An Exploratory Study of Suboxone (Buprenorphine/ Naloxone) Film Splitting: Cutting Methods, Content Uniformity, and Stability

Suboxone films are U.S. Food and Drug Administration approved to treat opioid dependence. While the package insert states that films should not be cut, physicians often prescribe film fractions for treatment and tapering. There is no data to support this practice, and this study was initiated to evaluate cutting methods, content uniformity, and stability of split films. Suboxone 8-mg buprenorphine/2-mg naloxone films were split using four methods: 1) ruler/razor cut, 2) scissor cut, 3) fold/rip, and 4) fold/scissor cut. United States Pharmacopeia Chapter \u3c905\u3e was used to evaluate the weight variation and content uniformity of split films. The stability of split films stored in polybags was evaluated over 7 days. A stability-indicating high-performance liquid chromatography method was used for content uniformity and stability evaluation. The weight variation results were acceptable for the half films from all four cutting methods, but this was not true for the quarter films. The method of ruler/razor cut was determined most favorable and used for the content uniformity test. Based on the high-performance liquid chromatography results, the half films from the ruler/razor cut method met the passing criteria of United States Pharmacopeia Chapter \u3c905\u3e with acceptance values of 9.8 to 10.4 for buprenorphine and 8.4 to 11.5 for naloxone (≤15 is considered passing). The stability results indicated that both actives retained \u3e97.7% of initial strength. Four cutting methods were found to be acceptable for splitting Suboxone films into half but not quarter fractions. The half films from the ruler/razor cut method also passed United States Pharmacopeia Chapter \u3c905\u3e content uniformity test. Both actives remained stable for 7 days when the half films were stored in polybags at room temperature

Hemagglutinin sequence conservation guided stem immunogen design from influenza A H3 subtype

Seasonal epidemics caused by influenza A (H1 and H3 subtypes) and B viruses are a major global health threat. The traditional, trivalent influenza vaccines have limited efficacy because of rapid antigenic evolution of the circulating viruses. This antigenic variability mediates viral escape from the host immune responses, necessitating annual vaccine updates. Influenza vaccines elicit a protective antibody response, primarily targeting the viral surface glycoprotein hemagglutinin (HA). However, the predominant humoral response is against the hypervariable head domain of HA, thereby restricting the breadth of protection. In contrast, the conserved, subdominant stem domain of HA is a potential ‘universal’ vaccine candidate. We designed an HA stem-fragment immunogen from the 1968 pandemic H3N2 strain (A/Hong Kong/1/68) guided by a comprehensive H3 HA sequence conservation analysis. The biophysical properties of the designed immunogen were further improved by C-terminal fusion of a trimerization motif, ‘isoleucine-zipper’ or ‘foldon’. These immunogens elicited cross-reactive, antiviral antibodies and conferred partial protection against a lethal, homologous HK68 virus challenge in vivo. Furthermore, bacterial expression of these immunogens is economical and facilitates rapid scale-up

The Evolution of the Effective Equation of State of the IGM

We develop a method to extract the "effective equation of state" of the intergalactic medium from the doppler b parameter distribution of the low-density Lyman-alpha forest. We test the method on numerical simulations and then apply it to published observations of the Lyman-alpha forest at redshifts z from 0 to 4. We find that the effective equation of state is close to isothermal at redshift z=3, indicating that a second reheating of the IGM took place at z=3. This reheating can plausibly be identified with the reionization of HeII observed to occur at z about 3.Comment: Revised version accepted for publication in ApJ. Vol. 534 May 1, 2000 (in press); 32 pages, 13 figures, 7 table

The Escape of Ionizing Photons from OB Associations in Disk Galaxies: Radiation Transfer Through Superbubbles

