A modeling-based approach to optimize COVID-19 vaccine dosing schedules for improved protection.

While the development of different vaccines has slowed the dissemination of SARS-CoV-2, the occurrence of breakthrough infections continues to fuel the pandemic. As a strategy to secure at least partial protection, with a single dose of a given COVID-19 vaccine to maximum possible fraction of the population, delayed administration of subsequent doses (or boosters) has been implemented in many countries. However, waning immunity and emergence of new variants of SARS-CoV-2 suggest that such measures may jeopardize the attainment of herd immunity due to intermittent lapses in protection. Optimizing vaccine dosing schedules could thus make the difference between periodic occurrence of breakthrough infections or effective control of the pandemic. To this end, we have developed a mechanistic mathematical model of adaptive immune response to vaccines and demonstrated its applicability to COVID-19 mRNA vaccines as a proof-of-concept for future outbreaks. The model was thoroughly calibrated against multiple clinical datasets involving immune response to SARS-CoV-2 infection and mRNA vaccines in healthy and immunocompromised subjects (cancer patients undergoing therapy); the model showed robust clinical validation by accurately predicting neutralizing antibody kinetics, a correlate of vaccine-induced protection, in response to multiple doses of mRNA vaccines. Importantly, we estimated population vulnerability to breakthrough infections and predicted tailored vaccination dosing schedules to maximize protection and thus minimize breakthrough infections, based on the immune status of a sub-population. We have identified a critical waiting window for cancer patients (or, immunocompromised subjects) to allow recovery of the immune system (particularly CD4+ T-cells) for effective differentiation of B-cells to produce neutralizing antibodies and thus achieve optimal vaccine efficacy against variants of concern, especially between the first and second doses. Also, we have obtained optimized dosing schedules for subsequent doses in healthy and immunocompromised subjects, which vary from the CDC-recommended schedules, to minimize breakthrough infections. The developed modeling tool is based on generalized adaptive immune response to antigens and can thus be leveraged to guide vaccine dosing schedules during future outbreaks.

A modeling-based approach to optimize COVID-19 vaccine dosing schedules for improved protection.

While the development of different vaccines slowed the dissemination of SARS-CoV-2, the occurrence of breakthrough infections has continued to fuel the COVID-19 pandemic. To secure at least partial protection in the majority of the population through 1 dose of a COVID-19 vaccine, delayed administration of boosters has been implemented in many countries. However, waning immunity and emergence of new variants of SARS-CoV-2 suggest that such measures may induce breakthrough infections due to intermittent lapses in protection. Optimizing vaccine dosing schedules to ensure prolonged continuity in protection could thus help control the pandemic. We developed a mechanistic model of immune response to vaccines as an in silico tool for dosing schedule optimization. The model was calibrated with clinical data sets of acquired immunity to COVID-19 mRNA vaccines in healthy and immunocompromised participants and showed robust validation by accurately predicting neutralizing antibody kinetics in response to multiple doses of COVID-19 mRNA vaccines. Importantly, by estimating population vulnerability to breakthrough infections, we predicted tailored vaccination dosing schedules to minimize breakthrough infections, especially for immunocompromised individuals. We identified that the optimal vaccination schedules vary from CDC-recommended dosing, suggesting that the model is a valuable tool to optimize vaccine efficacy outcomes during future outbreaks.

Gadolinium-enhanced magnetic resonance angiography for pulmonary embolism: a multicenter prospective study (PIOPED III).

BACKGROUND: The accuracy of gadolinium-enhanced magnetic resonance pulmonary angiography and magnetic resonance venography for diagnosing pulmonary embolism has not been determined conclusively. OBJECTIVE: To investigate performance characteristics of magnetic resonance angiography, with or without magnetic resonance venography, for diagnosing pulmonary embolism. DESIGN: Prospective, multicenter study from 10 April 2006 to 30 September 2008. SETTING: 7 hospitals and their emergency services. PATIENTS: 371 adults with diagnosed or excluded pulmonary embolism. MEASUREMENTS: Sensitivity, specificity, and likelihood ratios were measured by comparing independently read magnetic resonance imaging with the reference standard for diagnosing pulmonary embolism. Reference standard diagnosis or exclusion was made by using various tests, including computed tomographic angiography and venography, ventilation-perfusion lung scan, venous ultrasonography, d-dimer assay, and clinical assessment. RESULTS: Magnetic resonance angiography, averaged across centers, was technically inadequate in 25% of patients (92 of 371). The proportion of technically inadequate images ranged from 11% to 52% at various centers. Including patients with technically inadequate images, magnetic resonance angiography identified 57% (59 of 104) with pulmonary embolism. Technically adequate magnetic resonance angiography had a sensitivity of 78% and a specificity of 99%. Technically adequate magnetic resonance angiography and venography had a sensitivity of 92% and a specificity of 96%, but 52% of patients (194 of 370) had technically inadequate results. LIMITATION: A high proportion of patients with suspected embolism was not eligible or declined to participate. CONCLUSION: Magnetic resonance pulmonary angiography should be considered only at centers that routinely perform it well and only for patients for whom standard tests are contraindicated. Magnetic resonance pulmonary angiography and magnetic resonance venography combined have a higher sensitivity than magnetic resonance pulmonary angiography alone in patients with technically adequate images, but it is more difficult to obtain technically adequate images with the 2 procedures.

