To analyze and interpret the chemical record, the 2007 Phoenix Mars Lander includes four wet chemistry cells. These Wet Chemistry Laboratories (WCLs), part of the Microscopy, Electrochemistry, and ...Conductivity Analyzer (MECA) package, each consist of a lower “beaker” containing sensors designed to analyze the chemical properties of the regolith and an upper “actuator assembly” for adding soil, water, reagents, and stirring. The beaker contains an array of sensors and electrodes that include six membrane‐based ion selective electrodes (ISE) to measure Ca2+, Mg2+, K+, Na+, NO3−/ClO4−, and NH4+; two ISEs for H+ (pH); a Ba2+ ISE for titrimetric determination of SO42−; two Li+ ISEs as reference electrodes; three solid crystal pellet ISEs for Cl−, Br−, and I−; an iridium oxide electrode for pH; a carbon ring electrode for conductivity; a Pt electrode for oxidation reduction potential (Eh); a Pt and two Ag electrodes for determination of Cl−, Br−, and I− using chronopotentiometry (CP); a Au electrode for identifying redox couples using cyclic voltammetry (CV); and a Au microelectrode array that could be used for either CV or to indicate the presence of several heavy metals, including Cu2+, Cd2+, Pb2+, Fe2/3+, and Hg2+ using anodic stripping voltammetry (ASV). The WCL sensors and analytical procedures have been calibrated and characterized using standard solutions, geological Earth samples, Mars simulants, and cuttings from a Martian meteorite. Sensor characteristics such as limits of detection, interferences, and implications of the Martian environment are also being studied. A sensor response library is being developed to aid in the interpretation of the data.
We present a study of the temperature and density equilibration near the liquid-gas critical point of a composite system consisting of a thin circular disk of near-critical fluid surrounded by a ...copper wall. This system is a simplified model for a proposed space experiment cell that would have 60 thin fluid layers separated by perforated copper plates to aid in equilibration. Upper and lower relaxation time limits that are based on radial and transverse diffusion through the fluid thickness are shown to be too significantly different for a reasonable estimate of the time required for the space experiment. We therefore have developed the first rigorous analytical solution of the piston effect in two dimensions for a cylindrically symmetric three-dimensional cell, including the finite conductivity of the copper wall. This solution covers the entire time evolution of the system after a boundary temperature step, from the early piston effect through the final diffusive equilibration. The calculation uses a quasistatic approximation for the copper and a Laplace-transform solution to the piston effect equation in the fluid. Laplace inversion is performed numerically. The results not only show that the equilibration is divided into three temporal regimes but also give an estimate of the amplitudes of the remaining temperature and density inhomogeneity in each regime. These results yield characteristic length scales for each of the regimes that are used to estimate the expected relaxation times in the one- and two-phase regions near the critical point.
I have studied phonon scattering by ferroelectric domain walls in KH$\sb2$PO$\sb4$ (KDP) using thermal conductivity and phonon imaging measurements of samples in both single-domain (poled) and ...multi-domain states. Domains were eliminated by applying a 2-3kV/cm field using evaporated electrodes. Phonon images of a poled (001) sample (at 1.7K) show two-fold symmetric focusing patterns that clearly show the small orthorhombic distortion of the lattice. Poled images are qualitatively reproduced by calculations using continuum acoustics with room temperature tetragonal elastic moduli split to orthorhombic symmetry; a rough set of low temperature orthorhombic moduli is thereby determined. The presence of domains causes a large change in ST focusing structures but little change in L and FT patterns. There is an apparent decrease in overall intensity for all modes. The images show strongly mode and polarization dependent phonon scattering. Monte Carlo simulations using acoustic mismatch (phonon reflection) to model phonon/domain wall interactions accurately reproduce the changes seen in the domained images. The low temperature (0.03-3K) thermal conductivity, $\kappa$, of (100), (110), and (001) (tetragonal basis) oriented samples was measured. $\kappa$ in poled samples shows typical surface-limited behavior which is predicted to 13% by calculations including finite length and anisotropy and using elastic constants from the imaging simulations. Domain walls produce a 40% conductivity decrease in a (110) sample and a 30% decrease in (100) samples which is nearly independent of sample size, suggesting strong scattering of only a subset of phonons. Domain wall scattering is nearly temperature independent between 0.3K and 1K, but decreases at lower temperatures, and increases above 1K. The (001) sample couldn't be poled, but the dominated $\kappa$ is higher than that expected from sample surface scattering. Domains parallel to the heat flow may be channeling phonons and increasing $\kappa$. Acoustic mismatch calculations applied to $\kappa$ predict the right order of scattering, but do not reproduce the sample size effects. Orientation effects can be partially explained. The probability of diffuse scattering at the domain boundaries (often seen in Kapitza resistance studies) is at most 1%.
