While steady thruster jets caused only modest surface erosion during previous spacecraft landings on the Moon and Mars, the pulsed jets from the Phoenix spacecraft led to extensive alteration of its ...landing site on the martian arctic, exposed a large fraction of the subsurface water ice under the lander, and led to the discovery of evidence for liquid saline water on Mars. Here we report the discovery of the ‘explosive erosion’ process that led to this extensive erosion. We show that the impingement of supersonic pulsed jets fluidizes porous soils and forms cyclic shock waves which propagate through the soil and produce erosion rates more than an order of magnitude larger than that of other jet-induced processes. The understanding of ‘explosive erosion’ allows the calculation of bulk physical properties of the soils altered by it, provides insight into a new behavior of granular flow at extreme conditions and explains the rapid alteration of the Phoenix landing site’s ground morphology at the northern arctic plains of Mars.
The Phoenix mission, launched on 4 August 2007, landed in the far northern plains of Mars on 25 May 2008. In order to prepare for the landing events and the 90‐sol mission, a significant amount of ...work has gone into characterizing the atmospheric environment at this location on Mars for northern late spring through midsummer. In this paper we describe the motivation for the work and present our results on atmospheric densities and winds expected during the Phoenix entry, descent, and landing, as well as near‐surface pressure, temperature, winds, surface temperature, and visible optical depth expected over the course of the science mission.
Introduction
Ralinepag is a potent, titratable, orally administered prostacyclin (IP) receptor agonist to treat pulmonary arterial hypertension. A phase II randomized, double-blind, parallel-group, ...placebo-controlled, 22-week study of immediate-release (IR) ralinepag safety and efficacy met its primary endpoint, significantly reducing pulmonary vascular resistance (PVR) compared with placebo. This phase II open-label extension (OLE) study assessed long-term safety and tolerability of ralinepag.
Methods
Participants were eligible for the OLE if they completed the parent study or experienced a clinical worsening event while receiving placebo. Those previously receiving IR ralinepag remained on their current dose, and participants formerly administered placebo were titrated to the highest tolerated dose. Participants were transitioned to an extended-release ralinepag formulation toward the end of the OLE. The primary objective evaluated long-term safety and tolerability; secondary endpoints included changes in 6-min walk distance (6MWD), World Health Organization/New York Heart Association functional class, clinical worsening, and hemodynamic measures.
Results
In total, 45/61 participants enrolled in the OLE study, 30 from the IR ralinepag group and 15 from the placebo group. The most common adverse events (AEs) were known prostacyclin-related effects (e.g., headache, 64.4%; diarrhea, 37.8%; jaw pain, 33.3%). There was a notable decline in AEs after reaching and maintaining a stable dose. At month 24 after entering the OLE, 6MWD significantly increased by a mean of 36.3 m (
P
= 0.004) from OLE baseline, and most participants remained stable in their functional class (84.8%). Post-baseline PVR in 1 or 2 years decreased by a median of 52.2 dyn.s/cm
5
and mean pulmonary arterial pressure decreased by a median of 2.0 mmHg (
P
= 0.05).
Conclusion
Ralinepag produced sustained, durable improvements in 6MWD along with durable reductions in PVR and a manageable AE profile. Most participants continuing treatment with ralinepag maintained functional measures throughout the OLE and those switching from placebo to ralinepag often experienced functional improvements.
Plain Language Summary
Pulmonary arterial hypertension is a rare disease caused by elevated pressure in the blood vessels connecting the heart to the lungs. A previous phase 2 study found that ralinepag significanlty reduced pulmonary vascular resistance (the force or resistance that blood encounters as it flows through the blood vessels in the lungs) compared with placebo. This clinical study of 45 patients investigated whether ralinepag was safe and effective for long-term use to treat people with pulmonary arterial hypertension. All participants received ralinepag twice daily until a new once daily pill was available later in the study. The primary endpoints were long-term safety and tolerability, and secondary endpoints included exercise capacity, impact on daily life (functional class), clinical worsening, and hemodynamic measures (metrics to measure how well the heart is working). The study found that ralinepag had a manageable side effect profile, with a decrease in side effects for patients who continued taking ralinepag over time. Moreover, the study showed that ralinepag improved the ability to exercise, maintained functional measures, and helped to reduce pressure in the blood vessels connecting the heart to the lungs over a 24-month period for participants with pulmonary arterial hypertension.