Do Pandemics Obey the Elliott Wave Principle of Financial Markets?

The Elliott Wave principle is a time-honored, oft-used method for predicting variations in the financial markets. It is based on the notion that human emotions drive financial decisions. In the fight against COVID-19, human emotions are similarly decisive, for instance in that they determine one's willingness to be vaccinated, and/or to follow preventive measures including the wearing of masks, the application of social distancing protocols, and frequent handwashing. On this basis, we postulated that the Elliott Wave Principle may similarly be used to predict the future evolution of the COVID-19 pandemic. We demonstrated that this method reproduces the data pattern especially well for USA (daily new cases). Potential scenarios were then extrapolated, from the best-case corresponding to a rapid, full vaccination of the population, to the utterly disastrous case of slow vaccination, and poor adherence to preventive protocols.

Innate Immunity Plays a Key Role in Controlling Viral Load in COVID-19: Mechanistic Insights from a Whole-Body Infection Dynamics Model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pathogen of immense public health concern. Efforts to control the disease have only proven mildly successful, and the disease will likely continue to cause excessive fatalities until effective preventative measures (such as a vaccine) are developed. To develop disease management strategies, a better understanding of SARS-CoV-2 pathogenesis and population susceptibility to infection are needed. To this end, mathematical modeling can provide a robust in silico tool to understand COVID-19 pathophysiology and the in vivo dynamics of SARS-CoV-2. Guided by ACE2-tropism (ACE2 receptor dependency for infection) of the virus and by incorporating cellular-scale viral dynamics and innate and adaptive immune responses, we have developed a multiscale mechanistic model for simulating the time-dependent evolution of viral load distribution in susceptible organs of the body (respiratory tract, gut, liver, spleen, heart, kidneys, and brain). Following parameter quantification with in vivo and clinical data, we used the model to simulate viral load progression in a virtual patient with varying degrees of compromised immune status. Further, we ranked model parameters through sensitivity analysis for their significance in governing clearance of viral load to understand the effects of physiological factors and underlying conditions on viral load dynamics. Antiviral drug therapy, interferon therapy, and their combination were simulated to study the effects on viral load kinetics of SARS-CoV-2. The model revealed the dominant role of innate immunity (specifically interferons and resident macrophages) in controlling viral load, and the importance of timing when initiating therapy after infection.

Racial and ethnic disparities in SARS-CoV-2 pandemic: analysis of a COVID-19 observational registry for a diverse US metropolitan population.

