Parenteral treprostinil induction for rapid attainment of therapeutic doses of oral treprostinil.

RATIONALE: Oral treprostinil slows disease progression and improves exercise capacity in pulmonary arterial hypertension; however, titration can be prolonged. Published data suggests prostacyclin-naïve patients achieve total daily oral treprostinil doses of about 6 mg by Week 16, while those on prior parenteral treprostinil reach higher doses at the same timepoint. OBJECTIVES: EXPEDITE (NCT03497689), a single-arm, multicenter study, assessed the efficacy of rapid parenteral treprostinil induction to quickly reach higher doses of oral treprostinil for the treatment of pulmonary arterial hypertension. METHODS: Parenteral treprostinil was titrated for 2-8 weeks, followed by cross-titration of oral treprostinil. The primary endpoint was percentage of patients reaching ≥12 mg daily of oral treprostinil at Week 16. Secondary endpoints included clinical changes from baseline to Week 16. RESULTS: Twenty-nine prostacyclin-naïve patients were included in efficacy analyses. At Week 16, the mean daily oral treprostinil dose was 16.4 mg; 79% of patients met the primary endpoint. From baseline to Week 16, median REVEAL Lite 2 score improved (decreased) from 6 to 3.5 (p = 0.0006). Statistically significant improvements were also seen in World Health Organization Functional Class, N-terminal-pro brain natriuretic peptide levels, 6-minute walk distance, right atrial area, Borg Dyspnea Score, and emPHasis-10 score. Favorable trends were seen in risk stratification, echocardiography parameters, disease symptoms, and treatment satisfaction. CONCLUSION: Short-course parenteral treprostinil induction resulted in oral treprostinil doses over twice those reported in de novo initiations and may be a useful approach to quickly achieve the therapeutic benefits of oral treprostinil.

Implementing the EXPEDITE parenteral induction protocol: Rapid parenteral treprostinil titration and transition to oral treprostinil.

Treprostinil is a prostacyclin analogue that targets multiple cellular receptors to treat pulmonary arterial hypertension (PAH). In certain scenarios, patients may require aggressive treprostinil titration. Several studies have demonstrated that higher doses of treprostinil lead to greater clinical benefit. Data supports successful transitions from parenteral to oral treprostinil; however, administration routes, transition duration, and transition setting vary in the real-world. The EXPEDITE clinical trial (NCT03497689) prospectively studied whether rapid parenteral treprostinil induction can be used to achieve high doses of oral treprostinil (total daily dose: ≥12 mg) in prostacyclin naïve PAH patients. Parenteral prostacyclin induction may be more appropriate for patients who need to reach therapeutic dosing more urgently than longer titration durations reported with conventional de novo oral treprostinil initiation. This summary provides strategies utilized in EXPEDITE. Parenteral treprostinil was initiated at 2 ng/kg/min intravenously or subcutaneously; clinicians determined the frequency and dose increment of up-titration. Two distinct transition schedules from parenteral to oral treprostinil were employed: rapid cross-titration in an inpatient setting (median: 2 days) or gradual cross-titration in an outpatient setting (median: 5 days). Patient status was closely monitored after transition; oral treprostinil dose was titrated to clinical effect and tolerability. Factors considered when individualizing dosing strategies included parenteral and oral treprostinil target doses, nursing support, patient education, medication counseling and adverse events management. EXPEDITE demonstrated the time to a therapeutic dose of oral treprostinil is significantly shorter when utilizing a short-term parenteral induction strategy and may be suitable for patients requiring aggressive titration of oral treprostinil.

Sustainable intensification of agriculture for human prosperity and global sustainability.

There is an ongoing debate on what constitutes sustainable intensification of agriculture (SIA). In this paper, we propose that a paradigm for sustainable intensification can be defined and translated into an operational framework for agricultural development. We argue that this paradigm must now be defined-at all scales-in the context of rapidly rising global environmental changes in the Anthropocene, while focusing on eradicating poverty and hunger and contributing to human wellbeing. The criteria and approach we propose, for a paradigm shift towards sustainable intensification of agriculture, integrates the dual and interdependent goals of using sustainable practices to meet rising human needs while contributing to resilience and sustainability of landscapes, the biosphere, and the Earth system. Both of these, in turn, are required to sustain the future viability of agriculture. This paradigm shift aims at repositioning world agriculture from its current role as the world's single largest driver of global environmental change, to becoming a key contributor of a global transition to a sustainable world within a safe operating space on Earth.

Oxygen uptake response to stroke rate manipulation in freestyle swimming.

