Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial

Background: Interleukin 17A is a proinflammatory cytokine that is implicated in the pathogenesis of psoriatic arthritis. We assessed the efficacy and safety of subcutaneous secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis. Methods: In this phase 3, double-blind, placebo-controlled study undertaken at 76 centres in Asia, Australia, Canada, Europe, and the USA, adults (aged ≥18 years old) with active psoriatic arthritis were randomly allocated in a 1:1:1:1 ratio with computer-generated blocks to receive subcutaneous placebo or secukinumab 300 mg, 150 mg, or 75 mg once a week from baseline and then every 4 weeks from week 4. Patients and investigators were masked to treatment assignment. The primary endpoint was the proportion of patients achieving at least 20% improvement in the American College of Rheumatology response criteria (ACR20) at week 24. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01752634. Findings: Between April 14, and Nov 25, 2013, 397 patients were randomly assigned to receive secukinumab 300 mg (n=100), 150 mg (n=100), 75 mg (n=99), or placebo (n=98). A significantly higher proportion of patients achieved an ACR20 at week 24 with secukinumab 300 mg (54 [54%] patients; odds ratio versus placebo 6·81, 95% CI 3·42–13·56; p<0·0001), 150 mg (51 [51%] patients; 6·52, 3·25–13·08; p<0·0001), and 75 mg (29 [29%] patients; 2·32, 1·14–4·73; p=0·0399) versus placebo (15 [15%] patients). Up to week 16, the most common adverse events were upper respiratory tract infections (four [4%], eight [8%], ten [10%], and seven [7%] with secukinumab 300 mg, 150 mg, 75 mg, and placebo, respectively) and nasopharyngitis (six [6%], four [4%], six [6%], and eight [8%], respectively). Serious adverse events were reported by five (5%), one (1%), and four (4%) patients in the secukinumab 300 mg, 150 mg, and 75 mg groups, respectively, compared with two (2%) in the placebo group. No deaths were reported. Interpretation: Subcutaneous secukinumab 300 mg and 150 mg improved the signs and symptoms of psoriatic arthritis, suggesting that secukinumab is a potential future treatment option for patients with this disorder

Self-Report Daily Life Activity as a Prognostic Marker of Idiopathic Pulmonary Fibrosis

BACKGROUND Idiopathic pulmonary fibrosis (IPF) is a progressive disease, leading to substantial physical impairment. The distance walked in 6 min (6MWD) is a measure of exercise tolerance and is of prognostic relevance in IPF. While 6MWD is a punctual measurement which may not be representative, self-reported daily life activity may represent the patients' functional capacity more globally even in less severe affected patients. OBJECTIVES We evaluated and characterized a simple classification system based on the patients' self-reported daily activity and analyzed if this would add significantly to the prognostic information of the 6MWD alone in IPF patients. METHODS Daily life activity was assessed in IPF (n = 156) patients with standardized questions and categorized in activity classes (AC I-IV), comprising the less severe impaired in AC I and II. The 6MWD was also assessed. RESULTS ACs were related to the lung functional impairment and inversely correlated to the 6MWD. Thirty-two patients were in AC I/II, 98 in AC III and 26 patients in AC IV. Thirty-seven (23.7%) patients died during a median follow-up of 14.9 months, comprising 1 patient in AC I/II. In addition, a 6MWD \textless470 m predicted mortality. Combining AC I/II and a 6MWD \textgreater470 m identified a subgroup of patients with favorable outcome. CONCLUSIONS AC is a novel scoring system which can easily be obtained and correlates with lung functional and physical impairments as well as mortality. Moreover, AC adds prognostic information to the 6MWD

Lacustrine oxygen isotope records from biogenic silica (δ18OBSi) – a global compilation and review

Isotope records are crucial for proxy-model comparison in paleoclimatology because of their advantage of being directly comparable with isotope-enabled paleoclimate model outputs. Oxygen isotopes (δ18O) are commonly measured on carbonates (i.e. ostracods, authigenic carbonates) and biogenic silica (mainly diatoms). Oxygen isotopes in lacustrine carbonates (δ18OCaCO3) have been studied extensively for several decades, yet they are subject to complex species-dependent fractionation processes and not available globally. Lacustrine oxygen isotope records from biogenic silica (δ18OBSi), on the other hand, likely do not display species-dependent fractionation effects (or only very minor) and offer insight even in data-sparse regions devoid of carbonates, such as the Arctic. To date, more than 70 lacustrine δ18OBSi records have been published. These case studies have been complemented with additional efforts addressing climatic and hydrological backgrounds, laboratory techniques and possible species-dependent fractionation as well as deposition and dissolution effects. Here, we present the first comprehensive review and global compilation of lacustrine δ18OBSi records, with explicit regard to their individual lake basin parameters. With this work, we aim at contributing to bridging the gap between modelling and isotope geochemistry approaches regarding terrestrial archives in paleoclimatology. Departing from hitherto prevalent case studies, we assess what we can learn from lacustrine δ18OBSi records globally, considering lake basin characteristics, spatial and temporal coverage as well as hydrological background information. This improves both the usability of δ18OBSi for proxy-model comparison and our understanding of the general constraints for interpreting lacustrine δ18OBSi records

