Star formation shut down by multiphase gas outflow in a galaxy at a redshift of 2.45.

Large-scale outflows driven by supermassive black holes are thought to have a fundamental role in suppressing star formation in massive galaxies. However, direct observational evidence for this hypothesis is still lacking, particularly in the young universe where star-formation quenching is remarkably rapid1-3, thus requiring effective removal of gas4 as opposed to slow gas heating5,6. Although outflows of ionized gas are frequently detected in massive distant galaxies7, the amount of ejected mass is too small to be able to suppress star formation8,9. Gas ejection is expected to be more efficient in the neutral and molecular phases10, but at high redshift these have only been observed in starbursts and quasars11,12. Here we report JWST spectroscopy of a massive galaxy experiencing rapid quenching at a redshift of 2.445. We detect a weak outflow of ionized gas and a powerful outflow of neutral gas, with a mass outflow rate that is sufficient to quench the star formation. Neither X-ray nor radio activity is detected; however, the presence of a supermassive black hole is suggested by the properties of the ionized gas emission lines. We thus conclude that supermassive black holes are able to rapidly suppress star formation in massive galaxies by efficiently ejecting neutral gas.

Supporting each other: Older adults' experiences empowering food security and social inclusion in rural and food desert communities.

Older adults vulnerable to food insecurity are at risk of poor psychological and physical health. Poor public infrastructure or proximity to food sources can exacerbate risk of food insecurity. Reduced statutory services for social care has heightened the responsibility on third sector organisations and community-led volunteering, essential to supporting healthy ageing in place and reducing the inequalities of ageing. The aim of this qualitative study was to explore how older adults' volunteering with a third sector organisation focused on food access supports food security and builds social capital for socially or economically marginalised older adults within rural and food desert communities. The study aims to bridge the knowledge gap of how volunteering in vulnerable geographies affects food insecurity and community. Semi-structured interviews were conducted with seven older (55+) volunteer 'meal makers' working with the third sector organisation Food Train and its 'Meal Makers' project. Interview recordings were transcribed and thematically analysed. Ecomap methodology was used to illustrate the lived experiences of older adult volunteers as told through the interviews. Two themes were identified by Thematic Analysis: (1) Networks, connectedness, and exposure to social capital, and (2) Supplementary support. This study finds that older adult volunteers are well placed within community interventions supporting food insecure older adults in rural or food desert communities. Ecomaps demonstrated that high social capital volunteers can mediate food access barriers and highlighted points of local knowledge and social connection. Volunteer engagement provides opportunities for food secure older adults to share local knowledge and build networks of food support and social inclusion for food insecure older adults. Older age volunteering should be advocated as a multi-faceted intervention promoting mutual health and wellbeing in volunteer and beneficiary.

A comprehensive review of quantum bioreactor cell manufacture: Research and clinical applications.

The Quantum cell expansion system manufactured by Terumo-BCT is perhaps the most widely reported Good Manufacturing Practice-compliant bioreactor used for the expansion of adherent cell populations, both for research purposes and clinical cell-based therapies/trials. Although the system was originally designed for adherent cell expansion, more recently suspension cultures and extracellular vesicle manufacturing protocols have been published using the Quantum system. Cell therapy research and regenerative medicine in general is a rapidly expanding field and as such it is likely that the use of this system will become even more widespread and perhaps mandatory, for both research and development and in the clinic. The purpose of this review is to describe, compare and discuss the diverse range of research and clinical applications currently using the Quantum system, which to our knowledge has not previously been reviewed. In addition, current and future challenges will also be discussed.

Extracellular Vesicle Depletion Protocols of Foetal Bovine Serum Influence Umbilical Cord Mesenchymal Stromal Cell Phenotype, Immunomodulation, and Particle Release.

The immunomodulatory properties of MSCs can be recreated using their extracellular vesicles (EVs). Yet, the true capabilities of the MSC EVs cannot be distinguished from contaminating bovine EVs and protein derived from supplemental foetal bovine serum (FBS). FBS EV depletion protocols can minimise this, but vary in terms of depletion efficiency, which can negatively impact the cell phenotype. We explore the impact of FBS EV depletion strategies, including ultracentrifugation, ultrafiltration, and serum-free, on umbilical cord MSC characteristics. Whilst a greater depletion efficiency, seen in the ultrafiltration and serum-free strategies, did not impact the MSC markers or viability, the MSCs did become more fibroblastic, had slower proliferation, and showed inferior immunomodulatory capabilities. Upon MSC EV enrichment, more particles, with a greater particle/protein ratio, were isolated upon increasing the FBS depletion efficiency, except for serum-free, which showed a decreased particle number. Whilst all conditions showed the presence of EV-associated markers (CD9, CD63, and CD81), serum-free was shown to represent a higher proportion of these markers when normalised by total protein. Thus, we caution MSC EV researchers on the use of highly efficient EV depletion protocols, showing that it can impact the MSC phenotype, including their immunomodulatory properties, and stress the importance of testing in consideration to downstream objectives.

