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Nearly half of all stars similar to our Sun are in binary or multiple systems 1 , which may affect the evolution of the stars and their protoplanetary disks during their earliest stages. NGC 1333-IRAS2A is a young, Class 0, low-mass protostellar system located in the Perseus molecular cloud 2 . It is known to drive two bipolar outflows that are almost perpendicular to each other on the sky 3 , 4 and is resolved into binary components, VLA1 and VLA2, through long wavelength continuum observations 5 . Here we report spatially and spectrally resolved observations of a range of molecular species. We compare these to detailed magnetohydrodynamic simulations: the comparisons show that inhomogeneous accretion onto the circumstellar disks occurs in episodic bursts, driving a wobbling jet. We conclude that binarity and multiplicity in general strongly affect the properties of the emerging stars, as well as the physical and chemical structures of the protoplanetary disks and therefore potentially any emerging planetary systems. Binarity and multiplicity in general strongly affect the properties of emerging stars, as well as the physical and chemical structures of protoplanetary disks and therefore potentially any emerging planetary systems.

Biologic drugs (e.g. anti-tumor necrosis factors) are effective treatments for multiple chronic inflammatory diseases including rheumatoid arthritis, axial spondyloarthritis, and psoriatic arthritis. Administration of biologic drugs is usually via subcutaneous self-injection, which provides many patient benefits compared to infusions including increased flexibility, reduced costs, and reduced caregiver burden. However, it is also associated with challenges such as needle phobia, patient treatment misconceptions and incorrect drug administration, and can be impacted by dexterity problems. Evidence suggests these problems, along with other drug administration challenges (e.g. patient forgetfulness, busy lifestyles, and polypharmacy), can reduce patient adherence to treatment. To combat these challenges, patient feedback has been used to develop a range of self-injection devices, including pre-filled syringes, pre-filled pens, and electronic injection devices. Providing different devices for drug administration gives patients the opportunity to choose a device that addresses the challenges they face as an individual. Research suggests involving patients in medical device development, providing patients with a choice of devices and enrolling individuals in patient support programs can empower patients to take control of their treatment journey. By providing a portfolio of self-injection devices, designed based on patient needs, patient experience will improve, potentially improving adherence and hence, long-term treatment outcomes.

The growth of dust grains in protoplanetary disks is a necessary first step towards planet formation 1 . This growth has been inferred from observations of thermal dust emission 2 towards mature protoplanetary systems (age >2 million years) with masses that are, on average, similar to Neptune 3 . In contrast, the majority of confirmed exoplanets are heavier than Neptune 4 . Given that young protoplanetary disks are more massive than their mature counterparts, this suggests that planet formation starts early, but evidence for grain growth that is spatially and temporally coincident with a massive reservoir in young disks remains scarce. Here, we report observations on a lack of emission of carbon monoxide isotopologues within the inner ~15 au of a very young (age ~100,000 years) disk around the solar-type protostar TMC1A. By using the absence of spatially resolved molecular line emission to infer the gas and dust content of the disk, we conclude that shielding by millimetre-size grains is responsible for the lack of emission. This suggests that grain growth and millimetre-size dust grains can be spatially and temporally coincident with a mass reservoir sufficient for giant planet formation. Hence, planet formation starts during the earliest, embedded phases in the life of young stars. Evidence for the earliest phase of planet formation, dust grain growth, has been seen in the very young and massive circumstellar disk around low-mass protostar TMC1A. Such systems, still rich in gas, are responsible for the high-mass end of the exoplanet mass distribution.

The effects of metallicity on the evolution of protoplanetary disks may be studied in the outer Galaxy where the metallicity is lower than in the solar neighborhood. We present the VLT/KMOS integral field spectroscopy in the near-infrared of ∼120 candidate young stellar objects (YSOs) in the CMa-ℓ224 star-forming region located at a Galactocentric distance of 9.1 kpc. We characterize the YSO accretion luminosities and accretion rates using the hydrogen Brγ emission and find a median accretion luminosity of log(Lacc)=−0.82−0.82+0.80L⊙ . Based on the measured accretion luminosities, we investigate the hypothesis of star formation history in the CMa-ℓ224. Their median values suggest that Cluster C, where most of YSO candidates have been identified, might be the most evolved part of the region. The accretion luminosities are similar to those observed toward low-mass YSOs in the Perseus and Orion molecular clouds, and they do not reveal the impact of lower metallicity. Similar studies in other outer Galaxy clouds covering a wide range of metallicities are critical to gain a complete picture of star formation in the Galaxy.

