Background
Mogamulizumab was compared with vorinostat in the phase 3 MAVORIC trial (NCT01728805) in 372 patients with relapsed/refractory mycosis fungoides (MF) or Sézary syndrome (SS) who had failed ...≥1 prior systemic therapy. Mogamulizumab significantly prolonged progression‐free survival (PFS), with a superior objective response rate (ORR) vs. vorinostat.
Objectives
This post hoc analysis was performed to evaluate the effect of baseline blood tumour burden on patient response to mogamulizumab.
Methods
PFS, ORR, time to next treatment (TTNT), skin response (modified Severity‐Weighted Assessment Tool mSWAT) and safety were assessed in patients stratified by blood classification (B0 n = 126, B1 n = 62, or B2 n = 184, indicating increasing blood involvement).
Results
Investigator‐assessed PFS was longer for mogamulizumab versus vorinostat across all blood classes, significantly so for B1 and B2 patients. ORR was higher with mogamulizumab than with vorinostat in all blood classification groups and more markedly so with escalating B class (B0: 15.6% vs. 6.5%, P = 0.0549; B1: 25.8% vs. 6.5%, P = 0.2758; B2: 37.4% vs. 3.2%, P < 0.0001). TTNT was significantly longer for patients treated with mogamulizumab versus vorinostat with B1 (12.63 vs. 3.07 months; HR 0.32 95% CI 0.16–0.67; P = 0.0018) and B2 (13.07 vs. 3.53 months; HR 0.30 95% CI 0.21–0.43; P < 0.0001) blood involvement. In the mogamulizumab arm, 81 patients (43.5%) had ≥50% change in the mSWAT vs. 41 patients (22.0%) with vorinostat; mSWAT improvements with mogamulizumab occurred most often in B1 and B2 patients. Rapid, sustained reductions were seen in CD4+CD26‐ cell counts and CD4:CD8 ratios in mogamulizumab patients for all B classes. Treatment‐emergent adverse events were less frequent overall with mogamulizumab and similar in frequency regardless of B class.
Conclusions
This post hoc analysis indicates greater clinical benefit with mogamulizumab vs. vorinostat in patients with MF and SS classified as having B1 and B2 blood involvement.
Summary
Background
It has been shown that the interleukin (IL)‐23/IL‐17 axis is critical in the pathogenesis of psoriasis.
Objectives
To present the primary end point (week 12) and safety and ...efficacy data up to week 24 from a head‐to‐head trial (IXORA‐S) of the IL‐17A inhibitor ixekizumab (IXE) vs. the IL‐12/23 inhibitor ustekinumab (UST).
Methods
Randomized patients received IXE (160‐mg starting dose, then 80 mg every 2 weeks for 12 weeks, then 80 mg every 4 weeks, n = 136) or UST (45 mg or 90 mg weight‐based dosing per label, n = 166). The primary end point was the proportion of patients reaching ≥ 90% Psoriasis Area and Severity Index improvement (PASI 90). Hommel‐adjusted key secondary end points at week 12 included PASI 75, PASI 100, static Physician's Global Assessment (sPGA) score of 0 or 1, sPGA score of 0, Dermatology Life Quality Index (DLQI) score of 0 or 1, ≥ 4‐point reduction on the itch numerical rating scale (NRS) and changes in itch NRS and skin pain visual analogue scale.
Results
At week 12, IXE (n = 99, 72·8%) was superior to UST (n = 70, 42·2%) in PASI 90 response (response difference 32·1%, 97·5% confidence interval 19·8−44·5%, P < 0·001). Response rates for PASI 75, PASI 100 and sPGA (0,1) were significantly higher for IXE than for UST (adjusted P < 0·05). At week 24, IXE‐treated patients had significantly higher response rates than UST‐treated patients for PASI, sPGA and DLQI (unadjusted P < 0·05). No deaths were reported, and the treatments did not differ with regard to overall incidences of adverse events (P = 0·299).
Conclusions
The superior efficacy of IXE demonstrated at week 12 persisted up to week 24. The safety profiles were consistent with those previously reported for both treatments.
What's already known about this topic?
With the advancements in new biologics targeting the interleukin (IL)‐17A pathway, the majority of patients with moderate‐to‐severe psoriasis are now able to achieve complete or near complete clearance of psoriasis.
What does this study add?
The IL‐17A inhibitor ixekizumab provides superior efficacy over the IL‐12/23 inhibitor ustekinumab, with a similar safety profile after 24 weeks of treatment.
