M2-Deficient Single-Replication Influenza Vaccine-Induced Immune Responses Associated With Protection Against Human Challenge With Highly Drifted H3N2 Influenza Strain.

BACKGROUND: Current influenza vaccines are strain specific and demonstrate low vaccine efficacy against H3N2 influenza disease, especially when vaccine is mismatched to circulating virus. The novel influenza vaccine candidate, M2-deficient single replication (M2SR), induces a broad, multi-effector immune response. METHODS: A phase 2 challenge study was conducted to assess the efficacy of an M2SR vaccine expressing hemagglutinin and neuraminidase from A/Brisbane/10/2007 (Bris2007 M2SR H3N2; clade 1). Four weeks after vaccination, recipients were challenged with antigenically distinct H3N2 virus (A/Belgium/4217/2015, clade 3C.3b) and assessed for infection and clinical symptoms. RESULTS: Adverse events after vaccination were mild and similar in frequency for placebo and M2SR recipients. A single dose of Bris2007 M2SR induced neutralizing antibody to the vaccine (48% of recipients) and challenge strain (27% of recipients). Overall, 54% of M2SR recipients were infected after challenge, compared with 71% of placebo recipients. The subset of M2SR recipients with a vaccine-induced microneutralization response against the challenge virus had reduced rates of infection after challenge (38% vs 71% of placebo recipients; P = .050) and reduced illness. CONCLUSIONS: Study participants with vaccine-induced neutralizing antibodies were protected against infection and illness after challenge with an antigenically distinct virus. This is the first demonstration of vaccine-induced protection against a highly drifted H3N2 challenge virus.

Safety evaluation of long-term temperature controlled whole-body thermal treatment in female Aachen minipig.

Objective: Thermal treatment (TT), defined as treatment using supra-physiological body temperatures (39-45 C), somewhat resembles fever in terms of temperature range, one of the first natural barriers for the body to fight exposure to external pathogens. Methods: Whole-body thermal treatment (WBTT) consists of heating up the complete body to a temperature range of 39 to 45 C. Despite the recognized therapeutic potential of hyperthermia, the broad clinical use of WBTT has been limited by safety issues related to medical devices and procedures used to achieve WBTT, in particular adequate control of the body temperature. To circumvent this, a sophisticated medical device was developed, allowing long-term temperature controlled WBTT (41.5 C for up to 8 h). Technical feasibility and tolerability of the WBTT procedure (including complete anesthesia) were tested using female Aachen minipig. Optical fiber temperature sensors inserted in multiple organs were used and demonstrated consistent monitoring and control of different organs temperature over an extended period of time. Results: Clinical evaluation of the animals before, during and after treatment revealed minor clinical parameter changes, but all of them were clinically acceptable. These changes were limited and reversible, and the animals remained healthy throughout the whole procedure and follow-up. In addition, histopathological analysis of selected key organs showed no thermal treatment-related changes. Conclusion: It was concluded that WBTT (41.5 C for up to 8 h) was well tolerated and safe in female Aachen minipigs. Altogether, data supports the safe clinical use of the WBTT medical device and protocol, enabling its implementation into human patients suffering from life-threatening diseases.

Acoustic Radiation Force: A Review of Four Mechanisms for Biomedical Applications.

Radiation force is a universal phenomenon in any wave motion where the wave energy produces a static or transient force on the propagation medium. The theory of acoustic radiation force (ARF) dates back to the early 19th century. In recent years, there has been an increasing interest in the biomedical applications of ARF. Following a brief history of ARF, this article describes a concise theory of ARF under four physical mechanisms of radiation force generation in tissue-like media. These mechanisms are primarily based on the dissipation of acoustic energy of propagating waves, the reflection of the incident wave, gradients of the compressional wave speeds, and the spatial variations of energy density in standing acoustic waves. Examples describing some of the practical applications of ARF under each mechanism are presented. This article concludes with a discussion on selected ideas for potential future applications of ARF in biomedicine.

Probability characteristics of nonlinear dynamical systems driven by δ-pulse noise.

For a nonlinear dynamical system described by the first-order differential equation with Poisson white noise having exponentially distributed amplitudes of δ pulses, some exact results for the stationary probability density function are derived from the Kolmogorov-Feller equation using the inverse differential operator. Specifically, we examine the "effect of normalization" of non-Gaussian noise by a linear system and the steady-state probability density function of particle velocity in the medium with Coulomb friction. Next, the general formulas for the probability distribution of the system perturbed by a non-Poisson δ-pulse train are derived using an analysis of system trajectories between stimuli. As an example, overdamped particle motion in the bistable quadratic-cubic potential under the action of the periodic δ-pulse train is analyzed in detail. The probability density function and the mean value of the particle position together with average characteristics of the first switching time from one stable state to another are found in the framework of the fast relaxation approximation.

Nonlinear decay of random waves described by an integrodifferential equation.

