Abstract
Fast engineering wake models are the backbone of wind farm annual energy production (AEP) estimators, whereas the addition of induction zone models in existing tools is a more recent ...response to rising concerns over wind farm blockage associated losses. Here, “blockage” describes the combined induction fields of all wind turbines inside a farm. Unlike the term might suggest, blockage not only reduces flow speeds, but also increases them; for instance along the outer edges of wind farms. Evaluating the overall impact on AEP of these gains and losses necessitates accurate wind farm induction models. Whilst engineering wake models are tuned to predict wind farm performance, existing induction zone models are all derived for accurately predicting the near field induction not the far field value—important for wind farm simulations. This paper presents the induction models implemented in the wind farm simulation tool PyWake, as well as results from novel analytical models and compares their far field predictions to RANS-AD simulations of different turbines. We demonstrate that when including blockage in AEP simulations, the downstream speed-ups need to be included to avoid an unrealistic bias toward AEP loss and that wake expansion significantly impacts induction at rated thrust levels.
Introduction
Migraine is associated with substantial functional impairment and affects many aspects of daily life.
Methods
Using data from SAMURAI and SPARTAN (double-blind, placebo-controlled, phase ...3 studies) and GLADIATOR (an open-label, phase 3 study enrolling patients who had completed SAMURAI or SPARTAN), we assessed the effects of lasmiditan on migraine-related functional disability at multiple time points from 0.5 to 48 h post dose by asking patients to rate how much the migraine was interfering with normal activities. Pooled data from SAMURAI and SPARTAN (SAMURAI + SPARTAN) and data from GLADIATOR were analyzed using the intention-to-treat populations.
Results
For SPARTAN + SAMURAI, significantly more patients who received lasmiditan at any dose versus placebo reported freedom from migraine-related functional disability at every timepoint from 2 h post dose, and this difference persisted to 48 h (
p
< 0.05). Significant differences from placebo in freedom from migraine-related functional disability commenced at 1 h post dose for lasmiditan 200 mg, 1.5 h for lasmiditan 100 mg, and 2 h for lasmiditan 50 mg. Findings from GLADIATOR supported those from SAMURAI + SPARTAN.
Conclusion
All doses of lasmiditan resulted in an improvement in migraine-related functional disability that persisted to 48 h. In SAMURAI + SPARTAN, a significant difference from placebo was observed as early as 1 h post dose.
Trial registration at clinicaltrials.gov
SAMURAI (NCT02439320), SPARTAN (NCT02605174), and GLADIATOR (NCT02565186).
Natural killer (NK) cell subpopulations from 8 HLA-matched but killer cell immunoglobulin-like receptor (KIR)/HLA-ligand-mismatched patient-donor pairs were analyzed in the course of allogeneic ...hematopoietic stem cell transplantation (HCT). The patients' post-transplantation NKG2A
/LIR-1
NK cells, which expressed only inhibitory KIRs for which the patient had no HLA class I ligands, showed higher cytotoxic capacity than the NKG2A
/LIR-1
NK cells lacking any inhibitory KIRs that remained tolerant throughout the course of HCT. The NKG2A
NK cell subpopulations displayed the highest levels of cytotoxic activation, which appeared to be significantly enhanced in comparison with that in allogeneic graft's donors. LIR-1
NK cells were much more frequent after HCT than LIR-1
NK cells and LIR-1 expression on NKG2A
or NKG2A
NK cells was associated with significantly lower cytotoxic activities. Thus NKG2A
/LIR-1
NK cells expressing only HLA-mismatched KIRs show a partial break in tolerance in the first year following HCT. The failure to exclude LIR-1
cells within the NKG2A
NK cell subset in previous studies could explain the earlier conflicting results. Thus systemic immune activation in patients following HCT augments the GvL effect through both increasing overall NK cell activities and partially breaking tolerance of unlicensed NK cells.
