Atmospheric Input and Seasonal Inventory of Dissolved Iron in the Sargasso Sea: Implications for Iron Dynamics in Surface Waters of the Subtropical Ocean

Constraining the role of dust deposition in regulating the concentration of the essential micronutrient iron in surface ocean waters requires knowledge of the flux of seawater-soluble iron in aerosols and the replacement time of dissolved iron (DFe) in the euphotic zone. Here we estimate these quantities using seasonally resolved DFe data from the Bermuda Atlantic Time-series Study region and weekly-scale measurements of iron in aerosols and rain from Bermuda during 2019. In response to seasonal changes in vertical mixing, primary production and dust deposition, surface DFe concentrations vary from ∼0.2 nM in early spring to \u3e1 nM in late summer, with DFe inventories ranging from ∼30 to ∼80 μmol/m2, respectively, over the upper 200 m. Assuming the upper ocean approximates steady state for DFe on an annual basis, our aerosol and rainwater data require a mean euphotic-zone residence time of ∼0.8–1.9 years for DFe with respect to aeolian input

Gridded global surface ozone metrics for atmospheric chemistry model evaluation

The concentration of ozone at the Earth's surface is measured at many locations across the globe for the purposes of air quality monitoring and atmospheric chemistry research. We have brought together all publicly available surface ozone observations from online databases from the modern era to build a consistent data set for the evaluation of chemical transport and chemistry-climate (Earth System) models for projects such as the Chemistry-Climate Model Initiative and Aer-Chem-MIP. From a total data set of approximately 6600 sites and 500 million hourly observations from 1971-2015, approximately 2200 sites and 200 million hourly observations pass screening as high-quality sites in regionally representative locations that are appropriate for use in global model evaluation. There is generally good data volume since the start of air quality monitoring networks in 1990 through 2013. Ozone observations are biased heavily toward North America and Europe with sparse coverage over the rest of the globe. This data set is made available for the purposes of model evaluation as a set of gridded metrics intended to describe the distribution of ozone concentrations on monthly and annual timescales. Metrics include the moments of the distribution, percentiles, maximum daily 8-hour average (MDA8), sum of means over 35 ppb (daily maximum 8-h; SOMO35), accumulated ozone exposure above a threshold of 40 ppbv (AOT40), and metrics related to air quality regulatory thresholds. Gridded data sets are stored as netCDF-4 files and are available to download from the British Atmospheric Data Centre (doi:10.5285/08fbe63d-fa6d-4a7a-b952-5932e3ab0452). We provide recommendations to the ozone measurement community regarding improving metadata reporting to simplify ongoing and future efforts in working with ozone data from disparate networks in a consistent manner

Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial

Objective: Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. Methods: In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placebo→45 mg, 45 mg→90 mg, 90 mg→90 mg). The primary endpoint was ≥20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ≥75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naïve (n=132) patients and anti-TNF-experienced (n=180) patients. Results: More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p≤0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ≥1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change −0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change −0.13). No unexpected adverse events were observed through week 60. Conclusions: The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients

Effect of tofacitinib withdrawal and re-treatment on patient-reported outcomes:results from a Phase 3 study in patients with moderate to severe chronic plaque psoriasis

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor being investigated for psoriasis. A Phase 3 withdrawal/re‐treatment study (NCT01186744; OPT Retreatment) showed tofacitinib re‐treatment was effective in patients with chronic plaque psoriasis. OBJECTIVES: To describe the effects of tofacitinib withdrawal/re‐treatment on health‐related quality of life (HRQoL) and disease symptoms measured by patient‐reported outcomes (PROs). METHODS: The study was divided into initial treatment, treatment withdrawal, and re‐treatment periods. Initial treatment: patients were randomized to receive tofacitinib 5 (n = 331) or 10 mg (n = 335) BID for 24 weeks. Treatment withdrawal: patients who achieved both ≥ 75% reduction in Psoriasis Area and Severity Index (PASI) score from baseline and Physician's Global Assessment of ‘clear’/‘almost clear’ at Week (W)24 received placebo (withdrawal) or the previous dose (continuous treatment). Re‐treatment: at relapse (> 50% loss of W24 PASI response) or at W40, patients received their initial tofacitinib dose. PROs included: Dermatology Life Quality Index (DLQI), Itch Severity Item (ISI), Short Form‐36 (SF‐36) and Patient's Global Assessment (PtGA). RESULTS: After initial treatment with tofacitinib 5 and 10 mg BID, substantial and significant improvements were reported for mean DLQI (baseline: 12.6 and 12.6; W24: 5.1 and 2.6) and ISI (baseline: 6.7 and 6.9; W24: 2.9 and 1.6). Patients continuously treated with tofacitinib 5 and 10 mg BID maintained those improvements through Week 56 (DLQI: 3.0 and 2.1; ISI: 2.3 and 1.4). By W40, patients withdrawn from tofacitinib 5 and 10 mg BID showed worsening in DLQI (5.0 and 6.2) and ISI (3.7 and 4.0) scores; improvements were regained upon re‐treatment (W56, DLQI: 3.4 and 2.4; ISI: 2.2 and 1.6). Similar results were reported for PtGA and SF‐36. CONCLUSION: Continuous tofacitinib treatment provided sustained improvement in HRQoL and disease symptoms. Patients randomized to treatment withdrawal lost initial improvements. Upon re‐treatment, improvements were recaptured to levels comparable to those seen with continuous treatment

WAIS Divide ice core suggests sustained changes in the atmospheric formation pathways of sulfate and nitrate since the 19th century in the extratropical Southern Hemisphere

