Smallpox bioterror response.
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Bioterrorism↗
Biomedical subjects
Lawrence M Wein
Publications and source records attributed to Lawrence M Wein.
Emergency response to an anthrax attack.
We developed a mathematical model to compare various emergency responses in the event of an airborne anthrax attack. The system consists of an atmospheric dispersion model, an age-dependent dose-response model, a disease progression model, and a set of spatially distributed two-stage queueing systems consisting of antibiotic distribution and hospital care. Our results underscore the need for the extremely aggressive and timely use of oral antibiotics by all asymptomatics in the exposure region, distributed either preattack or by nonprofessionals postattack, and the creation of surge capacity for supportive hospital care via expanded training of nonemergency care workers at the local level and the use of federal and military resources and nationwide medical volunteers. The use of prioritization (based on disease stage andor age) at both queues, and the development and deployment of modestly rapid and sensitive biosensors, while helpful, produce only second-order improvements.
Anthrax↗
Validation and analysis of a mathematical model of a replication-competent oncolytic virus for cancer treatment: implications for virus design and delivery.
Motivated by the rapid expansion in the development of replication-competent viral agents for the treatment of solid tumors, we formulated and analyzed a three-dimensional mathematical model of a tumor that is infected by a replication-competent virus. We initially considered three patterns of intratumoral injection in which a fixed fraction of cells are initially infected with the virus throughout (a) the entire tumor, (b) the tumor core, and (c) the tumor rim, respectively. For each injection pattern, an approximate analysis of the model provides a simple and accurate condition for whether the virus will eradicate the tumor. The model was then generalized to incorporate nutrient-limited necrosis and an innate immune response against virus-infected tumor cells. Recent preclinical and clinical data were used to validate the model and estimate key parameter values. Our analysis has the following implications: even in the absence of an immune response, tumor eradication requires widespread distribution of the virus within the tumor at the time of infection; core or rim injections alone may result in tumor escape, particularly in a well-vascularized tumor; the more rapidly a virus lyses infected cells the more effective it will be at controlling the tumor; and the innate immune response to the virus can potentially prevent the virus from controlling the tumor, even with repeat injections. Therefore, in addition to diffuse intratumoral infection, tumor eradication by oncolytic adenovirus will probably require potent suppression of innate immune clearance mechanisms (e.g., by replacement of adenovirus E3 genes), combinations with traditional (chemotherapy, radiotherapy) treatments, and/or concomitant therapeutic gene expression with resultant bystander effects.
Models, Biological↗
Analyzing bioterror response logistics: the case of smallpox.
To evaluate existing and alternative proposals for emergency response to a deliberate smallpox attack, we embed the key operational features of such interventions into a smallpox disease transmission model. We use probabilistic reasoning within an otherwise deterministic epidemic framework to model the 'race to trace', i.e., attempting to trace (via the infector) and vaccinate an infected person while (s)he is still vaccine-sensitive. Our model explicitly incorporates a tracing/vaccination queue, and hence can be used as a capacity planning tool. An approximate analysis of this large (16 ODE) system yields closed-form estimates for the total number of deaths and the maximum queue length. The former estimate delineates the efficacy (i.e., accuracy) and efficiency (i.e., speed) of contact tracing, while the latter estimate reveals how congestion makes the race to trace more difficult to win, thereby causing more deaths. A probabilistic analysis is also used to find an approximate closed-form expression for the total number of deaths under mass vaccination, in terms of both the basic reproductive ratio and the vaccination capacity. We also derive approximate thresholds for initially controlling the epidemic for more general interventions that include imperfect vaccination and quarantine.
Bioterrorism↗
Optimal scheduling of radiotherapy and angiogenic inhibitors.
We incorporate a previously validated mathematical model of a vascularized tumor into an optimal control problem to determine the temporal scheduling of radiotherapy and angiogenic inhibitors that maximizes the control of a primary tumor. Our results reveal that optimal antiangiogenic monotherapy gives a large initial injection to attain a 20:1 ratio of tumor cell volume to supporting vasculature volume. It thereafter maintains this 20:1 ratio via a continuous dose rate that is intensified over time. The optimal radiation monotherapy schedule is characterized by a modest dose intensification over time. The best performance is achieved by our optimal combination regimen, where the antiangiogenic treatment again maintains a constant tumor-to-vasculature ratio, but is administered in a dose-intensified manner only during the latter portion of the radiation fractionation schedule.
Angiogenesis Inhibitors↗
Smallpox eradication in West and Central Africa: surveillance-containment or herd immunity?
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Africa, Central↗
Hepatic arterial infusion of a replication-selective oncolytic adenovirus (dl1520): phase II viral, immunologic, and clinical endpoints.
