Modeling effects of SGLT-2 inhibitor dapagliflozin treatment versus standard diabetes therapy on cardiovascular and microvascular outcomes.

AIMS: Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor, has been shown to lower glycated hemoglobin (HbA1c), weight, blood pressure and serum uric acid in clinical trials. Plasma lipids were also evaluated as exploratory variables. The goal of this study was to estimate the long-term cardiovascular (CV) and microvascular outcomes of dapagliflozin added to the standard of care (SOC) versus SOC using simulation methodology. METHODS: The Archimedes Model, a validated model of human physiology, diseases and healthcare systems, was used to model a type 2 diabetes mellitus (T2DM) population derived from National Health and Nutrition Examination Survey (NHANES) with HbA1c 7-10%, taking a single oral antidiabetic agent [metformin, sulfonylureas SU or thiazolidinedione (TZD)] at the beginning of the trial. A 20-year trial was simulated comparing dapagliflozin 10 mg, given in addition to SOC, with SOC alone. SOC was based on American Diabetes Association (ADA)/European Association for the Study of Diabetes (EASD) 2012 guidelines and included diet, metformin, SU, TZD, dipeptidyl peptidase-4 (DPP-4), glucagon-like peptide-1 (GLP-1), and insulin therapies, with usage levels reflective of those in NHANES. Dapagliflozin effects were derived from phase 3 clinical trial results. End points included CV and microvascular outcomes. RESULTS: Over a 20-year period, patients on dapagliflozin were projected to experience relative reductions in the incidence of myocardial infarction (MI), stroke, CV death, and all-cause death of 13.8, 9.1, 9.6 and 5.0%, respectively, and relative reductions in the incidence of end-stage renal disease (ESRD), foot amputation, and diabetic retinopathy of 18.7, 13.0 and 9.8%, respectively, when compared with SOC. CONCLUSIONS: On the basis of simulation results, adding dapagliflozin to currently available treatment options is projected to further decrease the CV and microvascular complications associated with T2DM.

Modeling the effects of omalizumab over 5 years among patients with moderate-to-severe persistent allergic asthma.

OBJECTIVE: Omalizumab is a monoclonal antibody indicated for adults and adolescents with moderate-to-severe persistent allergic asthma whose symptoms are inadequately controlled with inhaled corticosteroids. Omalizumab has been demonstrated to improve health outcomes of asthmatic patients as compared to placebo. However, to date, the trials conducted have been relatively short (less than 1 year) and have been restricted to a limited set of patients who met the clinical study criteria. This study examined the expected effects of omalizumab over 5 years on a representative sample of all patients eligible for omalizumab in the US. METHODS: The Archimedes Asthma Model was used to simulate the following treatment scenarios for US patients age 12 and older with moderate-to-severe persistent allergic asthma: (1) Current asthma treatment (CAT) (treatment according to National Heart, Lung, and Blood Institute (NHLBI) guidelines, without use of omalizumab, and with adherence levels as observed in the National Asthma Survey); (2) Guideline asthma treatment (GAT) without omalizumab (NHLBI guidelines without use of omalizumab, assuming perfect adherence); (3) GAT plus omalizumab; and (4) GAT plus omalizumab with steroid reduction. The simulation was run for 5 years. MAIN OUTCOME MEASURES: Symptom days, asthma exacerbations, emergency room/urgent care (ER/UC) visits, hospitalizations, and medication use. RESULTS: For the full simulated population of omalizumab-eligible patients, the simulation forecasted that omalizumab would decrease cumulative exacerbations by 30%, ER/UC visits by 37%, and hospitalizations by 38% over 5 years. Among responders to omalizumab, assuming that 60.5% of patients respond, the results suggest that omalizumab would decrease cumulative exacerbations by 50%, ER/UC visits by 62%, and hospitalizations by 63% over 5 years. In addition, the simulation predicted that omalizumab would allow 45% of patients who are taking more than the minimum steroid dose to reduce their steroid dose, while maintaining similar asthma control as achieved in the GAT plus omalizumab arm (no steroid dose reduction) and better asthma control than following treatment protocols that do not include omalizumab. CONCLUSION: Based on the results of this simulation, omalizumab is effective for those who respond, reducing serious events by more than 50% among the responder group, while also allowing many patients to reduce their steroid dose.