No saturation in the accumulation of alien species worldwide

Although research on human-mediated exchanges of species has substantially intensified during the last centuries, we know surprisingly little about temporal dynamics of alien species accumulations across regions and taxa. Using a novel database of 45,813 first records of 16,926 established alien species, we show that the annual rate of first records worldwide has increased during the last 200 years, with 37% of all first records reported most recently (1970–2014). Inter-continental and inter-taxonomic variation can be largely attributed to the diaspora of European settlers in the nineteenth century and to the acceleration in trade in the twentieth century. For all taxonomic groups, the increase in numbers of alien species does not show any sign of saturation and most taxa even show increases in the rate of first records over time. This highlights that past efforts to mitigate invasions have not been effective enough to keep up with increasing globalization

Lacustrine diatom oxygen isotopes as palaeo precipitation proxy - Holocene environmental and snowmelt variations recorded at Lake Bolshoye Shchuchye, Polar Urals, Russia

The diatom oxygen isotope composition (δ18Odiatom) from lacustrine sediments helps tracing the hydrological and climate dynamics in individual lake catchments, and is generally linked to changes in temperature and δ18Olake. Lake Bolshoye Shchuchye (67°53′N; 66°19′ E; 186 m a.s.l) is the largest and deepest freshwater reservoir in the Polar Urals, Arctic Russia. The diatom oxygen isotope interpretation is supported by modern (isotope) hydrology, local bioindicators such as chironomids, isotope mass-balance modelling and a digital elevation model of the catchment. The Bolshoye Shchuchye δ18Odiatom record generally follows a decrease in summer insolation and the northern hemisphere (NH) temperature history. However, it displays exceptional, short-term variations exceeding 5‰, especially in Mid and Late Holocene. This centennial-scale variability occurs roughly contemporaneously with and similar in frequency to Holocene NH glacier advances. However, larger Holocene glacier advances in the Lake Bolshoye Shchuchye catchment are unknown and have not left any significant imprint on the lake sediment record. As Lake Bolshoye Shchuchye is deep and voluminous, about 30–50% of its volume needs to be exchanged with isotopically different water within decades to account for these shifts in the δ18Odiatom record. A plausible source of water with light isotope composition inflow is snow, known to be transported in surplus by snow redistribution from the windward to the leeward side of the Polar Urals. Here, we propose snow melt variability and associated influx changes being the dominant mechanism responsible for the observed short-term changes in the δ18Odiatom record. This is the first time such drastic, centennial-scale hydrological changes in a catchment have been identified in Holocene lacustrine diatom oxygen isotopes, which, for Lake Bolshoye Shchuchye, are interpreted as proxy for palaeo precipitation and, on millennial timescales, for summer temperatures

Projecting the continental accumulation of alien species through to 2050

Biological invasions have steadily increased over recent centuries. However, we still lack a clear expectation about future trends in alien species numbers. In particular, we do not know whether alien species will continue to accumulate in regional floras and faunas, or whether the pace of accumulation will decrease due to the depletion of native source pools. Here, we apply a new model to simulate future numbers of alien species based on estimated sizes of source pools and dynamics of historical invasions, assuming a continuation of processes in the future as observed in the past (a business-as-usual scenario). We first validated performance of different model versions by conducting a back-casting approach, therefore fitting the model to alien species numbers until 1950 and validating predictions on trends from 1950 to 2005. In a second step, we selected the best performing model that provided the most robust predictions to project trajectories of alien species numbers until 2050. Altogether, this resulted in 3,790 stochastic simulation runs for 38 taxon-continent combinations. We provide the first quantitative projections of future trajectories of alien species numbers for seven major taxonomic groups in eight continents, accounting for variation in sampling intensity and uncertainty in projections. Overall, established alien species numbers per continent were predicted to increase from 2005 to 2050 by 36%. Particularly, strong increases were projected for Europe in absolute (+2,543 +/- 237 alien species) and relative terms, followed by Temperate Asia (+1,597 +/- 197), Northern America (1,484 +/- 74) and Southern America (1,391 +/- 258). Among individual taxonomic groups, especially strong increases were projected for invertebrates globally. Declining (but still positive) rates were projected only for Australasia. Our projections provide a first baseline for the assessment of future developments of biological invasions, which will help to inform policies to contain the spread of alien species