Oral treprostinil has been shown to improve exercise capacity and delay disease progression in patients with pulmonary arterial hypertension (PAH), but its effects on hemodynamics are not ...well-characterized. The FREEDOM-EV trial was a Phase III, international, placebo-controlled, double-blind, event-driven study in 690 participants with PAH who were taking a single oral PAH therapy. FREEDOM-EV demonstrated a significantly reduced risk for clinical worsening with oral treprostinil taken three times daily and did not uncover new safety signals in PAH patients. Sixty-one participants in the FREEDOM-EV trial volunteered for a hemodynamics sub-study. Pulmonary artery compliance (PAC), a ratio of stroke volume to pulmonary pulse pressure, significantly increased from Baseline to Week 24 in the oral treprostinil group compared with the placebo group (geometric mean 26.4% active vs. -6.0% placebo; ANCOVA p=0.007). There was a significant increase in cardiac output in the oral treprostinil group compared to the placebo group (geometric mean 11.3% active vs. -6.4% placebo; ANCOVA p=0.005) and a corresponding significant reduction in pulmonary vascular resistance (PVR) (geometric mean -21.5 active vs. -1.8% placebo; ANCOVA p=0.02) from Baseline to Week 24. These data suggest that increased compliance contributes to the physiological mechanism by which oral treprostinil improves exercise capacity and delays clinical worsening for patients with PAH.
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•In FREEDOM-EV, oral treprostinil significantly reduced PAH clinical worsening risk.•61 FREEDOM-EV participants had hemodynamic data collected in an optional sub-study.•Oral treprostinil improved pulmonary vascular resistance and cardiac output at Week 24.•Pulmonary artery compliance (stroke volume/pulse pressure) predicts outcomes in PAH.•Oral treprostinil taken TID improved pulmonary artery compliance at Week 24.
Introduction
In the event-driven FREEDOM-EV trial, oral treprostinil delayed clinical worsening in patients with pulmonary arterial hypertension (PAH). Open-label extension studies offer additional ...data about tolerability, efficacy, and survival, especially for those initially assigned placebo. The aim of the current study was to determine if oral treprostinil changed survival when considering the parent and extension study, if treprostinil provides functional benefits for participants initially assigned to placebo, and if the benefits observed for those treated with treprostinil were durable.
Methods
Both active and placebo participants from FREEDOM-EV could enroll in the FREEDOM-EV open-label extension (OLE) study after experiencing an investigator-assessed clinical worsening event or after parent study closure. All participants in the OLE were offered open-label oral treprostinil. Previously assigned placebo participants titrated to maximally tolerated doses; previously assigned treprostinil participants continued dose titration. We repeated assessments including functional class and 6-min walk distance (6MWD) at 12-week intervals and measured N-terminal pro-brain natriuretic peptide (NT-proBNP) at week 48. Survival was estimated by Kaplan–Meier analysis, and we estimated hazard ratio (HR) using Cox proportional hazards.