CONCERTO was a randomised, double-blind, parallel-armed study of methotrexate (MTX) in combination with adalimumab to assess whether an increasing trend of efficacy and decreased safety exists when ...increasing MTX dose in patients with early rheumatoid arthritis (RA).
Early, biologic and MTX-naive RA patients (N=395) were evenly randomised to open-label adalimumab (40 mg every other week) plus weekly blinded 2.5, 5, 10 or 20 mg MTX for 26 weeks. Clinical, radiographic and functional outcomes were analysed using two-sided linear trend tests or one-way analysis of covariance.
Statistically significant increasing trends were observed in the proportion of patients achieving the primary endpoint, 28-joint count disease activity score with C reactive protein (DAS28(CRP)) <3.2 (42.9%, 44.0%, 56.6% and 60.2% for 2.5, 5, 10 or 20 mg/week MTX, respectively), DAS28(CRP) <2.6 and American College of Rheumatology 50/70/90 responses with increasing doses of MTX in combination with adalimumab. No statistical differences in minimal clinically important differences in physical function were detected. Statistically significant trends for achieving low disease activity and remission were demonstrated with increasing MTX dose by validated clinical indices; differences comparing 10 and 20 mg MTX were minimal. Adalimumab serum concentrations increased with ascending dose up to 10 mg MTX. More patients experienced infectious adverse events with increasing MTX dose.
Increasing doses of MTX in combination with adalimumab demonstrated a statistically significant trend in improved clinical outcomes that mimicked the adalimumab pharmacokinetic profile. In early RA patients initiating adalimumab combination therapy, efficacy of 10 and 20 mg/week MTX appeared equivalent.
Abstract
Objective
The aim was to assess the safety and efficacy of up to 156 weeks of ixekizumab (an IL-17A antagonist) treatment in PsA patients.
Methods
In a phase III study, patients naïve to ...biologic treatment were randomized to placebo, adalimumab 40 mg every 2 weeks (ADA; active reference) or ixekizumab 80 mg every 2 weeks (IXEQ2W) or every 4 weeks (IXEQ4W) after an initial dose of 160 mg. At week 24 (week 16 for inadequate responders), ADA (after 8-week washout) and placebo patients were re-randomized to IXEQ2W or IXEQ4W. Outcomes were evaluated using a modified non-responder imputation linear extrapolation for radiographic progression (modified total Sharp score = 0) during extended treatment until week 156.
Results
Of 417 patients, 381 entered the extension, and 243 of 381 (63.8%) completed the 156-week study. Incidence rates of treatment-emergent and serious adverse events, respectively, were 38.0 and 5.2 with IXEQ2W (n = 189) and 38.1 and 8.0 with IXEQ4W (n = 197). One death occurred (IXEQ4W). With IXEQ2W and IXEQ4W, respectively, the response rates persisted to week 156 as measured by the ACR response ≥20% (62.5 and 69.8%), ≥50% (56.1 and 51.8%) and ≥70% (43.8 and 33.4%), psoriasis area and severity index (PASI) 75 (69.1 and 63.5%), PASI 90 (64.5 and 51.2%) and PASI 100 (60.5 and 43.6%). Inhibition of radiographic progression also persisted to week 156 in 61% of IXEQ2W and 71% of IXEQ4W patients.
Conclusion
In this 156-week study of ixekizumab, the safety profile remained consistent with previous reports, and improvements in signs and symptoms of PsA were observed, including persistent low rates of radiographic progression.
Trial registration
ClinicalTrials.gov, http://clinicaltrials.gov, NCT01695239, EudraCT 2011-002326-49.
Ultra stable frequency references such as the ones used in optical atomic clocks and for quantum metrology may be obtained by stabilizing a laser to an optical cavity that is stable over time. ...State-of-the-art frequency references are constructed in this way, but their stabilities are currently limited by thermally induced length fluctuations in the reference cavity. Several alternative approaches using the potential for frequency discriminating of highly forbidden narrow atomic transitions have been proposed in, e.g., 1 and 2. In this proceeding we will present some of the ongoing experimental efforts derived from these proposals, to use cavity-enhanced interaction with atomic 88Sr samples as a frequency reference for laser stabilization. Such systems can be realized using both passive and active approaches where either the atomic phase response is used as an error signal, or the narrow atomic transition itself is used as a source for a spectrally pure laser. Both approaches shows the promise of being able to compete with the current state of the art in stable lasers and have similar limitations on their ultimately achievable linewidths 1, 2.