Linked Comment: Chu et al. Br J Dermatol 2017; 177:896–897.
•Sorghum accumulates dhurrin (cyanide) and nitrate; forage can be toxic.•Partitioning of N to cyanide and nitrate was measured in FACE studies.•Cyanide, nitrate accumulation depended on tissue type, ...plant age and irrigation.•Drought effected increases in cyanide and nitrate were not moderated at high CO2.•Risk of toxicity likely to increase with climate change but not directly from rising CO2.
Sorghum Sorghum bicolor (L.) Moench is the world’s fifth most important crop, grown for forage, grain, and as a biofuel. Fast growing and drought tolerant, it is increasingly being planted as a climate change-ready alternative to maize. All parts of the sorghum plant except the grain contain the cyanogenic glucoside dhurrin, which breaks down to release hydrogen cyanide (prussic acid) when plant tissue is disrupted. Fresh forage, hay and silage may be toxic to stock when derived from plants that are young, droughted or heavily fertilized. Sorghum also stores nitrate, which can cause nitrite toxicity. The impact of elevated CO2 on dhurrin and nitrate concentration is unknown. It is important to understand how global environmental change will affect composition in order to be able to predict the safety of the crop in coming decades. Sorghum was grown experimentally at elevated CO2 in two free-air CO2 enrichment (FACE) experiments at ambient and elevated CO2 (ca. 550ppm) and either irrigated regularly or only once after sowing in consecutive years and sampled at different stages of development. Since FACE-grown sorghum has been shown to have improved water status we hypothesized that they would contain less dhurrin. We found the most important factors governing cyanide concentration were (in decreasing order): plant age, irrigation treatment and tissue type. For nitrate, tissue type was by far the most important factor, followed by plant age, and then irrigation treatment. The concentration of CO2 in the atmosphere had no significant effect on the total nitrogen concentration, or the concentrations of cyanide and nitrate. As sorghum is becomes more widely used for forage, it will be important to have simple methods to assess the cyanide levels in the field or to develop new, low cyanogenic varieties to ensure that it is safe for grazing.
Spiral MR imaging has several advantages compared with Cartesian MR imaging that can be leveraged for added clinical value. A multicenter multireader study was designed to compare spiral with ...standard-of-care Cartesian postcontrast structural brain MR imaging on the basis of relative performance in 10 metrics of image quality, artifact prevalence, and diagnostic benefit.
Seven clinical sites acquired 88 total subjects. For each subject, sites acquired 2 postcontrast MR imaging scans: a spiral 2D T1 spin-echo, and 1 of 4 routine Cartesian 2D T1 spin-echo/TSE scans (fully sampled spin-echo at 3T, 1.5T, partial Fourier, TSE). The spiral acquisition matched the Cartesian scan for scan time, geometry, and contrast. Nine neuroradiologists independently reviewed each subject, with the matching pair of spiral and Cartesian scans compared side-by-side, and scored on 10 image-quality metrics (5-point Likert scale) focused on intracranial assessment. The Wilcoxon signed rank test evaluated relative performance of spiral versus Cartesian, while the Kruskal-Wallis test assessed interprotocol differences.
Spiral was superior to Cartesian in 7 of 10 metrics (flow artifact mitigation, SNR, GM/WM contrast, image sharpness, lesion conspicuity, preference for diagnosing abnormal enhancement, and overall intracranial image quality), comparable in 1 of 10 metrics (motion artifacts), and inferior in 2 of 10 metrics (susceptibility artifacts, overall extracranial image quality) related to magnetic susceptibility (
< .05). Interprotocol comparison confirmed relatively higher SNR and GM/WM contrast for partial Fourier and TSE protocol groups, respectively (
< .05).
Spiral 2D T1 spin-echo for routine structural brain MR imaging is feasible in the clinic with conventional scanners and was preferred by neuroradiologists for overall postcontrast intracranial evaluation.
To evaluate the results of ventral intermediate (Vim) thalamic deep brain stimulation (DBS) in patients with tremor predominant Parkinson's disease (PD) at 6 years post surgery.
This was a prolonged ...follow-up study of 38 patients from eight centres who participated in a multicentre study, the 1 year results of which have been published previously. Total scores as well as scores for individual items of the motor part and the disability part of the Unified Parkinson's Disease Rating Scale were used for evaluation.
Tremor was still effectively controlled by DBS and appendicular rigidity and akinesia remained stable compared with baseline. Axial scores (speech, gait and postural instability), however, worsened, and in parallel the initial improvement in activities of daily living scores at the 1 year follow-up had disappeared at 6 years, despite sustained improvement of tremor. Remarkably, neither daily doses of dopaminergic medication nor fluctuations and dyskinesias had changed at 6 years compared with baseline in this particular patient group.