Background The aim of this study was to explore the impact of sex and disease classification on outcomes in axial spondyloarthritis (axSpA) patients, including both radiographic (r-) axSpA and non-radiographic (nr-) axSpA, in males and females, respectively. Methods AxSpA patients were consecutively recruited from two rheumatology outpatient university clinics. We explored how sex and axSpA disease classification affected patient-reported outcome measures (PROMs). General linear models were used to investigate if there was an association between the continuous variables and each of the main effects of interest (sex and axSpA classification), as well as the possible interaction between them. Categorical outcome measures were analyzed with the use of logistic regression with the same fixed effects. We analyzed the relationship between tender point count (TPC) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). The prevalence of extra-articular manifestations (EAMs) and the Charlson Comorbidity Index (CCI) were determined. Results According to the protocol, a total of 100 outpatients with axSpA were enrolled (r-axSpA males 30, r-axSpA females 10, nr-axSpA males 25, nr-axSpA females 35). The BASDAI scores appeared higher among nr-axSpA females (median [Q 1 ; Q 3 ], 47 [21; 60]) compared with the combined median for the 3 other subgroups 25 [12; 25]. Female sex was associated with a higher number of tender point count (TPC, P  < 0.001). TPC and BASDAI were correlated for female nr-axSpA patients ( r  = 0.44, P  = 0.008) and male nr-axSpA patients ( r  = 0.56, P  = 0.003). Being classified as nr-axSpA was associated with a lower SF-36 Mental Component Summary (median for the 4 subgroups: nr-axSpa females 46.7, nr-axSpA males 52.3 vs. r-axSpA males 56.9 and r-axSpA females 50.4). EAMs were frequent (up to 50%). The CCI was low in all 4 subgroups, and no difference in the CCI between the subgroups was observed ( P  = 0.14). However, male sex had a significant impact on the CCI ( P  = 0.03). Conclusions In summary, patients with r-axSpA, regardless of sex, appeared less affected on most PROMs compared with nr-axSpA patients. However, female sex was associated with a higher number of TPC. TPC could possibly confound disease activity outcomes such as BASDAI, and one can consider different thresholds for defining high disease activity depending on the patient’s sex. Trial registration The trial is registered and approved by the Region of Southern Denmark’s Ethics Committee ( S-20150219 ). Registered 19 February 2015.

Background: Tofacitinib is a Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA) and has been investigated for psoriasis (PsO). Objectives: This post hoc analysis examined baseline cardiovascular (CV) disease risk and its association with the occurrence of major adverse cardiovascular events (MACE) and malignancies in tofacitinib-treated patients with PsA and PsO. Design: Included three phase III/long-term extension (LTE) PsA trials and seven phase II/phase III/LTE PsO trials of patients receiving ⩾ 1 dose of tofacitinib. Methods: Incidence rates (IRs: patients with events/100 patient-years) for MACE and malignancies (excluding non-melanoma skin cancer) were determined in subgroups according to history of atherosclerotic CV disease (ASCVD), baseline 10-year risk of ASCVD (in patients without history of ASCVD), and baseline metabolic syndrome (MetS). Results: For patients with PsA (N = 783) and PsO (N = 3663), respectively, tofacitinib exposure was 2038 and 8950 patient-years (median duration: 3.0 and 2.4 years), and 40.9% and 32.7% had MetS. Excluding missing CV risk profile data, 51/773 (6.6%) and 144/3629 (4.0%) patients had history of ASCVD, and in patients without history of ASCVD, around 20.0% had intermediate/high baseline 10-year ASCVD risk. For PsA and PsO, IRs of MACE were greatest in those with history of ASCVD or high baseline 10-year ASCVD risk. For PsA, five of six patients with MACE had baseline MetS. Malignancy IRs in patients with PsA were greatest in those with intermediate/high baseline 10-year ASCVD risk. Of these, eight of nine patients with malignancies had baseline MetS. In the PsO cohort, IR of malignancies was notably greater with high versus low/borderline/intermediate baseline 10-year ASCVD risk. Conclusion: In tofacitinib-treated patients with PsA/PsO, increased ASCVD risk and baseline MetS were associated with higher IRs for MACE and malignancies. Our results support assessing CV risk in patients with PsA/PsO and suggest enhanced cancer monitoring in those with increased ASCVD risk. Registration (ClinicalTrials.gov): NCT01877668/NCT01882439/NCT01976364/NCT00678210/NCT01710046/NCT01241591/NCT01186744/NCT01276639/NCT01309737/NCT01163253 Plain Language Summary People who have psoriatic arthritis or psoriasis may have more heart-related problems and cancer if they have a higher risk of cardiovascular disease: A study in people with psoriatic arthritis or psoriasis receiving tofacitinib Why was this study done? • People with psoriatic arthritis (PsA) and psoriasis (PsO) are more likely than the general population to have a disease affecting the heart and blood vessels [cardiovascular (CV) disease]. • People who are more likely to have CV disease may also be more likely to have certain types of cancer. • Tofacitinib is a medicine to treat people with PsA and has been tested in people with PsO. • We wanted to know if the risk of CV disease affects the number of heart-related problems (including heart attack, stroke, or death) and cancer in people with PsA and PsO. What did the researchers do? • We used results from 10 clinical trials. • In these trials, people with PsA and PsO were taking tofacitinib 5 or 10 mg twice a day. • After the trials had ended, we measured people’s risk of CV disease using a risk calculator. This risk calculator showed if they had a low, borderline, intermediate, or high risk of CV disease over the next 10 years. We also checked if they had had CV disease before treatment. • We checked if people had a group of conditions linked to CV disease: diabetes, high blood pressure, and obesity. • We counted the cases of heart-related problems and cancer in people once they started taking tofacitinib. What did the researchers find? In people with PsA and PsO taking tofacitinib: • There were more cases of heart-related problems and cancer in people who had intermediate or high risk of CV disease. • There were more cases of heart-related problems in people who had had CV disease before. • More people with diabetes, high blood pressure, and obesity had heart-related problems and cancer than people without those conditions. What do the findings mean? • It is important to measure risk and assess history of CV disease in people with PsA and PsO, including those taking tofacitinib. • We should test for cancer in people with high risk of CV disease.