By solving the time-dependent radiation transfer problem of stellar radiation through evolving superbubbles within a smoothly varying HI distribution, we estimate the fraction of ionizing photons emitted by OB associations that escapes the HI disk of our Galaxy into the halo and intergalactic medium (IGM). We consider both coeval star-formation and a Gaussian star-formation history with a time spread sigma_t = 2 Myr. We consider both a uniform H I distribution and a two-phase (cloud/intercloud) model, with a negligible filling factor of hot gas. We find that the shells of the expanding superbubbles quickly trap or attenuate the ionizing flux, so that most of the escaping radiation escapes shortly after the formation of the superbubble. For the coeval star-formation history, the total fraction of Lyman Continuum photons that escape both sides of the disk in the solar vicinity is f_esc approx 0.15 +/- 0.05. For the Gaussian star formation history, f_esc approx 0.06 +/- 0.03, a value roughly a factor of two lower than the results of Dove & Shull (1994), where superbubbles were not considered. For a local production rate of ionizing photons Psi_LyC = 4.95 X 10^7 cm^{-2} s^{-1}, the flux escaping the disk is Phi_LyC approx (1.5-3.0) X 10^6 cm^{-2} s^{-1} for coeval and Gaussian star formation, comparable to the flux required to sustain the Reynolds layer.Comment: Revised version (expanded), accepted for publication by ApJ, 38 pages, 8 figures, aasms4.sty and aabib.sty files include

What is the effect of a decision aid in potentially vulnerable parents? Insights from the head CT choice randomized trial.

ObjectiveTo test the hypotheses that use of the Head CT Choice decision aid would be similarly effective in all parent/patient dyads but parents with high (vs low) numeracy experience a greater increase in knowledge while those with low (vs high) health literacy experience a greater increase in trust.MethodsThis was a secondary analysis of a cluster randomized trial conducted at seven sites. One hundred seventy-two clinicians caring for 971 children at intermediate risk for clinically important traumatic brain injuries were randomized to shared decision making facilitated by the DA (n = 493) or to usual care (n = 478). We assessed for subgroup effects based on patient and parent characteristics, including socioeconomic status (health literacy, numeracy and income). We tested for interactions using regression models with indicators for arm assignment and study site.ResultsThe decision aid did not increase knowledge more in parents with high numeracy (P for interaction [Pint ] = 0.14) or physician trust more in parents with low health literacy (Pint  = 0.34). The decision aid decreased decisional conflict more in non-white parents (decisional conflict scale, -8.14, 95% CI: -12.33 to -3.95; Pint  = 0.05) and increased physician trust more in socioeconomically disadvantaged parents (trust in physician scale, OR: 8.59, 95% CI: 2.35-14.83; Pint  = 0.04).ConclusionsUse of the Head CT Choice decision aid resulted in less decisional conflict in non-white parents and greater physician trust in socioeconomically disadvantaged parents. Decision aids may be particularly effective in potentially vulnerable parents

Quantum Moduli Spaces of N=1N=1 String Theories

Generically, string models with $N=1$ supersymmetry are not expected to have moduli beyond perturbation theory; stringy non-perturbative effects as well as low energy field-theoretic phenomena such as gluino condensation will lift any flat directions. In this note, we describe models where some subspace of the moduli space survives non-perturbatively. Discrete $R$ symmetries forbid any inherently stringy effects, and dynamical considerations control the field-theoretic effects. The surviving subspace is a space of high symmetry; the system is attracted to this subspace by a potential which we compute. Models of this type may be useful for considerations of duality and raise troubling cosmological questions about string theory. Our considerations also suggest a mechanism for fixing the expectation value of the dilaton.Comment: 26 pages; uses harvmac. Footnote re fixing dilaton adde

The survival of interstellar clouds against Kelvin-Helmholtz instabilities

We consider the stability of clouds surrounded by a hotter confining medium with respect to which they are in motion, against Kelvin-Helmholtz instabilities (KHI). In the presence of cooling, sound waves are damped by dissipation. Whenever cooling times are shorter than sound crossing times, as they are in the normal interstellar medium, this implies that the instability generated at the interface of the two media cannot propagate far from the interface itself. To study how this influences the overall stability, first we derive an analytic dispersion relation for cooling media, separated by a shear layer. The inclusion of dissipation does not heal the instability, but it is shown that only a small volume around the interface is affected, the perturbation decaying exponentially with distance from the surface; this is confirmed by numerical simulations. Numerical simulations of spherical clouds moving in a surrounding intercloud medium by which they are pressure confined show that these clouds develop a core/halo structure, with a turbulent halo, and a core in laminar flow nearly unscathed by the KHI. The related and previously reported ``champagne effect'', whereby clouds seem to explode from their top sides, is cured by the inclusion of radiative losses.Comment: 13 pages, AASTEX LATEX, accepted for publication in The Astrophysical Journa

On the influence of virtual camber effect on airfoil polars for use in simulations of Darrieus wind turbines