Impact of Celiac Disease on Dating.

BACKGROUND/AIMS: When seeking a romantic partner, individuals with celiac disease (CD) must navigate challenging social situations. We aimed to investigate dating-related behaviors in adults with CD. METHODS: A total of 11,884 affiliates of the Celiac Disease Center at Columbia University were invited to participate in an online survey. Adults (≥ 18 years) with biopsy-diagnosed CD were included. Among the 5,249 who opened the email, 538 fully completed the survey (10.2%). The survey included a CD-specific dating attitudes/behaviors questionnaire, a Social Anxiety Questionnaire (SAQ), a CD-specific quality of life instrument (CD-QOL), and a CD Food Attitudes and Behaviors scale (CD-FAB). RESULTS: Respondents were primarily female (86.8%) and the plurality (24.4%) was in the 23-35 year age range. 44.3% had dated with CD, and among them, 68.4% reported that CD had a major/moderate impact on their dating life. A major/moderate impact was more commonly reported among females (69.3%, p < 0.001), 23-35-year-olds (77.7%, p = 0.015), those with a household income < $50 K (81.7%, p = 0.019), and those with a lower CD-QOL score (50.5 vs. 73.4, p = 0.002). While on dates, 39.3% were uncomfortable explaining precautions to waiters, 28.2% engaged in riskier eating behaviors, and 7.5% intentionally consumed gluten. 39.0% of all participants were hesitant to kiss their partner because of CD; females more so than males (41.1% vs. 22.7%, p = 0.005). CONCLUSIONS: The majority of participants felt that CD had a major/moderate impact on their dating life. This impact may result in hesitation toward dating and kissing, decreased QOL, greater social anxiety, and less adaptive eating attitudes and behaviors. CD and the need to adhere to a gluten free diet have a major impact on dating and intimacy.

Photosynthesis of a Photocatalyst: Single Atom Platinum Captured and Stabilized by an Iron(III) Engineered Defect.

Single atom (SA), noble metal catalysts are of interest due to high projected catalytic activity while minimizing cost. Common issues facing many synthesis methodologies include complicated processes, low yields of SA product, and production of mixtures of SA and nanoparticles (NPs). Herein we report a simple, room-temperature synthesis of single Pt-atom decorated, anatase Fe-doped TiO2 particles that leverages the Fe dopant as an engineered defect site to photodeposit and stabilize atomically dispersed Pt. Both particle morphology and Fe dopant location are based on thermodynamic principles (Gibbs-Wulff construction). CO-DRIFTS (diffuse reflectance infrared Fourier transform spectroscopy) reveals absence of bridge-bonded CO signal, confirming atomically dispersed Pt. XAS (X-ray absorption spectroscopy) of both Pt and Fe indicates Fe-O-Pt bonding that persists through catalytic cycling. Mass balance indicates that the Pt loading on single particles is 2.5 wt % Pt; the single Pt-atom decorated nanoparticle yield is 17%. Pt-containing particles show more than an order-of-magnitude increased photooxidation efficiency relative to particles containing only Fe. High single-atom-Pt yield, ease of synthesis, and high catalytic activity demonstrate the utility and promise of this method. The principles of this photodeposition synthesis allow for its generalizability toward other SA metals of catalytic interest.

The risk of uveitis in patients with JIA receiving etanercept: the challenges of analysing real-world data.

OBJECTIVES: To describe and compare the occurrence of newly diagnosed uveitis in children with JIA receiving MTX, etanercept, adalimumab and infliximab. METHODS: This on-drug analysis included patients within UK JIA registries (British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study and Biologics for Children with Rheumatic Diseases) with non-systemic disease, registered at MTX or biologic start with no history of uveitis. Follow-up began from date of first treatment, continuing until first uveitis, discontinuation of registered drug, most recent follow-up up or death, whichever came first. Hazard ratios comparing risk of uveitis between drugs were calculated using propensity-adjusted Cox regression. RESULTS: A total of 2294 patients were included (943 MTX, 304 adalimumab/infliximab, 1047 etanercept). There were 44 reported cases of uveitis (27 MTX, 16 etanercept, 1 adalimumab). Unadjusted hazard ratio showed a reduced risk of uveitis in biologic cohorts compared with MTX. After adjusting for propensity deciles, there was no significant difference in the risk of uveitis between patients receiving etanercept or MTX [hazard ratio 0.5 (0.2-1.1)]. Fully adjusted comparisons were not possible for adalimumab/infliximab as there were too few events. CONCLUSIONS: In this first paper to compare the rate of new onset uveitis across the three main anti-TNF therapies used in JIA, a new diagnosis of uveitis is less common among patients starting biologics compared with MTX, although this did not reach statistical significance. The suggested protective effect of etanercept is likely explained by confounding, whereby patients in the MTX cohort are younger and earlier in disease, and therefore at greater risk of developing uveitis compared with etanercept patients.