Directional emission from asymmetric resonant cavities.

Asymmetric resonant cavities with highly noncircular but convex cross sections are predicted theoretically to have high-Q whispering gallery modes with highly anisotropic emission. We develop a ray dynamics model for the emission pattern and present numerical and experimental confirmation of the theory.

Ultrasensitive magnetic biosensor for homogeneous immunoassay.

A technique is described for specific, sensitive, quantitative, and rapid detection of biological targets by using superparamagnetic nanoparticles and a "microscope" based on a high-transition temperature dc superconducting quantum interference device (SQUID). In this technique, a mylar film to which the targets have been bound is placed on the microscope. The film, at room temperature and atmospheric pressure, is typically 40 micrometer from the SQUID, which is at 77 K in a vacuum. A suspension of magnetic nanoparticles carrying antibodies directed against the target is added to the mixture in the well, and 1-s pulses of magnetic field are applied parallel to the SQUID. In the presence of this aligning field the nanoparticles develop a net magnetization, which relaxes when the field is turned off. Unbound nanoparticles relax rapidly by Brownian rotation and contribute no measurable signal. Nanoparticles that are bound to the target on the film are immobilized and undergo Néel relaxation, producing a slowly decaying magnetic flux, which is detected by the SQUID. The ability to distinguish between bound and unbound labels allows one to run homogeneous assays, which do not require separation and removal of unbound magnetic particles. The technique has been demonstrated with a model system of liposomes carrying the FLAG epitope. The SQUID microscope requires no more than (5 +/- 2) x 10(4) magnetic nanoparticles to register a reproducible signal.

A new study of bacterial motion: superconducting quantum interference device microscopy of magnetotactic bacteria.

The recently developed "microscope" based on a high-Tc dc SQUID (superconducting quantum interference device) is used to detect the magnetic fields produced by the motion of magnetotactic bacteria, which have permanent dipole moments. The bacteria, in growth medium at room temperature, can be brought to within 15 micron of a SQUID at liquid nitrogen temperature. Measurements are performed on both motile and nonmotile bacteria. In the nonmotile case, we obtain the power spectrum of the magnetic field noise produced by the rotational Brownian motion of the ensemble of bacteria. Furthermore, we measure the time-dependent field produced by the ensemble in response to an applied uniform magnetic field. In the motile case, we obtain the magnetic field power spectra produced by the swimming bacteria. Combined, these measurements determine the average rotational drag coefficient, magnetic moment, and the frequency and amplitude of the vibrational and rotational modes of the bacteria in a unified set of measurements. In addition, the microscope can easily resolve the motion of a single bacterium. This technique can be extended to any cell to which a magnetic tag can be attached.

Detection of bacteria in suspension by using a superconducting quantum interference device.

We demonstrate a technique for detecting magnetically labeled Listeria monocytogenes and for measuring the binding rate between antibody-linked magnetic particles and bacteria. This sensitive assay quantifies specific bacteria in a sample without the need to immobilize them or wash away unbound magnetic particles. In the measurement, we add 50-nm-diameter superparamagnetic magnetite particles, coated with antibodies, to an aqueous sample containing L. monocytogenes. We apply a pulsed magnetic field to align the magnetic dipole moments and use a high-transition temperature superconducting quantum interference device, an extremely sensitive detector of magnetic flux, to measure the magnetic relaxation signal when the field is turned off. Unbound particles randomize direction by Brownian rotation too quickly to be detected. In contrast, particles bound to L. monocytogenes are effectively immobilized and relax in about 1 s by rotation of the internal dipole moment. This Néel relaxation process is detected by the superconducting quantum interference device. The measurements indicate a detection limit of (5.6 +/- 1.1) x 10(6) L. monocytogenes in our sample volume of 20 microl. If the sample volume were reduced to 1 nl, we estimate that the detection limit could be improved to 230 +/- 40 L. monocytogenes cells. Time-resolved measurements yield the binding rate between the particles and bacteria.