This study confirms that patients with tremor dominant PD who do not present with fluctuations and dyskinesias may have a relatively benign progression of the disease. Vim DBS, although having no effect on akinesia and rigidity, is a relatively lenient surgical procedure and may still have a place for long term symptomatic control of PD tremor in selected patients.
We report the discovery, mass, and radius determination of TOI-1801 b, a temperate mini-Neptune around a young M dwarf. TOI-1801 b was observed in TESS sectors 22 and 49, and the alert that this was ...a TESS planet candidate with a period of 21.3 days went out in April 2020. However, ground-based follow-up observations, including seeing-limited photometry in and outside transit together with precise radial velocity (RV) measurements with CARMENES and HIRES revealed that the true period of the planet is 10.6 days. These observations also allowed us to retrieve a mass of 5.74 ± 1.46
M
⊕
, which together with a radius of 2.08 ± 0.12
R
⊕
, means that TOI-1801 b is most probably composed of water and rock, with an upper limit of 2% by mass of H
2
in its atmosphere. The stellar rotation period of 16 days is readily detectable in our RV time series and in the ground-based photometry. We derived a likely age of 600–800 Myr for the parent star TOI-1801, which means that TOI-1801 b is the least massive young mini-Neptune with precise mass and radius determinations. Our results suggest that if TOI-1801 b had a larger atmosphere in the past, it must have been removed by some evolutionary mechanism on timescales shorter than 1 Gyr.
Spotted-fever-caused Rickettsia rickettsii infection is in Brazil the major tick-borne zoonotic disease. Recently, a second and milder human rickettsiosis caused by an agent genetically related to R. ...parkeri was discovered in the country (Atlantic rainforest strain). Both diseases clearly have an ecological background linked to a few tick species and their environment. Capybaras (Hydrochoerus hydrochaeris) and Amblyomma cajennense ticks in urban and rural areas close to water sources are the main and long-known epidemiological feature behind R. rickettsii-caused spotted-fever. Unfortunately, this ecological background seems to be increasing in the country and disease spreading may be foreseen. Metropolitan area of São Paulo, the most populous of the country, is embedded in Atlantic rainforest that harbors another important R. rickettsii vector, the tick Amblyomma aureolatum. Thus, at the city-forest interface, dogs carry infected ticks to human dwellings and human infection occurs. A role for R. rickettsii vectoring to humans of a third tick species, Rhipicephalus sanguineus in Brazil, has not been proven; however, there is circumstantial evidence for that. A R. parkeri-like strain was found in A. ovale ticks from Atlantic rainforest and was shown to be responsible for a milder febrile human disease. Rickettsia-infected A. ovale ticks are known to be spread over large areas along the Atlantic coast of the country, and diagnosis of human infection is increasing with awareness and proper diagnostic tools. In this review, ecological features of the tick species mentioned, and that are important for Rickettsia transmission to humans, are updated and discussed. Specific knowledge gaps in the epidemiology of such diseases are highlighted to guide forthcoming research.
Effects of increasing carbon dioxide concentration CO2 on wheat vary depending on water supply and climatic conditions, which are difficult to estimate. Crop simulation models are often used to ...predict the impact of global atmospheric changes on food production. However, models have rarely been tested for effects on crops of CO2 and drought for different climatic conditions due to limited data available from field experiments. Simulations of the effects of elevated CO2 and drought on spring wheat (Triticum aestivum L.) from three crop simulation models (LINTULCC2, AFRCWHEAT2, Sirius), which differ in structure and mechanistic detail, were compared with observations. These were from 2 years of free-air carbon dioxide enrichment (FACE) experiments in Maricopa, Arizona and 2 years of standardised (in crop management and soil conditions) open-top chamber (OTC) experiments in Braunschweig and Giessen, Germany. In a simulation exercise, models were used to assess the possible impact of increased CO2 on wheat yields measured between 1987 and 1999 at one farm site in the drought prone region of Andalucia, south Spain. The models simulated well final biomass (BM), grain yield (GY), cumulative evapotranspiration (ET) and water use efficiency (WUE) of wheat grown in the FACE experiments but simulations were unsatisfactory for OTC experiments. Radiation use efficiency (RUE) and yield responses to CO2 and drought were on average higher in OTC than in FACE experiments. However, there was large variation among OTC experiments. Plant growth in OTCs was probably modified by several factors related to plot size, the use (or not use) of border plants, airflow pattern, modification of radiation balance and/or restriction of rooting volume that were not included in the models. Variation in farm yields in south Spain was partly explained by the models, but sources of unexplained yield variation could not be identified and were most likely related to effects of pests and diseases that were not included in the models. Simulated GY in south Spain increased in the range between 30 and 65 ue to doubling CO2. The simulated increase was larger when a CO2xdrought interaction was assumed (LINTULCC2, AFRCWHEAT2) than when it was not (Sirius). It was concluded that crop simulation models are able to reproduce wheat growth and yield for different CO2 and drought treatments in a field environment. However, there is still uncertainty about the combined effects of CO2 and drought including the timing of drought stress and about relationships that determine yield variation at farm and larger scales that require further investigation including model testing.
