Vancouver Declaration II on Global Headache Patient Advocacy 2019.

In 2017, the International Headache Society convened a Global Patient Advocacy Summit (GPAS-1) to begin a collaborative effort involving patients, patient advocates, patient advocacy organizations, healthcare professionals, scientists, professional pain, neurology, and headache societies, pharmaceutical manufacturers, and regulatory agencies to advance issues of importance to patients affected by headache worldwide. In September 2019, the second Global Patient Advocacy Summit (GPAS-2) was convened to revisit issues from the inaugural meeting, assess the progress of the International Headache Society Global Patient Advocacy Coalition (IHS-GPAC) in meeting the goals set forth therein, and discuss strategies for achieving established goals and supporting future development. Short- and long-term mandates from the first Summit were realized, including publishing the Vancouver Declaration on Global Headache Patient Advocacy 2018, determining the governing and operational structures of the IHS-GPAC, and helping to facilitate the first World Federation of Neurology World Brain Day dedicated to migraine. Another short-term mandate, creating a unified advocacy strategy, was fulfilled by the Coalition's decision to focus on encouraging support from employers and implementing employee support programs for people with migraine. To help execute the strategy, the Coalition is developing an employer engagement toolkit that will educate employers and employees about the impact of migraine in the workplace, reduce stigma directed toward employees with migraine, and facilitate the care of employees with migraine to reduce the burden of illness and improve workplace productivity. Coalition members will disseminate the toolkit and encourage the adoption of migraine workplace programs by employers worldwide. The Coalition has established an alliance with two global, multinational employers to expand migraine awareness and support among policy makers and other stakeholders around the world. The IHS-GPAC met many of the goals established at GPAS-1, and it has initiated a global strategy focused on the psychosocial and economic toll of headache disorders, especially migraine, in the workplace. Ongoing and future activities will explore a range of opportunities with employers and across the full spectrum of advocacy goals.

Controlled bone formation using ultrasound-triggered release of BMP-2 from liposomes.

Recombinant human bone morphogenetic protein 2 (rhBMP-2) is used clinically to enhance implant-mediated bone regeneration. However, there are risks associated with the high rhBMP-2 dose that is required in the implant to mitigate diffusional loss over the therapeutic timespan. On-demand, localized control over delivery of rhBMP-2, days after implantation, would therefore be an attractive solution in the area of bone repair and reconstruction, yet this has posed a significant challenge, with little data to support in vivo efficacy to date. To address this, we have developed novel liposome-rhBMP-2 nanocomplexes that release rhBMP-2 in response to non-thermogenic, clinical diagnostic ultrasound exposure. In vitro validation shows that rhBMP-2 release is in proportion to applied ultrasound pressure and duration of exposure. Moreover, here we show in vivo validation of this ultrasound-triggered rhBMP-2 delivery system in a standard mouse bone regeneration model. Implanted into hindleg muscles, the liposome-rhBMP-2 nanocomplexes induced local bone formation only after ultrasound exposure. Such post-implantation control of delivery has potential to improve the safety, efficacy and cost of rhBMP-2 use in bone reconstruction. Furthermore, this first proof-of-concept demonstration of in vivo efficacy for ultrasound-triggered liposomal delivery of rhBMP-2 has broader implications for tunable delivery of a variety of drugs and biologics in medicine and tissue engineering.

On the acoustic properties of vaporized submicron perfluorocarbon droplets.

The acoustic characteristics of microbubbles created from vaporized submicron perfluorocarbon droplets with fluorosurfactant coating are examined. Utilizing ultra-high-speed optical imaging, the acoustic response of individual microbubbles to low-intensity diagnostic ultrasound was observed on clinically relevant time scales of hundreds of milliseconds after vaporization. It was found that the vaporized droplets oscillate non-linearly and exhibit a resonant bubble size shift and increased damping relative to uncoated gas bubbles due to the presence of coating material. Unlike the commercially available lipid-coated ultrasound contrast agents, which may exhibit compression-only behavior, vaporized droplets may exhibit expansion-dominated oscillations. It was further observed that the non-linearity of the acoustic response of the bubbles was comparable to that of SonoVue microbubbles. These results suggest that vaporized submicron perfluorocarbon droplets possess the acoustic characteristics necessary for their potential use as ultrasound contrast agents in clinical practice.

The efficiency and stability of bubble formation by acoustic vaporization of submicron perfluorocarbon droplets.

Submicron droplets of liquid perfluorocarbon converted into microbubbles with applied ultrasound have been studied, for a number of years, as potential next generation extravascular ultrasound contrast agents. In this work, we conduct an initial ultra-high-speed optical imaging study to examine the vaporization of submicron droplets and observe the newly created microbubbles in the first microseconds after vaporization. It was estimated that single pulses of ultrasound at 10 MHz with pressures within the diagnostic range are able to vaporize on the order of at least 10% of the exposed droplets. However, only part of the newly created microbubbles survives immediately following vaporization - the bubbles may recondense back into the liquid droplet state within microseconds of nucleation. The probability of bubble survival within the first microseconds of vaporization was shown to depend on ultrasound excitation pressure as well as on bubble coalescence during vaporization, a behavior influenced by the presence of coating material on the newly created bubbles. The results of this study show for the first time that although initial vaporization of droplets is necessary to create echogenic bubbles, additional factors, such as coalescence and bubble shell properties, are important and should be carefully considered for the production of microbubbles for use in medical imaging.