The ¹⁷O excess (Δ¹⁷O = δ¹⁷O−0.52 × δ¹⁸O) of sulfate and nitrate reflects the relative importance of their different production pathways in the atmosphere. A new record of sulfate and nitrate Δ¹⁷O spanning the last 2400 years from the West Antarctic Ice Sheet Divide ice core project shows significant changes in both sulfate and nitrate Δ¹⁷O in the most recent 200 years, indicating changes in their formation pathways. The sulfate Δ¹⁷O record exhibits a 1.1 ‰ increase in the early 19th century from (2.4 ± 0.2) ‰ to (3.5 ± 0.2) ‰, which suggests that an additional 12–18% of sulfate formation occurs via aqueous-phase production by O₃, relative to that in the gas phase. Nitrate Δ¹⁷O gradually decreases over the whole record, with a more rapid decrease between the mid-19th century and the present day of 5.6 ‰, indicating an increasing importance of RO₂ in NO_x cycling between the mid-19th century and the present day in the mid- to high-latitude Southern Hemisphere. The former has implications for the climate impacts of sulfate aerosol, while the latter has implications for the tropospheric O₃ production rate in remote low-NO_x environments. Using other ice core observations, we rule out drivers for these changes other than variability in extratropical oxidant (OH, O₃, RO₂, H₂O₂, and reactive halogens) concentrations. However, assuming OH, H₂O₂, and O₃ are the main oxidants contributing to sulfate formation, Monte Carlo box model simulations require a large (≥ 260%) increase in the O₃ / OH mole fraction ratio over the Southern Ocean in the early 19th century to match the sulfate Δ¹⁷O record. This unlikely scenario points to a~deficiency in our understanding of sulfur chemistry and suggests other oxidants may play an important role in sulfate formation in the mid- to high-latitude marine boundary layer. The observed decrease in nitrate Δ¹⁷O since the mid-19th century is most likely due to an increased importance of RO₂ over O₃ in NO_x cycling and can be explained by a 60–90% decrease in the O₃ / RO₂ mole fraction ratio in the extratropical Southern Hemisphere NO_x-source regions

The oral Janus kinase/spleen tyrosine kinase inhibitor ASN002 demonstrates efficacy and improves associated systemic inflammation in patients with moderate‐to‐severe atopic dermatitis: results from a randomized double‐blind placebo‐controlled study

BackgroundASN002 is an oral dual inhibitor of Janus kinase and spleen tyrosine kinase, which are involved in the pathogenesis of atopic dermatitis (AD) through their regulatory role on T helper (Th)1, Th2 and Th17/Th22 pathways.ObjectivesThe objectives of this study were to evaluate the efficacy, safety, pharmacokinetics and effects on systemic biomarkers of ASN002 in patients with moderate-to-severe AD. Methods A total of 36 patients with moderate-to-severe AD were randomized (3 : 1) to ASN002 or placebo in the phase Ib study. Three dosage cohorts were studied over a 28-day period (20 mg, 40 mg and 80 mg once daily).ResultsASN002 was superior to placebo for the proportion of patients achieving Eczema Area and Severity Index (EASI) 50 (20 mg 20%, P = 0·93; 40 mg 100%, P = 0·003; 80 mg 83%, P = 0·03; placebo 22%), EASI 75 (20 mg 0%, P = 0·27; 40 mg 71%, P = 0·06; 80 mg 33%, P = 0·65; placebo 22%) and in change from baseline in pruritus (20 mg -1·3 ± 2·1, P = 0·81; 40 mg -3·1 ± 2·7, P = 0·27; 80 mg -4·7 ± 2·1, P = 0·01; placebo -1·6 ± 1·8). Adverse events were generally mild and similar across all groups. ASN002 showed dose-dependent plasma exposure with low interpatient variability, significantly downregulated several serum biomarkers involved in Th1, Th2 and Th17/Th22 immunity, and decreased the atherosclerosis-associated biomarker E selectin/SELE.ConclusionsIn patients with moderate-to-severe AD, ASN002 showed strong efficacy with rapid onset of action and associated improvements in systemic inflammation

25750 Tapinarof cream 1% once daily for plaque psoriasis: Secondary efficacy outcomes from two pivotal phase 3 trials

Tapinarof is a novel therapeutic aryl hydrocarbon receptor modulating agent (TAMA) in development for treatment of psoriasis and atopic dermatitis. Tapinarof cream 1% once daily (QD) demonstrated highly statistically significant efficacy vs vehicle QD at 12 weeks and was well-tolerated in adults with mild to severe plaque psoriasis in two identical Phase 3 trials: PSOARING 1 (N = 510) and PSOARING 2 (N = 515). Here, we present secondary efficacy endpoints, including Physician Global Assessment (PGA) scores, body surface area (BSA) affected, and ≥90% reduction in Psoriasis Area and Severity Index (PASI90) – an endpoint more commonly assessed for systemic agents. Mean overall baseline PASI was 8.9 and 9.1 and BSA affected was 7.9% and 7.6% in PSOARING 1 and 2, respectively. At Week 12, significantly more patients achieved PGA score of 0 or 1 with tapinarof vs vehicle: 37.8% vs 9.9% (P =.0001) and 43.6% vs 8.1% (P ˂.0001); and mean BSA affected was significantly reduced with tapinarof vs vehicle: −3.5 vs −0.2 and −4.2 vs 0.1 (both P ˂.0001). A significantly higher proportion of tapinarof-treated patients achieved PASI90 at Week 12 vs vehicle: 18.8% vs 1.6% (P =.0005) and 20.9% vs 2.5% (P ˂.0001). All secondary endpoints were highly statistically significant, confirming the efficacy on the primary endpoint. Tapinarof significantly improved all measures of disease activity and showed clear and consistent separation vs vehicle. Tapinarof cream has the potential to provide physicians and patients with a novel nonsteroidal topical treatment option that is effective and well-tolerated