The Assessment of SpondyloArthritis international Society (ASAS) has defined core sets for (i) symptom-modifying anti-rheumatic drugs (SM-ARD), (ii) clinical record keeping, and (iii) disease-controlling anti-rheumatic therapy (DC-ART). These include the following domains for all three core sets: “physical function,” “pain,” “spinal mobility,” “spinal stiffness,” and “patient’s global assessment” (PGA). The core set for clinical record keeping further includes the domains “peripheral joints/entheses” and “acute phase reactants,” and the core set for DC-ART further includes the domains “fatigue” and “spine radiographs/hip radiographs.” The Outcome Measures in Rheumatology (OMERACT) endorsed the core sets in 1998. Using empirical evidence from axSpA trials, we investigated the efficacy (i.e., net benefit) according to the ASAS/OMERACT core outcome set for axSpA across all interventions tested in trials included in subsequent Cochrane reviews. For all continuous scales, we combined data using the standardized mean difference (SMD) to meta-analyze outcomes involving the same domains. Also, through meta-regression analysis, we examined the effect of the separate SMD measures (independent variables) on the primary endpoint (log [ OR ], dependent variable) across all trials. Based on 11 eligible Cochrane reviews, from these, 85 articles were screened; we included 43 trials with 63 randomized comparisons. Mean (SD) number of ASAS/OMERACT core outcome domains measured for SM-ARD/physical therapy trials was 4.2 (1.7). Six trials assessed all proposed domains. Mean (SD) for number of core outcome domains for DC-ART trials was 5.8 (1.7). No trials assessed all nine domains. Eight trials (16%) were judged to have inadequate (i.e., high risk of) selective outcome reporting bias. The most responsible core domains for achieving success in meeting the primary objective per trial were pain, OR (95% CI) 5.19 (2.28, 11.77), and PGA, OR (95% CI) 1.87 (1.14, 3.07). In conclusion, selective outcome reporting (and “missing data”) should be reduced by encouraging the use of the endorsed ASAS/OMERACT outcome domains in clinical trials. Overall outcome reporting was good for SM-ARD/physical therapy trials and poor for DC-ART trials. Our findings suggest that both PGA and pain provide a valuable holistic construct for the assessment of improvement beyond more objective measures of spinal inflammation.