Mycoplasma genitalium prevalence in Welsh sexual health patients: Low antimicrobial resistance markers and no association of symptoms to bacterial load.

OBJECTIVES: Mycoplasma genitalium (MG) is a common cause of sexually transmitted infection, however no prevalence data is available for Wales. MG was detected by qPCR (quantitative) as well as two separate SpeeDx commercial assays, and related to clinical symptoms, age, gender and sample type. METHODS: Cervical swabs, urethral swabs and/or urine were collected from 1000 patients at walk-in sexual health clinics at 3 Welsh health centres from October 2017-October 2018. Extracted DNA was investigated to determine concordance between an in-house quantitative PCR, SpeeDx ResistancePlus® MG and the SpeeDx MG + parC (beta 2) assays; mutations in parC were substantiated by Sanger sequencing. RESULTS: MG was detected in 17/600 female patients (2.7%) and 13/400 (3.5%) male patients, with a 100% concordance between in-house qPCR and both SpeeDx assays. Macrolide resistance was low (relative to other studies), but more common in males (4/13; 30.8%) than females (2/17; 11.8%) and the only fluoroquinolone resistant sample (3.4% overall) was also macrolide resistant and detected from an MSM. Vaginitis was clinically apparent in 12/17 MG-positive females (2 with additional cervicitis, 1 with additional pelvic inflammatory disease), while 7 MG-positive males were asymptomatic. MG bacterial load did not correlate to clinical symptoms and females (4559 ± 1646/ml) had significantly lower MG load than males (84,714 ± 41,813/ml; p = 0.0429). CONCLUSIONS: MG prevalence and antibiotic resistance in Welsh sexual health clinics is low. MG bacterial load did not correlate to clinical presentation, men have higher MG load/ml in urine than women, genders have different age bias for MG prevalence and urine and swabs are equivalent for detecting MG.

MYCO WELL D-ONE detection of Ureaplasma spp. and Mycoplasma hominis in sexual health patients in Wales.

The genital mycoplasmas are a unique group of inherently antibiotic-resistant sexually transmitted bacteria, often associated with non-gonococcal urethritis and bacterial vaginosis. The MYCO WELL D-ONE is a culture-based assay that aims to detect these organisms whilst concurrently screening them for antibiotic resistance. Urine and/or swabs from 856 informed and consented participants attending Welsh sexual health clinics were subjected to MYCO WELL D-ONE analysis, alongside qPCR and culture titration methodologies to determine sensitivity, specificity, PPV, NPV and accuracy. Resistance was confirmed by CLSI-compliant susceptibility testing and genetic mechanisms determined. The MYCO WELL D-ONE displayed a sensitivity and specificity of 91.98% and 96.44% for the detection of Ureaplasma spp., with sensitivity and specificity values of 78.23% and 98.84% for Mycoplasma hominis, compared with qPCR. Swabs harboured significantly greater bacterial loads than urine samples for both Ureaplasma spp. and M. hominis. Levofloxacin resistance rates, mediated by Ser83Leu mutation in ParC, for Ureaplasma spp. were 0.54%. Tetracycline resistance rates, mediated by tet(M), were 0.54% and 2% for Ureaplasma spp. and M. hominis, respectively; sequence analysis of tet(M)-positive Ureaplasma spp. and M. hominis strains isolated from a single individual confirmed separate resistance gene origins. The MYCO WELL D-ONE is a sensitive and specific assay for the detection of Ureaplasma spp. and M. hominis in genitourinary medicine samples, facilitating the accurate detection of these organisms within low-technology environments. While good for antibiotic resistance screening, accurate confirmation by MIC determination or molecular methods are required, and more optimally performed on urine samples.

Methotrexate persistence and adverse drug reactions in patients with juvenile idiopathic arthritis.