Results
Of 690 FREEDOM-EV participants, 470 enrolled in the OLE; vital status was available for 89% of initial Freedom-EV participants. When considering the combined parent and open-label data, initial assignment to oral treprostinil reduced mortality (HR 0.64, 95% confidence interval 0.46–0.91,
p
= 0.013); absolute risk reduction was 9%. Participants randomized to placebo who initiated oral treprostinil after clinical worsening and tolerated treatment through week 48 demonstrated favorable shifts in functional class (
p
< 0.0001), 6MWD improvements of + 84 m (
p
< 0.0001), and a reduction in NT-proBNP of − 778 pg/mL (
p
= 0.02), compared to OLE baseline. Modest trends toward benefit were measured for those initially assigned placebo who did not have clinical worsening, and 132/144 (92%) of treprostinil assigned participants without clinical worsening remained on drug at week 48 in the OLE study. Adverse events were consistent with FREEDOM-EV.
Conclusion
Initial treprostinil assignment improved survival in the entire data set; those who began treprostinil after a clinical worsening in the placebo arm and tolerated drug to week 48 enjoyed substantial functional gains.
Clinical Trial Registration
ClinicalTrials.gov identifier NCT01560637.
This study evaluated PYM00217, a proprietary blend of plant extracts, in the management of canine atopic dermatitis (AD). One hundred and twenty dogs were diagnosed with perennial AD on the basis of ...history, clinical signs, a positive test for perennial allergens and elimination of other dermatoses. Exclusion criteria included antimicrobials within 7 days, antihistamines within 14 days, oral/topical glucocorticoids or ciclosporin within 28 days, and parenteral glucocorticoids, essential fatty acids or immunotherapy within 56 days. Flea control, shampoos and ear cleaners were permitted. Dogs with a minimum canine atopic dermatitis extent and severity index (CADESI) of 25 were randomly allocated to receive PYM00217 (100, 200 or 400 mg kg⁻¹ day⁻¹) or placebo for 12 weeks. The mean reductions in CADESI (intention-to-treat population) were 3.9% (placebo; n = 29), 4.4% (100 mg kg⁻¹ day⁻¹; n = 30), 23.4% (200 mg kg⁻¹ day⁻¹; n = 29) and 8.5% (400 mg kg⁻¹ day⁻¹; n = 29). The reduction in the 200 mg kg⁻¹ day⁻¹ group was significant (P < 0.01). For dogs with a baseline CADESI >= 50, the mean changes were +10.6% (placebo; n = 12), +0.6% (100 mg kg⁻¹ day⁻¹; n = 14), -29.3% (200 mg kg⁻¹ day⁻¹; n = 14) and -3.4% (400 mg kg⁻¹ day⁻¹; n = 15). The 200 mg kg⁻¹ day⁻¹ dose was significantly more effective than placebo (P = 0.038). No serious adverse effects were reported. Minor adverse effects seen in 10% (placebo and 100 mg kg⁻¹ day⁻¹), 24% (200 mg kg⁻¹ day⁻¹) and 42% (400 mg kg⁻¹ day⁻¹) of cases were mainly minor gastrointestinal disorders and only five cases required cessation of dosing. Two dogs (one in each of the 100 mg kg⁻¹ day⁻¹ and 200 mg kg⁻¹ day⁻¹ groups) refused to eat the medicated food. In conclusion, PYM00217 at 200 mg kg⁻¹ appears to be an effective, palatable and well-tolerated treatment for canine AD.
Access to oral health care is a critical need for the adult Medicaid population. Following the 2014 expansion of Medicaid eligibility in Kentucky, millions of adults became eligible to receive dental ...benefits. We examined the impact of the expansion on adult Medicaid enrollees' use of hospital emergency departments (EDs) for conditions related to dental or oral health in the period 2010-14. Based on our analysis of data for Kentucky from the State Emergency Department Databases, we found that the rate of discharges for these conditions from the ED increased significantly, from 1,833 per 100,000 population in 2013 to 5,635 in 2014. Adults covered by Medicaid who used the ED for treatment of oral health conditions in 2014 had high levels of chronic comorbidities and were more likely to be male and nonwhite than those in earlier years. To avoid costly and inappropriate use of the ED, states considering adding an adult Medicaid dental benefit should consider also making changes to assist beneficiaries in obtaining access to the dental health care delivery system.
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