Darrieus vertical-axis wind turbines are experiencing renewed interest from researchers and manufacturers, though their efficiencies still lag those of horizontal-axis wind turbines. A better understanding of their aerodynamics is required to improve on designs, for example through the development of more accurate low-order (e.g. blade element momentum) models. Many of these models neglect the impact of the curved paths that are followed by blades on their performance. It has been theorized that the curved streamlines of the flow impart a virtual camber and incidence on them, giving a performance analogous to a cambered blade in a rectilinear flow. To test the extent of this effect, wind tunnel experiments have been conducted in a rectilinear flow to obtain lift and drag for three airfoils: a NACA 0018 and two conformal transforms of the profile. The transformed airfoils exhibit the virtual camber that the theory predicts is imparted to a NACA 0018 when used in a Darrieus turbine with blade chord-to-turbine radius ratios, c/R, of 0.114 and 0.25. A parallel computational fluid dynamics campaign has been conducted to study the aerodynamic behavior of the same blades in curvilinear flow in Darrieus-like motion with c/R = 0.114 and 0.25, at tip-speed ratios of 2.1 and 3.1, using novel techniques to obtain blade effective angles of attack. The analysis confirms that the theory holds, with the wind tunnel results for the NACA 0018 being analogous to numerical results for the relevant cambered airfoils. In addition, turbine performance is calculated using computational fluid dynamics and a blade element momentum code, for each of the blades in turn. The computational fluid dynamics results for the NACA 0018 agree closely to blade element momentum results for the equivalent cambered airfoil where c/R = 0.25, for both turbine power and blade tangential forces. Agreement between the two methods using geometrically identical blades is poor at both the blade and turbine level for c/R = 0.25. It is concluded that when modeling a Darrieus rotor using blade element momentum methods, applying experimental data for the profile used in the turbine will yield inaccurate results if the c/R ratio is high, in such cases it is necessary to select a profile based on the virtual shape of the blades

Distinct immune signatures in directly treated and distant tumors result from TLR adjuvants and focal ablation.

Both adjuvants and focal ablation can alter the local innate immune system and trigger a highly effective systemic response. Our goal is to determine the impact of these treatments on directly treated and distant disease and the mechanisms for the enhanced response obtained by combinatorial treatments. Methods: We combined RNA-sequencing, flow cytometry and TCR-sequencing to dissect the impact of immunotherapy and of immunotherapy combined with ablation on local and systemic immune components. Results: With administration of a toll-like receptor agonist agonist (CpG) alone or CpG combined with same-site ablation, we found dramatic differences between the local and distant tumor environments, where the directly treated tumors were skewed to high expression of F4/80, Cd11b and Tnf and the distant tumors to enhanced Cd11c, Cd3 and Ifng. When ablation was added to immunotherapy, 100% (n=20/20) of directly treated tumors and 90% (n=18/20) of distant tumors were responsive. Comparing the combined ablation-immunotherapy treatment to immunotherapy alone, we find three major mechanistic differences. First, while ablation alone enhanced intratumoral antigen cross-presentation (up to ~8% of CD45+ cells), systemic cross-presentation of tumor antigen remained low. Combining same-site ablation with CpG amplified cross-presentation in the draining lymph node (~16% of CD45+ cells) compared to the ablation-only (~0.1% of CD45+ cells) and immunotherapy-only cohorts (~10% of CD45+ cells). Macrophages and DCs process and present this antigen to CD8+ T-cells, increasing the number of unique T-cell receptor rearrangements in distant tumors. Second, type I interferon (IFN) release from tumor cells increased with the ablation-immunotherapy treatment as compared with ablation or immunotherapy alone. Type I IFN release is synergistic with toll-like receptor activation in enhancing cytokine and chemokine expression. Expression of genes associated with T-cell activation and stimulation (Eomes, Prf1 and Icos) was 27, 56 and 89-fold higher with ablation-immunotherapy treatment as compared to the no-treatment controls (and 12, 32 and 60-fold higher for immunotherapy-only treatment as compared to the no-treatment controls). Third, we found that the ablation-immunotherapy treatment polarized macrophages and dendritic cells towards a CD169 subset systemically, where CD169+ macrophages are an IFN-enhanced subpopulation associated with dead-cell antigen presentation. Conclusion: While the local and distant responses are distinct, CpG combined with ablative focal therapy drives a highly effective systemic immune response