ENHANCE was a phase 3 study that evaluated efficacy and safety of seladelpar, a selective peroxisome proliferator-activated receptor-δ (PPAR) agonist, versus placebo in patients with primary biliary ...cholangitis with inadequate response or intolerance to ursodeoxycholic acid (UDCA).
Patients were randomized 1:1:1 to oral seladelpar 5 mg (n=89), 10 mg (n=89), placebo (n=87) daily (with UDCA, as appropriate). Primary end point was a composite biochemical response alkaline phosphatase (ALP) < 1.67×upper limit of normal (ULN), ≥15% ALP decrease from baseline, and total bilirubin ≤ ULN at month 12. Key secondary end points were ALP normalization at month 12 and change in pruritus numerical rating scale (NRS) at month 6 in patients with baseline score ≥4. Aminotransferases were assessed. ENHANCE was terminated early following an erroneous safety signal in a concurrent, NASH trial. While blinded, primary and secondary efficacy end points were amended to month 3. Significantly more patients receiving seladelpar met the primary end point (seladelpar 5 mg: 57.1%, 10 mg: 78.2%) versus placebo (12.5%) (p < 0.0001). ALP normalization occurred in 5.4% (p=0.08) and 27.3% (p < 0.0001) of patients receiving 5 and 10 mg seladelpar, respectively, versus 0% receiving placebo. Seladelpar 10 mg significantly reduced mean pruritus NRS versus placebo 10 mg: -3.14 (p=0.02); placebo: -1.55. Alanine aminotransferase decreased significantly with seladelpar versus placebo 5 mg: 23.4% (p=0.0008); 10 mg: 16.7% (p=0.03); placebo: 4%. There were no serious treatment-related adverse events.
Patients with primary biliary cholangitis (PBC) with inadequate response or intolerance to UDCA who were treated with seladelpar 10 mg had significant improvements in liver biochemistry and pruritus. Seladelpar appeared safe and well tolerated.
Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple ...aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV.
HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log10 HBV DNA from Baseline to Week 12 and 24.
All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log10 IU/ml HBV DNA (–4.45 1.03) vs. PBO+ETV (–3.30 1.18; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log10 IU/ml HBV DNA (–5.33 1.59) vs. PBO+ETV (–4.20 0.98; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p <0.0001 and p <0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury.
In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile.
NCT03577171
Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted.
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•Complete suppression of HBV replication is essential for finite treatment regimens•Vebicorvir (VBR) is an HBV core protein inhibitor developed to treat chronic HBV•VBR interferes with 2 additional steps in HBV replication and thus complements NrtIs•VBR+ETV led to a significantly deeper reduction in HBV DNA and pregenomic RNA than ETV alone•VBR+ETV was associated with favorable safety and tolerability during 24 weeks of treatment
HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being ...undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs.
Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks.
Of 73 patients enrolled, 47 were HBeAg positive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported.
In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone.
NCT03576066.
Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.
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•Complete suppression of HBV replication is essential for finite treatment regimens.•Vebicorvir (VBR) is a novel inhibitor of the HBV core protein.•VBR interferes with two additional steps in HBV replication than NrtIs.•Added to NrtI, VBR did not significantly change mean HBV antigens over 24 weeks.•Added to NrtI, VBR further reduced HBV DNA and pgRNA by high-sensitivity PCR assays.
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