Replication-selective oncolytic adenoviruses are being developed for the treatment of cancer, but the safety and feasibility of repeated adenovirus delivery to tumors via the bloodstream was unknown, particularly in light of a patient death after hepatic artery infusion of a replication-defective adenovirus vector. We performed a Phase II trial of an oncolytic replication-selective adenovirus (dl1520, also known as Onyx-015) administered by hepatic artery infusion in patients with gastrointestinal carcinoma metastatic to the liver (n = 27). dl1520 was infused into the hepatic artery (2 x 10(12) particles) on days 1 and 8 as a single agent, and thereafter starting on day 22 in combination with i.v. 5-fluorouracil and leucovorin every 28 days. Repeated viral infusions were feasible, and no deaths occurred on study; reversible grade 3/4 hyperbilirubinemia occurred in 2 patients. Systemic inflammatory cytokine responses varied greatly between patients and even between cycles within a given patient. Proinflammatory cytokines [e.g., tumor necrosis factor, IFN-gamma, and interleukin (IL) 6] typically rose within 3 h and were followed at 18 h by a rise in IL-10. However, in the single patient who suffered a severe but reversible systemic inflammatory response, a unique cytokine profile was detected: marked acute increases of IL-6 (20-fold higher than average for all of the patients) and inhibition of IL-10 production. Delayed secondary peaks of viremia were reproducibly detected 3-6 days after treatment, even in the presence of high level neutralizing antibody titers and antiviral cytokines. Mathematical modeling was used to calculate the number of virus particles produced and shed into the blood with each replication cycle. The combination of virotherapy and chemotherapy had antitumoral activity in some chemotherapy-resistant colorectal tumors. The intra-arterial infusion of oncolytic adenoviruses warrants additional study.
Adenoviruses, Human↗
Emergency response to a smallpox attack: the case for mass vaccination.
In the event of a smallpox bioterrorist attack in a large U.S. city, the interim response policy is to isolate symptomatic cases, trace and vaccinate their contacts, quarantine febrile contacts, but vaccinate more broadly if the outbreak cannot be contained by these measures. We embed this traced vaccination policy in a smallpox disease transmission model to estimate the number of cases and deaths that would result from an attack in a large urban area. Comparing the results to mass vaccination from the moment an attack is recognized, we find that mass vaccination results in both far fewer deaths and much faster epidemic eradication over a wide range of disease and intervention policy parameters, including those believed most likely, and that mass vaccination similarly outperforms the existing policy of starting with traced vaccination and switching to mass vaccination only if required.
Centers for Disease Control and Prevention, U.S.↗
A mathematical model of the impact of novel treatments on the A beta burden in the Alzheimer's brain, CSF and plasma.
With the advent of novel therapies for Alzheimer's disease, there is pressing need for biomarkers that are easy to monitor, such as the amyloid-beta (A beta) levels in the cerebrospinal fluid (CSF) and plasma. To gain a better understanding of the explanatory power of these biomarkers, we formulate and analyze a compartmental mathematical model for the A beta accumulation in the brain, CSF and plasma, throughout the course of Alzheimer's treatment. Our analysis reveals that the total A beta burden in the brain is dictated by a unitless quantity called the polymerization ratio, which is the product of the production and elongation rates divided by the product of the fragmentation and loss rates. In this ratio, the production rate and loss rate include a source and sink term, respectively, related to the intercompartmental transport. Our results suggest that production inhibitors are likely to reduce the A beta levels in all three compartments. In contrast, agents that ingest monomers off of polymers, or that increase fragmentation or block elongation, may also reduce A beta burden in the brain, but may produce little change in--or even transiently increase--CSF and plasma A beta levels. Hence, great care must be taken when interpreting these biomarkers.
Alzheimer Disease↗
Sequencing surgery, radiotherapy and chemotherapy: insights from a mathematical analysis.
We present results from a mathematical analysis that is aimed at finding the best way to sequence the three traditional cancer treatments: surgery (S), chemotherapy (C), and radiotherapy (R). The mathematical model tracks the temporal evolution of the primary tumor and its associated metastases, and incorporates the primary tumor's effect on the dormancy and growth of the metastases. We show that the SCR schedule (i.e., surgery followed by chemotherapy followed by radiotherapy) achieves a higher cure probability than SRC if the primary tumor is sufficiently large or if the metastatic population is sufficiently large relative to the primary tumor. We also show that a novel schedule, SRCR, which splits the radiotherapy regimen into two disjoint portions, is optimal among all schedules, provided that the patient's dormant metastatic tumors do not become vascularized within about 40 days after surgery.
Breast Neoplasms↗
A mathematical model of the impact of infused targeted cytotoxic agents on brain tumours: implications for detection, design and delivery.
Motivated by the recent development of highly specific agents for brain tumours, we develop a mathematical model of the spatio-temporal dynamics of a brain tumour that receives an infusion of a highly specific cytotoxic agent (e.g. IL-4-PE, a cytotoxin comprised of IL-4 and a mutated form of Pseudomonas exotoxin). We derive an approximate but accurate mathematical formula for the tumour cure probability in terms of the tumour characteristics (size at time of detection, proliferation rate, diffusion coefficient), drug design (killing rate, loss rate and convection constants for tumour and tissue), and drug delivery (infusion rate, infusion duration). Our results suggest that high specificity is necessary but not sufficient to cure malignant gliomas; a nondispersed spatial profile of pretreatment tumour cells and/or good drug penetration are also required. The most important levers to improve tumour cure appear to be earlier detection, higher infusion rate, lower drug clearance rate and better convection into tumour, but not tissue. In contrast, the tumour cure probability is less sensitive to a longer infusion duration and enhancements in drug potency and drug specificity.
Antineoplastic Agents↗