INTRODUCTION: Data on race and ethnic disparities for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are limited. We analysed sociodemographic factors associated with higher likelihood of SARS-CoV-2 infection and explore mediating pathways for race and ethnic disparities in the SARS-CoV-2 pandemic. METHODS: This is a cross-sectional analysis of the COVID-19 Surveillance and Outcomes Registry, which captures data for a large healthcare system, comprising one central tertiary care hospital, seven large community hospitals and an expansive ambulatory/emergency care network in the Greater Houston area. Nasopharyngeal samples for individuals inclusive of all ages, races, ethnicities and sex were tested for SARS-CoV-2. We analysed sociodemographic (age, sex, race, ethnicity, household income, residence population density) and comorbidity (Charlson Comorbidity Index, hypertension, diabetes, obesity) factors. Multivariable logistic regression models were fitted to provide adjusted OR (aOR) and 95% CI for likelihood of a positive SARS-CoV-2 test. Structural equation modelling (SEM) framework was used to explore three mediation pathways (low income, high population density, high comorbidity burden) for the association between non-Hispanic black (NHB) race, Hispanic ethnicity and SARS-CoV-2 infection. RESULTS: Among 20 228 tested individuals, 1551 (7.7%) tested positive. The overall mean (SD) age was 51.1 (19.0) years, 62% were females, 22% were black and 18% were Hispanic. NHB and Hispanic ethnicity were associated with lower socioeconomic status and higher population density residence. In the fully adjusted model, NHB (vs non-Hispanic white; aOR, 2.23, CI 1.90 to 2.60) and Hispanic ethnicity (vs non-Hispanic; aOR, 1.95, CI 1.72 to 2.20) had a higher likelihood of infection. Older individuals and males were also at higher risk of infection. The SEM framework demonstrated a significant indirect effect of NHB and Hispanic ethnicity on SARS-CoV-2 infection mediated via a pathway including residence in densely populated zip code. CONCLUSIONS: There is strong evidence of race and ethnic disparities in the SARS-CoV-2 pandemic that are potentially mediated through unique social determinants of health.

Innate immunity plays a key role in controlling viral load in COVID-19: mechanistic insights from a whole-body infection dynamics model.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a pathogen of immense public health concern. Efforts to control the disease have only proven mildly successful, and the disease will likely continue to cause excessive fatalities until effective preventative measures (such as a vaccine) are developed. To develop disease management strategies, a better understanding of SARS-CoV-2 pathogenesis and population susceptibility to infection are needed. To this end, physiologically-relevant mathematical modeling can provide a robust in silico tool to understand COVID-19 pathophysiology and the in vivo dynamics of SARS-CoV-2. Guided by ACE2-tropism (ACE2 receptor dependency for infection) of the virus, and by incorporating cellular-scale viral dynamics and innate and adaptive immune responses, we have developed a multiscale mechanistic model for simulating the time-dependent evolution of viral load distribution in susceptible organs of the body (respiratory tract, gut, liver, spleen, heart, kidneys, and brain). Following calibration with in vivo and clinical data, we used the model to simulate viral load progression in a virtual patient with varying degrees of compromised immune status. Further, we conducted global sensitivity analysis of model parameters and ranked them for their significance in governing clearance of viral load to understand the effects of physiological factors and underlying conditions on viral load dynamics. Antiviral drug therapy, interferon therapy, and their combination was simulated to study the effects on viral load kinetics of SARS-CoV-2. The model revealed the dominant role of innate immunity (specifically interferons and resident macrophages) in controlling viral load, and the importance of timing when initiating therapy following infection.

Multidetector computed tomography for acute pulmonary embolism.

BACKGROUND: The accuracy of multidetector computed tomographic angiography (CTA) for the diagnosis of acute pulmonary embolism has not been determined conclusively. METHODS: The Prospective Investigation of Pulmonary Embolism Diagnosis II trial was a prospective, multicenter investigation of the accuracy of multidetector CTA alone and combined with venous-phase imaging (CTA-CTV) for the diagnosis of acute pulmonary embolism. We used a composite reference test to confirm or rule out the diagnosis of pulmonary embolism. RESULTS: Among 824 patients with a reference diagnosis and a completed CT study, CTA was inconclusive in 51 because of poor image quality. Excluding such inconclusive studies, the sensitivity of CTA was 83 percent and the specificity was 96 percent. Positive predictive values were 96 percent with a concordantly high or low probability on clinical assessment, 92 percent with an intermediate probability on clinical assessment, and nondiagnostic if clinical probability was discordant. CTA-CTV was inconclusive in 87 of 824 patients because the image quality of either CTA or CTV was poor. The sensitivity of CTA-CTV for pulmonary embolism was 90 percent, and specificity was 95 percent. CTA-CTV was also nondiagnostic with a discordant clinical probability. CONCLUSIONS: In patients with suspected pulmonary embolism, multidetector CTA-CTV has a higher diagnostic sensitivity than does CTA alone, with similar specificity. The predictive value of either CTA or CTA-CTV is high with a concordant clinical assessment, but additional testing is necessary when the clinical probability is inconsistent with the imaging results.

Reconstructed 4-chamber views compared with axial imaging for assessment of right ventricular enlargement on CT pulmonary angiograms.