Introduction Routine care studies of psoriatic arthritis (PsA) and ankylosing spondylitis (AS) demonstrated attenuated responses to tumor necrosis factor inhibitors in current/past versus never smokers. This post hoc analysis assessed tofacitinib efficacy and safety in patients with PsA or AS by cigarette smoking status at trial screening. Methods Pooled data from phase 3 and long-term extension (safety only) PsA trials and phase 2 and 3 AS trials were assessed by current/past versus never smoker status. Analysis included efficacy and safety data for tofacitinib 5 (PsA/AS) and 10 (PsA only) mg twice daily (BID) or placebo, and safety data in AS for tofacitinib 2 and 10 mg BID. Efficacy outcomes included American College of Rheumatology ≥ 50% responses (ACR50) and minimal disease activity (MDA) responses to month (M)6/M3 (tofacitinib/placebo) in PsA; and ≥ 40% improvement in Assessment of SpondyloArthritis international Society responses (ASAS40) and AS Disease Activity Score (ASDAS) < 2.1 responses to week (W)16 in AS. Safety was assessed to M48/W48 (PsA/AS), adjusted for treatment/smoking status/median body mass index (BMI) status/sex/trial/treatment-smoking status interaction. Results PsA/AS cohorts included 342/178 current/past and 572/194 never smokers. Tofacitinib efficacy was generally greater versus placebo to M3/W6 (PsA/AS), and comparable in current/past and never smokers to M6/W16 (PsA/AS). In patients receiving ≥ 1 tofacitinib dose, adjusted treatment-emergent adverse event (TEAE)/serious AE (SAE)/discontinuation due to AE incidence rates (IRs) to M48 in PsA were higher in current/past versus never smokers; adjusted IRs to W48 in AS were higher in current/past versus never smokers for TEAEs, but similar for SAEs/discontinuation due to AEs. Conclusions In both patients with PsA and AS, tofacitinib efficacy was greater versus placebo, and comparable across smoking categories. Adjusted IRs were higher in current/past versus never smokers for TEAEs, SAEs, discontinuation due to AEs in PsA, and for TEAEs in AS, complementing reports of associations between smoking and comorbidities in spondyloarthritis. Findings support increased surveillance/caution for patients with PsA or AS with smoking history. Trial Registration ClinicalTrials.gov: NCT01877668/NCT01882439/NCT03486457/NCT01976364/NCT01786668/NCT03502616.

ObjectivesWeight loss is commonly recommended for gout, but the magnitude of the effect has not been evaluated in a systematic review. The aim of this systematic review was to determine benefits and harms associated with weight loss in overweight and obese patients with gout.MethodsWe searched six databases for longitudinal studies, reporting the effect of weight loss in overweight/obese gout patients. Risk of bias was assessed using the tool Risk of Bias in Non-Randomised Studies of Interventions. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation.ResultsFrom 3991 potentially eligible studies, 10 were included (including one randomised trial). Interventions included diet with/without physical activity, bariatric surgery, diuretics, metformin or no intervention. Mean weight losses ranged from 3 kg to 34 kg. Clinical heterogeneity in study characteristics precluded meta-analysis. The effect on serum uric acid (sUA) ranged from −168 to 30 μmol/L, and 0%–60% patients achieving sUA target (<360 μmol/L). Six out of eight studies (75%) showed beneficial effects on gout attacks. Two studies indicated dose–response relationship for sUA, achieving sUA target and gout attacks. At short term, temporary increased sUA and gout attacks tended to occur after bariatric surgery.ConclusionsThe available evidence is in favour of weight loss for overweight/obese gout patients, with low, moderate and low quality of evidence for effects on sUA, achieving sUA target and gout attacks, respectively. At short term, unfavourable effects may occur. Since the current evidence consists of a few studies (mostly observational) of low methodological quality, there is an urgent need to initiate rigorous prospective studies (preferably randomised controlled trials).Systematic review registrationPROSPERO, CRD42016037937.

The Large Magellanic Cloud (LMC) is the nearest laboratory for detailed studies on the formation and survival of complex organic molecules (COMs), including biologically important ones, in low-metallicity environments—typical of earlier cosmological epochs. We report the results of 1.2 mm continuum and molecular line observations of three fields in the star-forming region N 105 with the Atacama Large Millimeter/submillimeter Array. N 105 lies at the western edge of the LMC bar with ongoing star formation traced by H2O, OH, and CH3OH masers, ultracompact H ii regions, and young stellar objects. Based on the spectral line modeling, we estimated rotational temperatures, column densities, and fractional molecular abundances for 12 1.2 mm continuum sources. We identified sources with a range of chemical makeups, including two bona fide hot cores and four hot core candidates. The CH3OH emission is widespread and associated with all the continuum sources. COMs CH3CN and CH3OCH3 are detected toward two hot cores in N 105 together with smaller molecules typically found in Galactic hot cores (e.g., SO2, SO, and HNCO) with the molecular abundances roughly scaling with metallicity. We report a tentative detection of the astrobiologically relevant formamide molecule (NH2CHO) toward one of the hot cores; if confirmed, this would be the first detection of NH2CHO in an extragalactic subsolar metallicity environment. We suggest that metallicity inhomogeneities resulting from the tidal interactions between the LMC and the Small Magellanic Cloud might have led to the observed large variations in COM abundances in LMC hot cores.