, misclassification rates, and information contents. Prediction rule sensitivities ranged from 12.5% to 87.5%, specificities from 37.2% to 77.9%, and misclassification rates from 23.5% to 60.8%. Of the four prediction rules examined, one emerged as significantly more sensitive than the others, and also served to reduce diagnostic uncertainty a full order of magnitude more than the others, as determined by an information content analysis. Disadvantages to this rule, however, were found in its more complex nature and the assessment of a very high rate of misclassification. Through a critique of existing strategies, this study purports to determine the potential for establishing a useful clinical prediction rule to guide selective CT scanning in the diagnostic evaluation of dementia.

Prolonged electrocardiographic monitoring in patients with syncope. Importance of frequent or repetitive ventricular ectopy.

The purposes of this study were to document the findings on prolonged electrocardiographic monitoring in patients with syncope, correlate these findings with symptoms during monitoring, and define the prognostic importance of these findings. A total of 235 patients with syncope in whom a cause was not assigned or suggested by the initial history, physical examination, and electrocardiography were studied. Although a variety of arrhythmias were documented during monitoring, the vast majority of arrhythmias were of short duration and did not produce symptoms. At two years, the patients with frequent or paired premature ventricular contractions (PVCs) when compared with patients with rare PVCs, had a higher incidence of sudden death (18.2 percent versus 4.0 percent; p less than 0.001) and higher overall mortality (28.3 percent versus 10.8 percent; p less than 0.003). Similarly, patients with ventricular tachycardia, when compared with patients with rare PVCs, had a higher incidence of sudden death (18.7 percent versus 4.0 percent; p less than 0.0001) and higher overall mortality (36.5 percent versus 10.8 percent; p less than 0.00001). Cox regression analyses revealed that frequent or repetitive PVCs and sinus pauses were independent electrocardiographic predictors of sudden death and mortality in patients presenting with syncope. Therefore, patients with syncope and frequent or repetitive ventricular ectopy or sinus pauses constitute a high-risk subgroup and may be candidates for more extensive diagnostic evaluation.

Defecation syncope. A symptom with multiple etiologies.

To our knowledge, there is no previous clinical description in the literature of patients with defecation syncope. We evaluated 20 patients with this disorder who were a subgroup of a larger, prospective study of syncope, 13 women and seven men, with a mean age of 59 years. Eleven patients had had one episode and nine had experienced multiple episodes. Fourteen patients were recumbent before the urge to defecate, nine of these asleep. The diagnostic evaluation disclosed that two patients had gastrointestinal tract problems, three had cardiac diseases, and one had transient ischemic attacks. Three additional patients had marked orthostatic hypotension. No identifiable cause for defecation syncope was found in 11 patients, but new medical problems were noted in four of those patients. In follow-up at two years, syncope had recurred in ten patients, but the majority of recurrences were unassociated with defecation. Seven patients died during the follow-up period of underlying chronic diseases. We conclude that defecation syncope is not a single distinct clinical entity. Multiple pathologic abnormalities in association with physiologic changes during sleep and defecation may contribute to syncope. Patients with defecation syncope should undergo a careful evaluation for diagnosis of underlying illness causing syncope.