PURPOSE: To test the hypothesis that right enlargement assessed from right ventricular/left ventricular (RV/LV) dimension ratios of computed tomographic (CT) angiograms are equivalent irrespective of whether measured on axial views or reconstructed 4-chamber views. METHODS: RV/LV dimension ratios were calculated from measurements on axial views, manually reconstructed 4-chamber views and computer generated reconstructed 4-chamber views of CT angiograms in 152 patients with PE. RESULTS: Paired readings of the axial view and manually reconstructed 4-chamber view showed agreement with RV/LV > or =1 or RV/LV <1 in 114 of 127 (89.8%). Paired readings also showed agreement in 119 of 127 (93.7%) with axial views and computer generated reconstructed 4-chamber views. The McNemar test showed no statistically significant difference between assessments of RV enlargement (RV/LV > or = 1) with any method. CONCLUSION: Right ventricular enlargement can be determined from axial views on CT angiograms, which are readily and immediately available, without obtaining 4-chamber reconstructed views.

Acute pulmonary embolism: sensitivity and specificity of ventilation-perfusion scintigraphy in PIOPED II study.

PURPOSE: To use Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) II data to retrospectively determine sensitivity and specificity of ventilation-perfusion (V/Q) scintigraphic studies categorized as pulmonary embolism (PE) present or PE absent and the proportion of patients for whom these categories applied. MATERIALS AND METHODS: The PIOPED II study had institutional review board approval at all participating centers. Patient informed consent was obtained; the study was HIPAA compliant. Approval and consent included those for future retrospective research. Patients in the PIOPED II database of clinical and imaging results were included if they had diagnosis at computed tomographic (CT) angiography, Wells score, and diagnosis at V/Q scanning. V/Q scan central readings were recategorized as PE present (PIOPED II reading = high probability of PE), PE absent (PIOPED II reading = very low probability of PE or normal), or nondiagnostic (PIOPED II reading = low or intermediate probability of PE). A composite reference standard was used: the PIOPED II digital subtraction angiographic (DSA) result, or if there was no definitive DSA result, CT angiographic results that were concordant with the Wells score (ie, positive CT angiographic result and Wells score > 2 or negative CT angiographic result and Wells score < 6). Sensitivity and specificity of recategorized central readings were computed. RESULTS: With the exclusion of patients with intermediate or low probability, the sensitivity of a high probability (PE present) scan finding was 77.4% (95% confidence interval [CI]: 69.7%, 85.0%), while the specificity of very low probability or normal (PE absent) scan finding was 97.7% (95% CI: 96.4%, 98.9%). The percentage of patients with a PE present or PE absent scan finding was 73.5% (95% CI: 70.7%, 76.4%). CONCLUSION: In a population similar to that in PIOPED II, results of V/Q scintigraphy can be diagnostically definitive in a majority of patients; thus, it can be considered an appropriate pulmonary imaging procedure in patients for whom CT angiography may be disadvantageous.

Sensitivity and specificity of perfusion scintigraphy combined with chest radiography for acute pulmonary embolism in PIOPED II.

UNLABELLED: We used the archived Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) data and images to test the hypothesis that reading perfusion scans with chest radiographs but without ventilation scans, and categorizing the perfusion scan as "pulmonary embolism (PE) present" or "PE absent," can result in clinically useful sensitivity and specificity in most patients. METHODS: Patients recruited into PIOPED II were eligible for the present study if they had a CT angiography (CTA) or digital subtraction angiography (DSA) diagnosis, an interpretable perfusion scan and chest radiographs, and a Wells' score. Four readers reinterpreted the perfusion scans and chest radiographs of eligible patients. Two readers used the modified PIOPED II criteria and 2 used the Prospective Investigative Study of Pulmonary Embolism Diagnosis (PISAPED) criteria. The chest radiographs were read as "normal/near normal," "abnormal," or "nondiagnostic," and the perfusion scans were read as "PE present," "PE absent," or "nondiagnostic." The primary analysis used a composite reference standard: the PIOPED II DSA result or, if there was no definitive DSA result, CTA results that were concordant with the Wells' score as defined in PIOPED II (CTA positive and Wells' score > 2, or CTA negative and Wells' score < 6). RESULTS: The prevalence of PE in the sample was 169 of 889 (19%). Using the modified PIOPED II criteria, the sensitivity of a "PE present" perfusion scan was 84.9% (95% confidence interval [CI], 80.1%-88.8%), and the specificity of "PE absent" was 92.7% (95% CI, 91.1%-94.1%), excluding "nondiagnostic" results, which occurred in 20.6% (95% CI, 18.8%-22.5%). Using PISAPED criteria, the sensitivity of a "PE present" perfusion scan was 80.4% (95% CI, 75.9%-84.3%) and the specificity of "PE absent" was 96.6% (95% CI, 95.5%-97.4%), whereas the proportion of patients with "nondiagnostic" scans was 0% (95% CI, 0.0%-0.2%). CONCLUSION: Perfusion scintigraphy combined with chest radiography can provide diagnostic accuracy similar to both CTA and ventilation-perfusion scintigraphy, at lower cost and with lower radiation dose. With modified PIOPED II criteria, a higher proportion of scans were nondiagnostic than with CTA, and with PISAPED criteria none were nondiagnostic.

