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.

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.

Guidelines for the use of spiral computed tomography in screening for lung cancer.

Screening should be considered in lung cancer, more than any other cancer. Not only is the disease highly fatal, essentially incurable, when diagnosed on the prompting of symptoms and/or clinical signs, but its occurrence is also highly concentrated in identifiably high-risk persons. The degree of usefulness of computed tomography (CT)-based screening for lung cancer must be thought of in reference to a particular, presumably optimal, regimen of pursuing early stage diagnosis. This is an algorithm that begins with the initial test ("screening CT") and ends in either discontinuation of the diagnostic pursuit or in diagnosis of lung cancer. A carefully developed, extensively pilot tested and critically reviewed, updated protocol for CT-based screening for lung cancer is presented here. Its implementation is addressed, together with quality assurance. Finally, the associated curability rate for lung cancer is addressed in the light of what is known or can be surmised from evidence already available. However, recommendation for or against screening requires further information. Principally, the patients risk for lung cancer (in the near future) and the patients life expectancy (when spared of death from lung cancer). These two factors influence when, if ever, to begin screening, and if it is initiated, when to discontinue it. Finally, cost-effectiveness of the screening program should also be considered.

Early lung cancer action project: initial findings on repeat screenings.

BACKGROUND: The Early Lung Cancer Action Project (ELCAP) was designed to evaluate the usefulness of annual computed tomography (CT) screening for lung carcinoma. With the baseline results having been reported previously, the focus of the current study was on the early results of the repeat screenings. METHODS: A cohort of 1000 high-risk individuals was recruited for baseline and annual repeat CT screening. At last follow-up, a total of 1184 annual repeat screenings had been performed. A positive result from the screening test was defined as newly detected, one to six noncalcified pulmonary nodules with interim growth. The diagnostic workup of the individuals was guided by recommendations supplied by the ELCAP investigators to the collaborating clinicians. RESULTS: Of the 1184 repeat CT screenings, the test result was positive in 30 (2.5%). In 2 of these 30 cases, the individual died (of an unrelated cause) before diagnostic workup and the nodule(s) resolved in another 12 individuals. In the remaining 16 individuals, the absence of further growth was documented by repeat CT in 8 individuals and further growth was documented in the remaining 8 individuals. All eight individuals with further nodular growth underwent biopsy and malignancy was diagnosed in seven. Six of these seven malignancies were nonsmall cell carcinomas (five of which were Stage IA and one of which was Stage IIIA) and the one small cell carcinoma was found to be of limited stage. The median size dimension of these malignancies was 8 mm. In another two subjects, symptoms prompted the interim diagnosis of lung carcinoma. Neither of these malignancies was nodule-associated but rather were endobronchial; one was a Stage IIB nonsmall cell carcinoma and the other was a small cell carcinoma of limited stage. CONCLUSIONS: False-positive screening test results are uncommon and usually manageable without biopsy; compared with no screening, such screenings permit diagnosis at substantially earlier and thus more curable stages. Annual repetition of CT screening is sufficient to minimize symptom-prompted interim diagnoses of nodule-associated malignancies.

Early lung cancer action project: a summary of the findings on baseline screening.

PURPOSE: The Early Lung Cancer Action Project (ELCAP) is designed to evaluate baseline and annual repeat screening by low radiation dose computed tomography (low-dose CT) in persons at high-risk for lung cancer. METHODS: Since starting in 1993, the ELCAP has enrolled 1,000 asymptomatic persons, 60 years of age or older, with at least 10 pack-years (1 pack per day for 10 years, or 2 packs per day for 5 years) of cigarette smoking, no prior cancer, and medically fit to undergo thoracic surgery. After a structured interview and informed consent, baseline chest radiographs and low-dose CT were obtained on each subject. The diagnostic work-up of screen-detected noncalcified pulmonary nodules (NCN) was guided by ELCAP recommendations which included short-term high-resolution CT follow-up for the smallest nodules. Baseline RESULTS: On low-dose CT at baseline compared to chest radiography, NCN were detected three times as commonly (23% versus 7%), malignancies four times as commonly (2.7% versus 0.7%), and stage I malignancies six times as commonly (2.3% versus 0.4%). Of the 27 CT-detected cancers, 96% (26/27) were resectable; 85% (23/27) were stage I, and 83% (19 of the 23 stage I) were not seen on chest radiography. Following the ELCAP recommendations, biopsies were performed on 28 of the 233 subjects with NCN; 27 had a malignant and one a benign NCN. Another three individuals underwent biopsy outside of the ELCAP recommendations; all had benign NCNS: No one had thoracotomy for a benign nodule. CONCLUSION: Baseline CT screening for lung cancer provides for detecting the disease at earlier and presumably more commonly curable stages in a cost-effective manner.