Atmospheric CO2 concentration (C(a)) continues to rise. An imperative exists, therefore, to elucidate the interactive effects of elevated C(a) and drought on plant water relations of wheat (Triticum ...aestivum L.). A spring wheat (cv. Yecora Rojo) crop was exposed to ambient (Control: 370 micromol mol(-1)) and free-air CO2 enrichment (FACE: ambient + 180 micromol mol(-1)) under ample (Wet), and reduced (Dry), water supplies (100 and 50% replacement of evapotranspiration, respectively) over a 2-yr study. Our objective was to characterize and quantify the responses of 26 edaphic, gas exchange, water relations, carbohydrate pool dynamics, growth, and development parameters to rising C(a) and drought. Increasing C(a) minimized the deleterious effects of soil-water depletion by increasing drought avoidance (i.e., lower stomatal conductance and transpiration rate, and growth and development of a more robust root system) and drought tolerance (i.e., enhanced osmoregulation and adaptation of tissue) mechanisms, resulting in a 30% reduction in water stress-induced midafternoon depressions in net assimilation rate. An elevated C(a)-based increase in daily and seasonal carbon gain resulted in a positive feedback between source capacity (shoots) and sink demand (roots). Devoid of a concomitant rise in global temperature resulting from the rise in C(a), improved water relations for a herbaceous, cool-season, annual, C3 cereal monocot grass (i.e., wheat) are anticipated in a future high-CO2 world. These findings are applicable to other graminaceous species of a similar function-type as wheat common to temperate zone grassland prairies and savannas, especially under dryland conditions.
Experimentation with dynamics of soil carbon pools as affected by elevated CO2 can better define the ability of terrestrial ecosystems to sequester global carbon. In the present study, 6 N HCl ...hydrolysis and stable-carbon isotopic analysis (δ13C) were used to investigate labile and recalcitrant soil carbon pools and the translocation among these pools of sorghum residues isotopically labeled in the 1998-1999 Arizona Maricopa free air CO2 enrichment (FACE) experiment, in which elevated CO2 (FACE: 560 μmol mol-1) and ambient CO2 (Control: 360 μmol mol-1) interact with water-adequate (wet) and water-deficient (dry) treatments. We found that on average 53% of the final soil organic carbon (SOC) in the FACE plot was in the recalcitrant carbon pool and 47% in the labile pool, whereas in the Control plot 46% and 54% of carbon were in recalcitrant and labile pools, respectively, indicating that elevated CO2 transferred more SOC into the slow-decay carbon pool. Also, isotopic mixing models revealed that increased new sorghum residue input to the recalcitrant pool mainly accounts for this change, especially for the upper soil horizon (0-30 cm) where new carbon in recalcitrant soil pools of FACE wet and dry treatments was 1.7 and 2.8 times as large as that in respective Control recalcitrant pools. Similarly, old C in the recalcitrant pool under elevated CO2 was higher than that under ambient CO2, indicating that elevated CO2 reduces the decay of the old C in recalcitrant pool. Mean residence time (MRT) of bulk soil carbon at the depth of 0-30 cm was significantly longer in FACE plot than Control plot by the averages of 12 and 13 yr under the dry and wet conditions, respectively. The MRT was positively correlated to the ratio of carbon content in the recalcitrant pool to total SOC and negatively correlated to the ratio of carbon content in the labile pool to total SOC. Influence of water alone on the bulk SOC or the labile and recalcitrant pools was not significant. However, water stress interacting with CO2 enhanced the shift of the carbon from labile pool to recalcitrant pool. Our results imply that terrestrial agroecosystems may play a critical role in sequestrating atmospheric CO2 and mitigating harmful CO2 under future atmospheric conditions.
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