Very low probability interpretation of V/Q lung scans in combination with low probability objective clinical assessment reliably excludes pulmonary embolism: data from PIOPED II.

UNLABELLED: Use of a very low probability interpretation of ventilation/perfusion (V/Q) lung scans, if verified by prospective evaluation to have a low positive predictive value (PPV), will reduce the number of nondiagnostic interpretations of V/Q scans and may be particularly useful in patients with a relative contraindication to CT. The purpose of this investigation was to test the hypothesis that a very low probability interpretation of the V/Q scan has a PPV of <10%. METHODS: Data are from PIOPED II (Prospective Investigation of Pulmonary Embolism Diagnosis II). Very low probability criteria are (a) nonsegmental perfusion abnormalities, (b) perfusion defect smaller than corresponding radiographic lesion, (c) > or =2 matched V/Q defects with regionally normal chest radiograph, (d) 1-3 small segmental perfusion defects (<25% of a segment), (e) solitary triple matched defect in middle or upper lung zones, (f) stripe sign around the perfusion defect(s), and (g) perfusion defect from pleural effusion equal to one third or more of the pleural cavity with no other perfusion defect. RESULTS: A very low probability consensus interpretation of the V/Q scan was made in 56% of patients. The PPV of a very low probability interpretation of the V/Q scans was 36 of 440 patients (8.2%). Among patients with suspected pulmonary embolism who had a low clinical probability objective clinical assessment and a very low probability V/Q scan, the PPV was 8 of 259 patients (3.1%). Among women < or =40 y, the PPV of the very low probability V/Q with a low objective clinical assessment was 1 of 50 (2%). CONCLUSION: The very low probability V/Q scan together with a low probability clinical assessment reliably excludes pulmonary embolism.

Usefulness of multidetector spiral computed tomography according to age and gender for diagnosis of acute pulmonary embolism.

Data from the Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) were evaluated to test the hypothesis that the performance of multidetector computed tomographic (CT) pulmonary angiography and CT venography is independent of a patient's age and gender. In 773 patients with adequate CT pulmonary angiography and 737 patients with adequate CT pulmonary angiography and CT venography, the sensitivity and specificity for pulmonary embolism for groups of patients aged 18 to 59, 60 to 79, and 80 to 99 years did not differ to a statistically significant extent, nor were there significant differences according to gender. Overall, however, the specificity of CT pulmonary angiography was somewhat greater in women, but in men and women, it was > or =93%. In conclusion, the results indicate that multidetector CT pulmonary angiography and CT pulmonary angiography and CT venography may be used with various diagnostic strategies in adults of all ages and both genders.

CT venography and compression sonography are diagnostically equivalent: data from PIOPED II.

OBJECTIVE: The purpose of this study was to compare the clinical value of CT venography (CTV) after MDCT angiography (CTA) with venous compression sonography for the diagnosis of venous thromboembolism (VTE). The Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) showed that lower extremity imaging detects about 7% more patients requiring anticoagulation than CTA alone. SUBJECTS AND METHODS: PIOPED II was a prospective multicenter study investigating the accuracy of CTA alone and CTA and CTV together. A composite reference standard was used to confirm, or rule out, pulmonary embolus. Adequate quality CTV and sonographic images were obtained in 711 patients. RESULTS: There was 95.5% concordance between CTV and sonography for the diagnosis or exclusion of deep venous thrombosis (DVT); the kappa statistic was 0.809. The sensitivity and specificity of combined CTA and CTV were equivalent to those of combined CTA and sonography. Diagnostic results in subgroups, including patients with signs or symptoms of DVT, asymptomatic patients, and patients with a history of DVT, were similar whether CTV or sonography was used. Patients with signs or symptoms of DVT were eight times more likely to have DVT, and patients with a history of DVT were twice as likely to have positive findings. CONCLUSION: CTV and sonography showed similar results in diagnosing or excluding DVT. The incidence of positive studies in patients without signs, symptoms, or history of DVT is low. In terms of clinical significance, CT venography and lower extremity sonography yield equivalent diagnostic results; the incidence of positive studies in patients without signs, symptoms, or history of DVT is low; thus the choice of imaging technique can be made on the basis of safety, expense, and time constraints.

