Quantitative assessment of the impact of standard agreement templates on multisite clinical trial start up time.

Contracting delays remain a challenge to the successful initiation of multisite clinical research in the US. The Clinical and Translational Science Awards (CTSA) Contracts Processing Study showed average contract negotiation duration of > 100 days for industry-sponsored or investigator-initiated contracts. Such delays create enormous costs to sponsors and to patients waiting to use new evidence-based treatments. With support from the National Institutes of Health's National Center for Advancing Translational Sciences, the Accelerated Clinical Trial Agreement (ACTA) was developed by 25 major academic institutions and medical centers engaged in clinical research in collaboration with the University-Industry Demonstration Partnership and with input from pharmaceutical companies. The ACTA also informed the development of subsequent agreements, including the Federal Demonstration Partnership Clinical Trial Subaward Agreement (FDP-CTSA); both ACTA and the FDP-CTSA are largely non-negotiable agreements that represent pre-negotiated compromises in contract terms agreed upon by industry and/or medical center stakeholders. When the involved parties agree to use the CTSA-developed and supported standard agreement templates as a starting point for negotiations, there can be significant time savings for trials. Use of the ACTA resulted in an average savings of 48 days and use of the FDP-CTSA saved an average of 57 days of negotiation duration.

The influence of an all-female healthcare environment on mentorship and empowerment of female healthcare professionals.

Low- and middle-income countries (LMICs) have the greatest need for additional healthcare providers, and women outside the workforce help address the need. Women in healthcare need more mentorship and leadership training to advance their careers due to systemic barriers. This study evaluates how women working together on a medical team influences mentorship, leadership and empowerment. A single all-female volunteer team participating in a cleft surgery mission in Oujda, Morocco were surveyed before and after the mission. Statistical analysis with student's t-test or chi-squared were performed. 95 female volunteers from 23 countries participated on this team and 85% completed surveys. Volunteers from high-income countries (32%) and LMICs (68%) had similar mission roles (p = 0.58). Experience as a mission volunteer (p = 0.47), team leader (p = 0.28), and educator (p = 0.18) were equivalent between cohorts. 73% of women had previously received mentorship but 98% wanted more. 75% had previously mentored others, but 97% wanted to be mentors. 73% of volunteers who had no prior mentorship found their first mentor during the mission. All participants found a long-term peer relationship and felt motivated to mentor women at home. 95% were inspired to pursue leadership positions, advance professionally, and continue working with other women. This population of female healthcare professionals overwhelmingly desired more mentorship than is felt to be available. An all-female healthcare environment appears to provide opportunities for mentorship and create lasting motivation to teach, lead, and advance professionally. Findings raise the potential that increasing visibility of female professionals may effectively empower women in healthcare.

Interaction between the legionnaires' disease bacterium (Legionella pneumophila) and human alveolar macrophages. Influence of antibody, lymphokines, and hydrocortisone.

We have studied the interaction between virulent Legionella pneumophila and human alveolar macrophages, the resident phagocytes at the site of infection in Legionnaires' disease. L. pneumophila multiplied 2.5-5 logs within 3 d, as measured by colony forming units, when incubated with freshly explanted alveolar macrophages in monolayer culture. At the peak of bacterial multiplication, the alveolar macrophage monolayers were destroyed. L. pneumophila multiplied more rapidly in 4-d-old than in freshly explanted alveolar macrophages. Inside alveolar macrophages, L. pneumophila were located within membrane-bound vacuoles whose cytoplasmic sides were studded with ribosomes. Alveolar macrophages that were incubated with concanavalin A (Con A) stimulated human mononuclear cell supernatants (cytokines), inhibited L. pneumophila multiplication, and the degree of inhibition was proportional to the concentration of Con A supernatant added. Anti-L. pneumophila antibody in conjunction with complement promoted phagocytosis of L. pneumophila by alveolar macrophages. By electron microscopy, most (75%) of the phagocytized L. pneumophila were intracellular. However, freshly explanted alveolar macrophages were able to kill only 0-10% of an innoculum of L. pneumophila even in the presence of antibody and complement. At the same time, alveolar macrophages also killed opsonized Escherichia coli poorly. Increasing the ratio of macrophages to bacteria, adhering the macrophages to microcarrier beads, or preincubating the macrophages for 24 or 48 h with Con A supernatants failed to augment alveolar macrophage killing of opsonized E. coli. Corticosteroids appear to increase patient susceptibility to Legionnaires' disease. However, pretreatment of alveolar macrophages and monocytes with hydrocortisone had no influence on intracellular multiplication of L. pneumophila or on the inhibition of that multiplication by activated alveolar macrophages or monocytes. Hydrocortisone did impair cytokine-induced aggregation of alveolar macrophages. These findings demonstrate that L. pneumophila multiplies in human alveolar macrophages and that they do so within a ribosome-lined phagosome; that freshly explanted alveolar macrophages kill few L. pneumophila even in the presence of antibody and complement; that activated alveolar macrophages inhibit L. pneumophila multiplication; and that steroids do not exert a direct suppressive effect on the anti-L. pneumophila activity of activated or nonactivated alveolar macrophages. Our findings indicate that alveolar macrophages may play a central role in both the pathogenesis of Legionnaires' disease and in host defense against it. This paper shows that human resident macrophage can be activated to a higher state of antimicrobial capacity and that the human alveolar macrophage can serve as an effector call in call-mediated immunity.

Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer.

PURPOSE: Preclinical studies suggest that treatment with a selective cyclo-oxygenase-2 (COX-2) inhibitor may augment the antitumor effects of chemotherapy. In this study, patients with non-small-cell lung cancer (NSCLC) were preoperatively treated with celecoxib in combination with chemotherapy. End points were toxicity, response rates, and measurement of intratumoral levels of prostaglandin E2 (PGE2). METHODS: In this phase II trial, 29 patients with stages IB to IIIA NSCLC were treated with two preoperative cycles of paclitaxel and carboplatin, as well as daily celecoxib, followed by surgical resection. Levels of PGE2 in the primary tumors and adjacent normal lung tissue were compared in 17 study patients versus 13 controls, who received preoperative paclitaxel/carboplatin without celecoxib. RESULTS: All patients completed preoperative chemotherapy, and 26 completed preoperative celecoxib. The overall clinical response rate was 65% (48% with partial response; 17% with complete response). Grade 3 or 4 neutropenia was observed in 18 patients (62%). Twenty-eight patients were explored and underwent complete resection of their tumors. There were no complete pathologic responses, but seven patients (24%) had minimal residual microscopic disease. The addition of celecoxib to a regimen of paclitaxel and carboplatin abrogated the marked increase in levels of PGE2 detected in primary tumors after treatment with paclitaxel and carboplatin alone. CONCLUSION: In comparison with historically reported response rates, these data suggest that the addition of a selective COX-2 inhibitor may enhance the response to preoperative paclitaxel and carboplatin in patients with NSCLC. Moreover, treatment with celecoxib 400 mg twice daily was sufficient to normalize the increase in PGE2 levels found in NSCLC patients after treatment with paclitaxel and carboplatin. Confirmatory trials are planned.

The solitary pulmonary nodule: update 1995.

PURPOSE: This study analyzed the clinical characteristics, diagnostic evaluation, prevalence of malignancy, and outcome of patients with a solitary pulmonary nodule (SPN) encountered in the outpatient practice of a pulmonologist in an urban university hospital from 1990 to 1993. PATIENTS AND METHODS: SPN was defined as a round or ovoid density < or = 3 cm in diameter within the lung parenchyma. Patients with and without lung cancer in SPNs were compared. RESULTS: Forty patients had a mean age of 65 years, an almost equal sex distribution, high prevalences of cardiovascular disease (53%) and chronic obstructive pulmonary disease (COPD) (33%), but a low incidence of tuberculosis. The mean size of SPNs was 1.8 cm. The prevalence of malignancy was 53%. In SPNs < or = 2 cm in diameter, the prevalence of malignancy was 43%. Nonsurgical biopsy techniques made a diagnosis in 78% of patients. In 94% of patients with lung cancer in SPNs, the tumor was resectable (stage 1, 2, or 3A), emphasizing the need for early detection. Despite the small size of the SPNs, the prevalence of malignancy was high. CONCLUSION: Despite the advanced age and high prevalence of cardiovascular disease and COPD in patients with SPNs, lung cancer that occurs in these lesions appears to have a favorable prognosis if detected promptly.

Acute respiratory failure in scoliosis or kyphosis: prolonged survival and treatment.