The evolution of random nonlinear waves (high-intensity noise) in a dissipative and dispersive media is studied. To describe wave processes, the mathematical model in the form of a nonlinear integrodifferential equation is used. The concrete integrand kernels are determined by both frequency-dependent absorption and velocity of the wave. The nonlinear energy loss of broadband noise is considered in two limiting cases: (i) at the initial stage of propagation, when the wave profile contains a small number of shock fronts, and (ii) at the later stage when the wave reshapes to a sawtoothlike one with randomly located shocks.

Muscle as a molecular machine for protecting joints and bones by absorbing mechanical impacts.

We hypothesize that dissipation of mechanical energy of external impact to absorb mechanical shock is a fundamental function of skeletal muscle in addition to its primary function to convert chemical energy into mechanical energy. In physical systems, the common mechanism for absorbing mechanical shock is achieved with the use of both elastic and viscous elements and we hypothesize that the viscosity of the skeletal muscle is a variable parameter which can be voluntarily controlled by changing the tension of the contracting muscle. We further hypothesize that an ability of muscle to absorb shock has been an important factor in biological evolution, allowing the life to move from the ocean to land, from hydrodynamic to aerodynamic environment with dramatically different loading conditions for musculoskeletal system. The ability of muscle to redistribute the energy of mechanical shock in time and space and unload skeletal joints is of key importance in physical activities. We developed a mathematical model explaining the absorption of mechanical shock energy due to the increased viscosity of contracting skeletal muscles. The developed model, based on the classical theory of sliding filaments, demonstrates that the increased muscle viscosity is a result of the time delay (or phase shift) between the mechanical impact and the attachment/detachment of myosin heads to binding sites on the actin filaments. The increase in the contracted muscle's viscosity is time dependent. Since the forward and backward rate constants for binding the myosin heads to the actin filaments are on the order of 100s(-1), the viscosity of the contracted muscle starts to significantly increase with an impact time greater than 0.01s. The impact time is one of the key parameters in generating destructive stress in the colliding objects. In order to successfully dampen a short high power impact, muscles must first slow it down to engage the molecular mechanism of muscle viscosity. Muscle carries out two functions, acting first as a nonlinear spring to slow down impact and second as a viscous damper to absorb the impact. Exploring the ability of muscle to absorb mechanical shock may shed light to many problems of medical biomechanics and sports medicine. Currently there are no clinical devices for real-time quantitative assessment of viscoelastic properties of contracting muscles in vivo. Such assessment may be important for diagnosis and monitoring of treatment of various muscle disorders such as muscle dystrophy, motor neuron diseases, inflammatory and metabolic myopathies and many more.

Biomedical applications of radiation force of ultrasound: historical roots and physical basis.

Radiation force is a universal phenomenon in any wave motion, electromagnetic or acoustic. Although acoustic and electromagnetic waves are both characterized by time variation of basic quantities, they are also both capable of exerting a steady force called radiation force. In 1902, Lord Rayleigh published his classic work on the radiation force of sound, introducing the concept of acoustic radiation pressure, and some years later, further fundamental contributions to the radiation force phenomenon were made by L. Brillouin and P. Langevin. Many of the studies discussing radiation force published before 1990 were related to techniques for measuring acoustic power of therapeutic devices; also, radiation force was one of the factors considered in the search for noncavitational, nonthermal mechanisms of ultrasonic bioeffects. A major surge in various biomedical applications of acoustic radiation force started in the 1990s and continues today. Numerous new applications emerged including manipulation of cells in suspension, increasing the sensitivity of biosensors and immunochemical tests, assessing viscoelastic properties of fluids and biological tissues, elasticity imaging, monitoring ablation of lesions during ablation therapy, targeted drug and gene delivery, molecular imaging and acoustical tweezers. We briefly present in this review the major milestones in the history of radiation force and its biomedical applications. In discussing the physical basis of radiation force and its applications, we present basic equations describing the relationship of radiation stress with parameters of acoustical fields and with the induced motion in the biological media. Momentum and force associated with a plane-traveling wave, equations for nonlinear and nonsteady-state acoustic streams, radiation stress tensor for solids and biological tissues and radiation force acting on particles and microbubbles are considered.

Radiation force and shear motions in inhomogeneous media.

An action of radiation force induced by ultrasonic beam in waterlike media such as biological tissues (where the shear modulus is small as compared to the bulk compressibility) is considered. A new, nondissipative mechanism of generation of shear displacement due to a smooth (nonreflecting) medium inhomogeneity is suggested, and the corresponding medium displacement is evaluated. It is shown that a linear primary acoustic field in nondissipative, isotropic elastic medium cannot excite a nonpotential radiation force and, hence, a shear motion, whereas even smooth inhomogeneity makes this effect possible. An example is considered showing that the generated displacement pulse can be significantly longer than the primary ultrasound pulse. It is noted that, unlike the dissipative effect, the nondissipative action on a localized inhomogeneity (such as a lesion in a tissue) changes its sign along the beam axis, thus stretching or compressing the focus area.