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.

Nursing drives interdisciplinary health care workforce planning in Wisconsin: one state's experience.

The Consortium for Primary Care in Wisconsin convened a forum to develop an interdisciplinary primary care workforce plan to address issues related to the supply of and demand for primary health care providers in Wisconsin. Nursing leaders played a pivotal role in making this effort successful and in ensuring that the focus would be on all primary health care professionals, not just physicians. This process used a primary care workforce planning tool (IRM) developed by the Bureau of Health Professions, U.S. Public Health Service which allowed Wisconsin to (1) examine its own workforce needs with data produced in Wisconsin, (2) compare the state's situation with national trends, and (3) include these data and projections in a cooperative process for state-level planning for interdisciplinary workforce development. The Bureau has encouraged other states and organizations to adopt a similar strategy through a series of IRM workshops in which the Wisconsin process serves as a model for training materials developed for these workshops. The Wisconsin planning process is an innovative model for other states to follow in facilitating workforce development and serves to encourage other states to share their experiences in the academic literature.

Early Lung Cancer Action Project: overall design and findings from baseline screening.

BACKGROUND: The Early Lung Cancer Action Project (ELCAP) is designed to evaluate baseline and annual repeat screening by low-radiation-dose computed tomography (low-dose CT) in people at high risk of lung cancer. We report the baseline experience. METHODS: ELCAP has enrolled 1000 symptom-free volunteers, aged 60 years or older, with at least 10 pack-years of cigarette smoking and no previous cancer, who were medically fit to undergo thoracic surgery. After a structured interview and informed consent, chest radiographs and low-dose CT were done for each participant. The diagnostic investigation of screen-detected non-calcified pulmonary nodules was guided by ELCAP recommendations, which included short-term high-resolution CT follow-up for the smallest non-calcified nodules. FINDINGS: Non-calcified nodules were detected in 233 (23% [95% CI 21-26]) participants by low-dose CT at baseline, compared with 68 (7% [5-9]) by chest radiography. Malignant disease was detected in 27 (2.7% [1.8-3.8]) by CT and seven (0.7% [0.3-1.3]) by chest radiography, and stage I malignant disease in 23 (2.3% [1.5-3.3]) and four (0.4% [0.1-0.9]), respectively. Of the 27 CT-detected cancers, 26 were resectable. Biopsies were done on 28 of the 233 participants with non-calcified nodules; 27 had malignant non-calcified nodules and one had a benign nodule. Another three individuals underwent biopsy against the ELCAP recommendations; all had benign non-calcified nodules. No participant had thoracotomy for a benign nodule. INTERPRETATION: Low-dose CT can greatly improve the likelihood of detection of small non-calcified nodules, and thus of lung cancer at an earlier and potentially more curable stage. Although false-positive CT results are common, they can be managed with little use of invasive diagnostic procedures.

AP-2alpha transcription factor is required for early morphogenesis of the lens vesicle.

AP-2 transcription factors are a family of retinoic acid-responsive genes, which are involved in complex morphogenetic processes. In the current study, we determine the requirement for AP-2alpha in early morphogenesis of the eye by examining the nature of the ocular defects in AP-2alpha null and chimeric mice. AP-2alpha null embryos exhibited ocular phenotypes ranging from a complete lack of eyes (anophthalmia) to defects in the developing lens involving a persistent adhesion of the lens to the overlying surface ectoderm. Two genes involved in lens development and differentiation, Pax6 and MIP26 were also misexpressed. AP-2alpha mutants also exhibited defects in the optic cup consisting of transdifferentiation of the dorsal retinal pigmented epithelium into neural retina and the absence of a defined ganglion cell layer. Newly generated chimeric embryos consisting of a population of AP-2alpha-/- and AP-2alpha+/+ cells exhibit ocular defects similar to those seen in the knockout embryos. Immunolocalization of AP-2 proteins (alpha, beta, and gamma) to the normal developing eye revealed both unique and overlapping expression patterns, with AP-2alpha expressed in a number of the ocular tissues that exhibited defects in the mutants, including the developing lens where AP-2alpha is uniquely expressed. Together these findings demonstrate a requirement for AP-2alpha in early morphogenesis of the eye.