Acute respiratory failure (ARF) in adults with severe thoracic spinal deformity is said to be a preterminal event with a median survival of one year. Twenty patients with ARF (mean +/- S.D., arterial oxygen tension [PaO2] 35 +/- 7 mm Hg, arterial carbon dioxide tension [PaCO2] 63 +/- 9 mm Hg, pH 7.34 +/- 0.08) due to severe scoliosis or kyphosis (spinal curve 113 +/- 28 degrees ) were seen between 1965 and 1980. All 20 survived the initial episode of ARF and during the follow-up period (median, six years) experienced 2.4 additional episodes of ARF. The age at presentation was 52 years (mean, range 13 to 78), and the cause of spinal deformity was idiopathic (seven patients), poliomyelitis (seven), tuberculosis (five), and arthrogryposis multiplex congenita (one). ARF was treated with controlled low dose oxygen by Venturi mask and intensive general measures in 13 patients and by mechanical ventilation in seven. Of the latter seven patients, ventilatory failure was treated in two with a tank respirator and a cuirass, avoiding endotracheal intubation. Outpatient management was similar to conventional therapy for chronic obstructive pulmonary disease (COPD). Severe restrictive ventilatory impairment characterized the group after recovery from the first episode of ARF: vital capacity (VC) 906 +/- 362 ml (31 percent predicted) and FEV1 589 +/- 197 ml (23 percent). During follow-up, the VC decreased by 1.5 ml/year and the FEV1 by 13.9 ml/year. The PaO2 increased by 2.6 mm Hg/year and the PaCO2 increased by 1.7 mm Hg/year. Successful management of ARF due to severe scoliosis or kyphosis is possible in the great majority of patients, and long-term survival may be expected. Unlike COPD, pulmonary function following ARF in kyphosis or scoliosis deteriorates at a slower than expected rate and, in fact, may improve with treatment over many years.

Syphilitic aortic aneurysm presenting with the superior vena cava syndrome.

In a 65 year old man with hemoptysis, chest pain, weight loss, clubbing of the digits and a large mediastinal mass, the superior vena cava syndrome developed. He was treated for malignancy with radiation therapy and corticosteroids, but he died shortly after his admission to the hospital. Autopsy revealed syphilitic aortitis with an aneurysm of the ascending aorta compressing the superior vena cava and right mainstem bronchus. The postmortem serology corroborated the morphologic findings of tertiary syphilis. In this report we emphasize the important, although now uncommon, association between the superior vena cava syndrome and aneurysm of the aorta.

Cricoarytenoid arthritis in ankylosing spondylitis. A cause of acute respiratory failure and cor pulmonale.

A man with ankylosing spondylitis developed cor pulmonale and acute respiratory failure due to cricoarytenoid arthritis. He was successfully treated by endoscopic arytenoidectomy, and the surgical specimen showed ossified cartilage. Flow-volume curves documented extra-thoracic airway obstruction produced by ankylosis of the cricoarytenoid joints.

Simultaneous pulmonary and renal malignancy.

Simultaneous primary malignancy of the lung and kidney has been rarely recognized during life. Three patients with synchronous primary pulmonary and renal cancer are described. The pulmonary tumors were asymptomatic and were discovered on plain chest roentgenography. The renal tumors, also asymptomatic, were incidentally discovered on CT, performed for staging. Although one patient was treated with interleukin-2 for a presumed solitary pulmonary metastasis from renal carcinoma, in all three patients, both the kidney and lung tumors were eventually removed either concurrently or sequentially. Prior autopsy case series are reviewed. In the elderly, synchronous asymptomatic pulmonary and renal malignancy is not surprising, and it should be approached as a distinct clinical problem. With the use of chest roentgenography for screening high risk populations and CT for staging, simultaneous primary pulmonary and renal malignancy will probably be recognized increasingly.

Early lung cancer action project: annual screening using single-slice helical CT.

The advent of helical CT imaging held promise for the early diagnosis, and thereby, for enhanced curability of lung cancer--a highly fatal disease. In 1993, the Early Lung Cancer Action Project (ELCAP) was initiated and experimentally screened a cohort of 1,000 high-risk persons. Here we summarize the results of the baseline and annual repeat CT screening of these 1,000 subjects. CT-based screening (compared to traditional radiology) was clearly shown to enhance the detection of lung cancer at earlier and more curable stages. A discussion follows of the meaning of the results and possible future screening protocols.

Will minority physician supply meet U.S. needs?

We project the future racial and ethnic composition of the U.S. physician workforce under different assumptions. Our projections show that reaching racial and ethnic population parity with a managed care-based requirement of 218 physicians per 100,000 population would require the number of first-year residents to roughly double for Hispanic and black physicians, triple for Native American physicians, and be reduced by about two-fifths for white physicians and two-thirds for physicians of Asian or Pacific Island origin.

The substitution of physician assistants and nurse practitioners for physician residents in teaching hospitals.