Characterization of submicron phase-change perfluorocarbon droplets for extravascular ultrasound imaging of cancer.

Because many tumors possess blood vessels permeable to particles with diameters of 200 nm, it is possible that submicron perfluorocarbon droplets could constitute a novel extravascular ultrasound contrast agent capable of selectively enhancing tumors. Under exposure to bursts of ultrasound of sufficient rarefactional pressure, droplets can undergo vaporization to form echogenic microbubbles. In this study, phase-change thresholds of 220-nm-diameter droplets composed of perfluoropentane were studied in polyacrylamide gel phantoms maintained at temperatures of 21-37°C, exposed to high-pressure bursts of ultrasound with frequencies ranging from 5-15 MHz and durations of 1 µs to 1 ms. The thresholds were found to depend inversely and significantly (p < 0.001) on ultrasound frequency, pulse duration, and droplet temperature, ranging from 9.4 ± 0.8 MPa at 29°C for a 1-µs burst at 5 MHz to 3.2 ± 0.5 MPa at 37°C for a 1-ms burst at 15 MHz. The diameters of microbubbles formed from droplets decreased significantly as phantom stiffness increased (p < 0.0001), and were independent of pulse duration, although substantially more droplets were converted to microbubbles for 1-ms pulse durations compared with briefer exposures. In vivo experiments in a mouse tumor model demonstrated that intravenously injected droplets can be converted into highly echogenic microbubbles 1 h after administration.

Optical studies of vaporization and stability of fluorescently labelled perfluorocarbon droplets.

Droplets of liquid perfluorocarbon (PFC) are under study as the next generation of contrast agents for ultrasound (US). These droplets can be selectively vaporized into echogenic gas bubbles in situ by externally applied US, with numerous applications to diagnosis and therapy. However, little is known about the mechanisms of droplet vaporization and the stability of the bubbles so produced. Here we observe optically the vaporization of fluorescent PFC droplets and the stability of the newly created bubbles. Fluorescent markers were used to label selectively either the liquid PFC core or the shell of the droplets. It was found that, following vaporization, the fluorescent marker is quickly expelled from the core of the newly created bubble and is retained on the gas-liquid interface. At the same time, it was shown that bubbles retain the original shells encapsulating their droplet precursors. The efficiency of encapsulation was found to depend strongly on the nature of the stabilizing material itself. These results provide direct evidence of droplet encapsulation post-vaporization, and suggest that the behaviour of the vaporized droplets is strongly dependent on the choice of the stabilizing material for the emulsion.

Investigation of vaporized submicron perfluorocarbon droplets as an ultrasound contrast agent.

Acoustically activated submicron droplets of liquid perfluorocarbon are investigated as a new class of ultrasound contrast agent. In the liquid state, intravascular droplets can extravasate within tumours. Activation is then accomplished by using bursts of ultrasound to vaporize the droplets. We use acoustical and optical techniques to assess the characteristics of vaporized droplets and the resulting microbubbles in vitro, including size, conversion threshold, echogenicity and nonlinearity. Under exposure to single 5-50 cycle bursts of ultrasound at 7.5 MHz and mechanical index <1.0, droplets with mean diameter of 400 nm convert into microbubbles with mean diameter of 1.4 µm at 1 ms after vaporization, expanding to 5.6 µm by 1 s. The growth of microbubbles produced by vaporization causes a characteristic time-dependent increase in linear and nonlinear echogenicity, enabling selective detection with conventional bubble-specific imaging. These results suggest that submicron perfluorocarbon droplets, activated in situ, may be a candidate for an extravascular ultrasound contrast agent.

Digital radiography using amorphous selenium: photoconductively activated switch (PAS) readout system.

A new amorphous selenium (a-Se) digital radiography detector is introduced. The proposed detector generates a charge image in the a-Se layer in a conventional manner, which is stored on electrode pixels at the surface of the a-Se layer. A novel method, called photoconductively activated switch (PAS), is used to read out the latent x-ray charge image. The PAS readout method uses lateral photoconduction at the a-Se surface which is a revolutionary modification of the bulk photoinduced discharge (PID) methods. The PAS method addresses and eliminates the fundamental weaknesses of the PID methods--long readout times and high readout noise--while maintaining the structural simplicity and high resolution for which PID optical readout systems are noted. The photoconduction properties of the a-Se surface were investigated and the geometrical design for the electrode pixels for a PAS radiography system was determined. This design was implemented in a single pixel PAS evaluation system. The results show that the PAS x-ray induced output charge signal was reproducible and depended linearly on the x-ray exposure in the diagnostic exposure range. Furthermore, the readout was reasonably rapid (10 ms for pixel discharge). The proposed detector allows readout of half a pixel row at a time (odd pixels followed by even pixels), thus permitting the readout of a complete image in 30 s for a 40 cm x 40 cm detector with the potential of reducing that time by using greater readout light intensity. This demonstrates that a-Se based x-ray detectors using photoconductively activated switches could form a basis for a practical integrated digital radiography system.