UNLABELLED: During gait, humans choose a combination of step length and step rate that minimizes V˙O2. However, little work has been reported on the existence of such optimization in swimming. PURPOSE: The purpose of this study was to examine the manipulation of stroke rate on V˙O2 in submaximal, constant speed freestyle swimming. METHODS: Preferred stroke rate for swimming freestyle at 1.0 m·s(-1) in a flume was determined for 10 competitive swimmers (mean ± SD: age = 33.3 ± 13.6 yr, height = 175.3 ± 8.6 cm, weight = 74.9 ± 12.2 kg). Participants then completed flume swims at 1.0 m·s(-1) with stroke rates equal to -20%, -10%, 0%, +10%, and +20% of their preferred stroke rate in a randomized order during which V˙O2 was continuously monitored. Each trial continued for 1 min after steady-state V˙O2 was verified (∼4-5 min). During the final minute of each trial, V˙O2 was measured using the Douglas bag technique, HR was recorded, and kick rate (KR) was computed using the time needed to complete 30 kicks. RPE was reported immediately after each trial. RESULTS: V˙O2 increased 11%-16% (P < 0.05) when stroke rate was reduced but was nominally affected when stroke rate was increased. Likewise, HR increased 4%-6% (P < 0.05), and RPE increased 15%-30% (P < 0.05) when stroke rate was reduced but not affected when stroke rate was increased. CONCLUSIONS: These data suggest that these swimmers preferred to swim freestyle at the lowest stroke rate (or the longest stroke length) that did not require an increase in V˙O2.

Topics and cases for online education in engineering.

When considering offering online education for engineering ethics instruction, making choices necessary for the effective development and delivery of an engineering ethics curriculum is an important first step. Selecting the topics and types of cases for the most effective ethics education of engineering students is a vital step in preparing an effective program. Examples are presented for topics which are considered good candidates for online presentation, and the adaptability of these topics for web-based instruction is discussed. Types of cases which are useful in engineering ethics education are presented. Methods of teaching applied ethics, as well as ideas for web-based ethics course design are suggested. The market for web-based instruction is discussed

Effect of sampling strategy on measures of VO2peak obtained using commercial breath-by-breath systems.

The purpose of this study was to determine the effect of sampling strategy (i.e., number of breaths) on measured peak rate of oxygen uptake ( VO(2peak)) elicited by a range of severe intensity exercise bouts. The hypothesis was that a smaller sample (i.e., fewer breaths) would produce a higher measure of VO(2peak) and that this effect would be greater in shorter tests than in longer tests. Thirty-three university students performed constant-power cycle ergometer tests at intensities selected to elicit fatigue in ~3.0 min (short duration), approximately 5.5 min (medium duration), and approximately 8.0 min (long duration). Values for VO(2peak) were the highest rates of oxygen uptake obtained using the following sampling methods: single breath, and 3-, 5-, 15- and 30-breath rolling averages. As hypothesized, measures of VO(2peak) increased systematically with decreasing sample size. Contrary to the hypothesis, the effect of sample size was greater in medium duration and long duration tests than in the short duration tests. The interaction between test duration and sample size on measures of VO(2peak) highlights the importance of standardizing the analysis protocol for exercise in the severe domain. If such standardization is not feasible, it should be recognized that specific analysis protocols may exert a substantial effect upon the reported VO(2peak).

The relationship between power and the time to achieve .VO(2max).

PURPOSE: The severe exercise intensity domain may be defined as that range of work rates over which .VO(2max) can be elicited during constant-load exercise. The purpose of this study was to help characterize the .VO(2) response within this domain. METHODS: Eleven participants performed cycle ergometer exercise tests to fatigue at several discrete work rates between 95% and 135% of the maximum power (P(max)) achieved during an incremental exercise test. RESULTS: As previously demonstrated, the relationship between power and time to fatigue was hyperbolic. The asymptote of power (critical power, P(critical)) was 198 +/- 44 W. The rapidity of the .VO(2) response increased systematically at higher work rates such that the relationship between power and time to .VO(2max) was also well fit by a hyperbola. The power asymptote of this relationship (196 +/- 42 W) was not different from P(critical)(P > 0.05). The two hyperbolic relationships converged at 342 +/- 70 W (136% P(max)). CONCLUSION: These data suggest that, for this population of male and female university students, the upper boundary of the severe exercise intensity domain is approximately 136% P(max). This upper boundary is the highest work rate for which exercise duration is prolonged sufficiently (in this study, 136 +/- 17 s) to allow .VO(2) to rise to its maximal value. The lower boundary for severe exercise is just above P(critical), which is the highest work rate that is sustainable for a prolonged duration and that will not elicit .VO(2max).