This study documents features of clinical departments in teaching hospitals that are using physician assistants (PAs) and nurse practitioners (NPs) to perform some tasks previously done by medical or surgical residents. More than 60 percent of teaching hospital medical directors surveyed reported experience with substitution in their hospitals. The experience overall appears to be positive; one-third of the departments are planning to increase the number of PAs and NPs they use. The results imply that some of the services lost in house-staff reductions called for in many physician workforce reform proposals could be provided by alternative health professionals.

Pulmonary toxicity of drugs used to treat systemic autoimmune diseases.

A number of drugs used to treat systemic autoimmune diseases can cause respiratory complications. These include bronchospasm, noncardiac pulmonary edema, interstitial pneumonitis and fibrosis, hypersensitivity, and numerous other disorders. Additionally, some of these drugs increase the risk of infections, particularly with opportunistic organisms. This article reviews the clinical presentation and mechanism of toxicity of drug related pulmonary complications.

The feasibility of consortia for internal medicine graduate medical education: perspectives from a survey of residency directors.

PURPOSE: To assess the perspectives of internal medicine (IM) residency directors on issues that might determine the feasibility of consortia for IM graduate medical education (GME). METHOD: A self-administered questionnaire was mailed to all 413 U.S. IM program directors in June 1994. Of the 413 IM programs, 215 were located in community hospitals; 123 in university hospitals; and 75 in municipal, Veterans Administration, or military hospitals, or hospitals associated with multispecialty clinics ("other"). The questionnaire elicited responses concerning (1) perspectives on the quality of academic affiliations, (2) experience with formal institutional collaboration on GME issues and projection of consortium success, and (3) possible barriers to the success of consortia. Data were analyzed by comparing responses from the three program categories. RESULTS: In all, 330 (80%) program directors responded. Two-thirds reported ongoing academic affiliations. A larger percentage of university program directors considered these ties to be strong and advantageous than did their colleagues in community or other hospitals, who also considered their affiliations to be less equitable and less mutually trusting. Only 31% of community and university programs and 40% of other programs reported any prior experience with institutional collaboration on GME issues. A high percentage of those respondents considered these collaborative experiences to be successful and were optimistic about the projected success of consortia. Of seven possible barriers to consortium success, competition, governance, bureaucracy, and mistrust were most often perceived as major barriers. CONCLUSION: The data appear to indicate some optimism for the prospects of GME consortia, thereby supporting their feasibility for IM GME. Although many respondents perceived barriers to success, such perceptions were less common among program directors who had had direct experience with previous collaborative efforts. Nevertheless, these barriers may require attention if consortia are to succeed in achieving their many possible advantages.

Impact of metastases on nodal immunoreactivity in head and neck cancer.

It has been previously demonstrated by the authors that lymph nodes from patients with head and neck cancer are capable of regional immunoreactivity and that this immunoreactivity could be enhanced with certain nonspecific immunostimulants. However, it is unknown how metastases to the neck nodes would affect this immunoreactivity. The purpose of this study is to compare the immunoreactivity of matched node pairs (metastatic versus nonmetastatic) from head and neck cancer patients. The soft agar assay system was the methodology employed. The effect of nodal lymphocytes on tumor growth in soft agar was studied with and without nonspecific immunostimulation in both normal and metastatic nodes from the same location in the neck in 16 patients. The results demonstrate that lymph nodes from head and neck cancer patients are capable of an immune reaction to cancer, and that this immunoreactivity appears to be significantly increased in metastatic lymph nodes with and without the use of specific immunostimulants.

Ova fertilization and sperm number per fertilized ovum for selenium and vitamin E-treated charolais cattle.

Fertilization of ova, number of sperm per fertilized ovum and serum and myometrial Se concentrations were determined in Charolais cows treated with selenium and vitamin E (Se+E). Cows were considered low in Se status prior to allotment to either a control (n=20) or a Se+E-treated (n=21) group. Se+E-treated cows received 40 mg of Se as selenite and 544 IU of alpha-tocopherol acetate by IM injection at 14-day intervals throughout the study, whereas control cows received saline. Starting on day 75 of treatment, cows were checked for estrus and inseminated. Reproductive tracts were removed at slaughter with ova collected and examined for fertilization and number of adhered sperm. The proportion of recovered ova that were fertilized for control and Se+E-treated cows was 8 of 11 and 12 of 15, respectively (P > .05). For spermatozoal data, a few extreme values accounted for a non-significant trend in which a greater number of sperm were adhered to fertilized ova collected from Se+E-treated than control cows (35.6 +/- 7.2 and 24.8 +/- 7.7, respectively). When analyzing only ova with spermatozoal numbers within one S.D. of the mean number of sperm per fertilized ovum, mean (+/- S.E.M.) spermatozoal numbers for control and Se+E-treated cows were 13.5 +/- 3.1 and 36.4 +/- 5.3, respectively (P <. 005). Spermatozoal number was correlated (P <. 01) with serum and myometrial Se concentrations (r=.67 and .78, respectively) and these concentrations were greater (P <. 001) in treated animals. Low Se status was not associated with ova fertilization in this study; however, greater spermatozoal numbers for fertilized ova collected from Se+E-treated cows suggests increased sperm transport.