CT-guided transthoracic needle biopsy following indeterminate fiberoptic bronchoscopy in solitary pulmonary nodules.

We evaluated the role of computed tomography (CT)-guided transthoracic needle biopsy (TNB) in patients with solitary pulmonary nodule and indeterminate flexible fiberoptic bronchoscopy (FOB). A review of 112 patients with solitary nodules under 3 cm in size who underwent TNB was carried out. A total of 48 patients had prior FOB with negative or indeterminate results. We reviewed the results of CT-guided TNB of these 48 patients with respect to the cytology results, nodule size and location, and complications of the procedure. Among the 48 patients who had FOB with indeterminate cytology, 32 were found to have malignant cytology on subsequent TNB. Among the remaining 16 patients, eight had diagnostic thoracotomy, which showed that six of the nodules were benign and two were malignant. The remaining eight patients who did not undergo surgery have been followed for more than 2 years, without evidence of growth. Results were not influenced by size or location. TNB offers a high yield for diagnosis in this patient population.

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.

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.

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.

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.

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.

Collaborative use of informatics among hospitals to benchmark medication use processes.

BACKGROUND: In spring 1995 pharmacists representing each of the 23 member hospitals in Synernet, a hospital cooperative in Maine, decided to collaborate in developing a multihospital medication use evaluation (MUE) program. The committee set up task forces for adverse drug reaction reporting and prevention, MUE plans, and medication error reporting and prevention, for exploration of opportunities to eliminate duplication of efforts, compare performance, and share best practices. PLANNING THE PROGRAM: The members retained a consulting firm to manage the SynRx medication use program from conceptualization through implementation. Modules--on individual drug dosing, switching from intravenous to oral administration, pharmacists' clinical recommendations, and surgical antibiotic prophylaxis--were designed so that participants could adopt the entire plan as a turnkey procedure by inserting their hospital name in the appropriate blanks, modify it to more closely fit their own organizations, use portions of it for inclusion in their current plans, or not use it at all. The goal was to build in maximum flexibility to accommodate the variations in the participating hospital pharmacies and their respective hospitals. RESULTS: Early program benefits include improvements in medication event reporting, documentation of the measured aspects of medication use, delivery of care processes, and administrative efficiency. LESSONS LEARNED AND CONCLUSIONS: The participants, consultants, and programmers involved in the SynRx program learned firsthand the complexity and magnitude of hospital medication use processes. Yet it is possible to overcome the wide variability in systems among hospitals to create standards that allow for more meaningful comparisons of medication use.

Domestic production vs international immigration: Options for the US physician workforce.

OBJECTIVE: To determine alternate combinations for reductions in US medical school graduates (USMGs), international medical graduate (IMG) immigration, and graduate medical education (GME) residencies, based on future physician supply targets. DESIGN: A demographic projection model of the physician supply was constructed and calibrated to fit observed American Medical Association Physician Masterfile data and current supply forecasts. Total annual input to GME was backcast from given future supply targets, adjusting for the portion of IMGs in GME who do not enter the US workforce. MAIN OUTCOME MEASURES: The annual number of new physicians added to supply from domestic or international sources needed to reach future physician-to-population ratio targets. RESULTS: Because of the low rate of attrition from the physician supply, it takes up to 50 years for workforce policy to effectively stabilize the physician-to-population ratio at a target level. All target ratios considered here would require immediate reductions in the total number of GME positions. These reductions must be followed by gradual annual increases to account for population growth. The size of USMG and IMG reductions are interrelated and depend critically on the percentage of IMG trainees who remain to practice in the United States. CONCLUSIONS: Reductions in future physician supply can come from either the IMG or USMG component of physician production, or both. The model developed here allows the estimation of multiple combinations of both GME components.