Objective
To identify factors predicting response (2‐hour headache pain freedom or most bothersome symptom freedom) to lasmiditan based on individual patient characteristics, migraine disease ...characteristics, and migraine attack characteristics. Further, efficacy specifically in difficult‐to‐treat patient/migraine disease characteristics or attack characteristics (ie, historically considered less responsive to certain acute therapies) subgroups was analyzed.
Background
Knowledge of factors associated with a positive or negative response to acute treatment would be useful to practitioners prescribing acute treatments for migraine. Additionally, practitioners and patients would benefit from understanding the efficacy of lasmiditan specifically in subgroups of patients with migraine disease characteristics and migraine attack characteristics historically associated with decreased pain threshold, reduced efficacy of acute treatment, or increased burden of migraine.
Methods
Pooled analyses were completed from 2 Phase 3 double‐blind clinical trials, SPARTAN and SAMURAI. Data from baseline to 2 hours after taking lasmiditan (50, 100, or 200 mg) or placebo were analyzed to assess efficacy based on patient characteristics, migraine disease characteristics, and migraine attack characteristics. A total of 3981 patients comprising the intent‐to‐treat population were treated with placebo (N = 1130), lasmiditan 50 mg (N = 598), lasmiditan 100 mg (N = 1133), or lasmiditan 200 mg (N = 1120). Data were analyzed for the following efficacy measures at 2 hours: headache pain freedom and most bothersome symptom freedom.
Results
None of the analyzed subgroups based on individual patient characteristics, migraine disease characteristics, or migraine attack characteristics predicted headache pain freedom or most bothersome symptom freedom response at 2 hours following lasmiditan treatment (interaction P ≥ .1). For the difficult‐to‐treat patient/migraine disease characteristics subgroups (defined as those with ≥24 headache days in the past 3 months, duration of migraine history ≥20 years, severe disability Migraine Disability Assessment score ≥21, obesity ≥30 kg/m2, and history of psychiatric disorder), single doses of lasmiditan (100 or 200 mg) were significantly more effective than placebo (P ≤ .002) in achieving both endpoints. Headache pain freedom response rates for higher doses of lasmiditan were numerically greater than for lower doses of lasmiditan. For the difficult‐to‐treat migraine attack subgroups, patients with severe headache, co‐existent nausea at the time of treatment, or who delayed treatment for ≥2 hours from the time of headache onset, both endpoint response rates after lasmiditan 100 or 200 mg were significantly greater than after placebo. Among those who delayed treatment for ≥4 hours from the time of headache onset, headache pain freedom response rates for the 200 mg dose of lasmiditan met statistical significance vs placebo (32.4% vs 15.9%; odds ratio = 2.7 1.17, 6.07; P = .018). While the predictors of response interaction test showed similar efficacy of lasmiditan vs placebo across subgroups defined by baseline functional disability (mild, moderate, or needs complete bed rest) at the time of treatment, analyses of lasmiditan efficacy within the subgroup “needs complete bed rest” appeared to show less efficacy (eg, in the 200 mg vs placebo group, 25.9% vs 18.5%; odds ratio = 1.56 0.96, 2.53; P = .070).
Conclusions
Efficacy of lasmiditan 200 and 100 mg for headache pain freedom and most bothersome symptom freedom at 2 hours post‐treatment was generally not influenced by the individual patient characteristics, migraine disease history, or migraine attack characteristics that were analyzed. In the analyses of difficult‐to‐treat subgroups, patients receiving lasmiditan achieved greater responses (2‐hour headache pain freedom and most bothersome symptom freedom) vs placebo recipients.
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