Serum and testis selenium concentrations and testis morphology in ram lambs of varying ages.

Serum and testis selenium (Se) concentrations, body and testes weights, seminiferous tubule height and width measurements and percent of tubules containing luminal spermatozoa were determined in Se-treated (SSe) and control (NSe) crossbred ram lambs at 60, 90, 120, 150 and 180 days of age. With IM injections, SSe lambs received 3 mg of Se as selenite and NSe lambs received 0.9% saline at 30-day intervals throughout the study. For each age group, lambs were weighed, jugular vein blood collected and testes removed at the designated age. Serum and testis tissue samples for each lamb were assayed for Se, and testis tissue was also evaluated for histological parameters. For all parameters, only serum Se concentrations were affected (P<0.0001) by Se treatment; however, all other parameters were affected (P<0.0001) by age. For combined groups, mean testis Se concentration (0.33 ppm), testes weights, seminiferous tubule measurements and percent of tubules (82.2) containing luminal spermatozoa were greatest (P<0.05) at 180 days of age, and mean testis Se concentrations were significantly correlated with these testicular parameters. These data lend support to the hypothesis that the increase in concentration of testicular Se to adult concentrations (>0.3 ppm) around the time of puberty is associated with rapid testicular development and production of spermatozoa.

Clinical utility of computed tomography in the diagnosis of pulmonary embolism.

This prospective clinical pilot study describes the clinical utility and cost effectiveness of computed tomography (CT) with contrast in the diagnosis and management of pulmonary embolism. The setting is a university teaching hospital, and the 20 patients, 26 to 81 years old, were found to have CT findings consistent with pulmonary embolism. Intraluminal pulmonary artery clots were observed on CT and contributed to clinical management, often obviating pulmonary arteriography. CT, particularly spiral CT, may demonstrate pulmonary embolism and offers advantages over ventilation-perfusion lung scanning and pulmonary arteriography in making the diagnosis of pulmonary embolism in high-risk patients or patients with preexisting parenchymal lung disease.

CT-guided transthoracic needle biopsy of small solitary pulmonary nodules.

The use of CT guidance in performing transthoracic needle biopsy is well established. We evaluated its accuracy in the diagnosis of small solitary nodules and found it to be highly accurate regardless of size or location. While specific benign diagnoses were uncommon, additional confidence in a benign diagnosis can be gained by careful analysis of needle tip location using strict CT criteria.

Radiographic screening for cancer. Proposed paradigm for requisite research.

Computed tomography (CT) imaging as an excellent approach to the detection and characterization of small solitary pulmonary nodules (SSPN) raises three questions: (1) How often does CT imaging lead to detection of SSPN? (2) How often is such an SSPN malignant? (3) If malignant, how curable is it? The first question pertains to decisions about screening use of CT (clinical or mass screening), the second to decisions about screening for SSPN and diagnosis of malignancy given SSPN, and the third--in the context of known curability at ordinary clinical diagnosis--to decisions about screening for SSPN, diagnosis given SSPN and intervention given malignant SSPN. We present a three component study design that addresses these questions. The first is directed primarily to the first question. Some 1000 persons at high risk for lung cancer will be screened for SSPN using screening-type CT. The primary aim is to determine the prevalence of CT-detectable SSPN as a joint function of risk-relevant aspects of the person. The second component addresses the prevalence of malignancy among the detected cases of SSPN. To develop the prevalence function, a larger series of CT-detected SSPN will be obtained by developing a multi-center SSPN "registry." A subsequent, third component will focus on the registered cases of malignant SSPN screening incidentally detected and address their curability on the basis of long-term follow-up. This design, in lieu of a randomized trial, may represent a new paradigm for applied research on radiologic technologies in cancer screening, given its advantages in terms of research efficiency and implications to decisions about diagnostic workup and therapeutic intervention.