CT venography for deep venous thrombosis: continuous images versus reformatted discontinuous images using PIOPED II data.

OBJECTIVE: This study was designed to determine whether discontinuous CT of the lower extremities for the detection of deep venous thrombosis (DVT) yields results similar to those of complete helical imaging using cases from the Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II). MATERIALS AND METHODS: In PIOPED II, CT venography followed CT angiography (CTA) to detect pulmonary embolus, using 7.5-mm continuous helical imaging from the iliac crest to the tibial plateau. DVT was detected in 105 of 737 patients (14.2%). We randomly chose 54 positive cases and 96 negative cases for our study. The continuous helical images were reformatted as 7.5-mm images and two of every three images were deleted. These images (7.5 mm; skip = 15 mm) were then sent--without identifying information--to the original reviewers. From 1 to 3.5 years had elapsed since the original interpretations. The results of the new interpretations were compared with the original CT venography consensus interpretations of PIOPED II. RESULTS: There was agreement for the presence of DVT in at least one leg (same leg) or for the absence of DVT in both legs in 133 of the 150 study patients (89%). The kappa statistic showed substantial agreement between the consensus interpretations and the test interpretations (kappa = 0.75; 95% CI = 0.64-0.86) per patient. CONCLUSION: There was good--but not perfect--agreement between continuous helical and discontinuous axial imaging for the detection of DVT. Given the vagaries of interobserver and intraobserver variation, there appears to be little difference between the two approaches. Adopting discontinuous imaging and other dose-reduction strategies can reduce pelvic radiation by more than 75%.

Building a transcontinental affiliation: a new model for academic health centers.

The recent affiliation of The Methodist Hospital (TMH) with Weill Medical College (WMC) of Cornell University and NewYork-Presbyterian Hospital is the first transcontinental primary affiliation between major, not-for-profit academic health centers (AHCs) in the United States. The authors describe the process followed, the issues involved, the initial accomplishments, and the opportunities envisioned. The key enablers of this affiliation were a rapid process, mutual trust based on existing professional relationships, and commitment to the project by Board leadership. Because of their geographic separation, the parties were not competitors in providing clinical care to their regional populations. The affiliation is nonexclusive, but is reciprocally primary in New York and Texas. Members of the TMH medical staff are eligible for faculty appointments at WMC. The principal areas of collaboration will be education, research, quality improvement, information technology, and international program development. The principal challenge has been the physical distance between the parties. Although extensive use of videoconferencing has been successful, personal contact is essential in establishing relationships. External processes impose a slower sequence and tempo of events than some might wish. This new model for AHCs creates exciting possibilities for the tripartite mission of research, education, and patient care. Realizing the potential of these opportunities will require unconstrained ideas and substantial investment of time and other critical resources. Since many consider that AHCs are in economic and cultural crisis, successful development of such possibilities could have importance beyond the collective interests of these three institutions.

Overview of Prospective Investigation of Pulmonary Embolism Diagnosis II.

The Prospective Investigation of Pulmonary Embolism Diagnosis II (PIOPED II) is a prospective multicenter study funded by the National Heart, Lung, and Blood Institute which began recruiting patients in the fall of 2001. It was designed to assess the efficacy of the spiral computed tomographic pulmonary angiogram in patients suspected of having acute pulmonary embolism (PE). In contrast to the original PIOPED study, which used contrast pulmonary angiography as the primary reference test for PE, PIOPED II will use a composite reference test for venous thromboembolism that is based on the ventilation/perfusion lung scan, venous compression ultrasound of the lower extremities, digital subtraction pulmonary angiography, and contrast venography in various combinations to establish the PE status of the patient. New criteria for ventilation/perfusion lung scan diagnosis have been developed for PIOPED II. This article describes the various techniques that will be used, the combination of the composite reference tests that will be used to determine the PE status of the patient, and the PIOPED II diagnostic criteria that will be used for the ventilation/perfusion scan diagnosis of PE in the study.