OBJECTIVES: This analysis aims to calculate MTX monotherapy persistence and describe the occurrence of and factors associated with the occurrence of adverse drug reactions (ADRs) with MTX. METHODS: Patients with JIA starting MTX monotherapy from two UK studies were included. Patient characteristics, treatment details and ADR occurrence were collected at treatment start, 6 months, 1 year and annually. The following groups of ADRs were included: gastrointestinal, elevated liver enzymes, leukopenia, drug hypersensitivity, rash, needle phobia and any events leading to permanent MTX discontinuation. Treatment exposure was calculated from MTX start until MTX monotherapy cessation, last follow-up or 31 December 2017 (cut-off), whichever came first. Survival analysis assessed the time on MTX monotherapy and the time to the first ADR on MTX monotherapy within 2 years. Multivariable logistic regression assessed characteristics associated with any ADR and gastrointestinal ADRs. RESULTS: A total of 577 patients started MTX. At 2 years, 310 (54%) were no longer on MTX monotherapy. Reasons included ineffectiveness (60%; 161/185 started a biologic), adverse event (25%), remission (8%) and patient/family decision (3%). Over this time, 212 (37%) patients experienced one or more ADR; commonly gastrointestinal (68%) or elevated liver enzymes (26%). Lower physician global assessment and older age predicted any ADR and gastrointestinal ADR, respectively. Patients with polyarticular RF and JIA had reduced odds of both any ADR and a gastrointestinal ADR. CONCLUSION: After 2 years, more than half the patients were no longer on MTX monotherapy, while more than one-third experienced one or more ADR, most commonly gastrointestinal. Research focusing on identifying which children will respond and/or experience ADRs is crucial to inform treatment decisions and management planning.

Short-term outcomes in patients with systemic juvenile idiopathic arthritis treated with either tocilizumab or anakinra.

Objectives: To investigate real-world short-term outcomes among patients with systemic JIA starting tocilizumab or anakinra. Methods: This analysis included all systemic JIA patients within the UK Biologics for Children with Rheumatic Diseases study starting tocilizumab or anakinra between 2010 and 2016. Disease activity was assessed at baseline and one year. At one year the following outcomes were assessed: minimal disease activity, clinically inactive disease, 90% ACR Paediatric response (ACRPedi90). Univariable logistic regression was used to identify baseline characteristics associated with these outcomes. Multiple imputation was used to account for missing data. Results: Seventy-six systemic JIA patients were included (54 tocilizumab; 22 anakinra). More patients starting anakinra as their first biologic compared with tocilizumab (86% vs 63%; P = 0.04), with shorter disease duration (1 vs 2 years; P = 0.003) and higher frequency of prior macrophage activation syndrome (37% vs 8%; P = 0.004). Overall, at one year, 42% achieved ACRPedi90, 51% minimal disease activity, and 39% clinically inactive disease, with similar responses seen between the two drugs. Response was not associated with baseline disease characteristics. Fifteen (20%) patients stopped biologic treatment by one year. Treatment survival was better with tocilizumab (89% at one year vs 59% anakinra; P = 0.002), with three stopping for anakinra injection-related problems. Conclusion: In this real-world cohort of patients with systemic JIA receiving tocilizumab or anakinra, approximately half achieved a minimal disease state by one year. Treatment responses appeared similar between the two therapies albeit with better persistence observed with tocilizumab.

Use and effectiveness of rituximab in children and young people with juvenile idiopathic arthritis in a cohort study in the United Kingdom.

Objectives: Rituximab (RTX) may be a treatment option for children and young people with JIA, although it is not licensed for this indication. The aim of this study was to describe RTX use and outcomes among children with JIA. Methods: This analysis included all JIA patients within the UK Biologics for Children with Rheumatic Diseases study starting RTX. Disease activity was assessed at RTX start and at follow-up. The total number of courses each patient received was assessed. Serious infections and infusion reactions occurring following RTX were reported. Results: Forty-one JIA patients starting RTX were included, the majority with polyarthritis: polyarthritis RF negative [n = 14 (35%)], polyarthritis RF positive [n = 13 (33%)] and extended oligoarthritis [n = 9 (23%)]. Most were female (80%) with a median age of 15 years [interquartile range (IQR) 12-16] and a median disease duration of 9 years (IQR 5-11). The median improvement in the clinical Juvenile Arthritis Disease Activity Score (cJADAS; three-variable 71-joint JADAS) from RTX start was 9 units (n = 7; IQR -14-2). More than half reported more than one course of RTX. The median time between each course was 219 days (IQR 198-315). During follow-up, 17 (41%) patients reported switching to another biologic, including tocilizumab (n = 8), abatacept (n = 6) and TNF inhibitor (n = 3). Three patients (7%) reported a serious infection on RTX (rate of first serious infection 6.2/100 person-years). Four patients (10%) reported an infusion reaction. Conclusions: This real-world cohort of children with JIA, the majority with polyarticular or extended oligoarticular JIA, showed RTX may be an effective treatment option for children who do not respond to TNF inhibitor, with a low rate of serious infections on treatment.

PKA-site phosphorylation of importin13 regulates its subcellular localization and nuclear transport function.

Importin 13 (IPO13) is a key member of the importin ß superfamily, which can transport cargoes both into and out of the nucleus to contribute to a variety of important cellular processes. IPO13 is known to undergo phosphorylation, but the impact of this on function has not been investigated. Here, we show for the first time that IPO13 is phosphorylated by cAMP-dependent protein kinase A specifically at serine 193. Results from fluorescence recovery after photobleaching and fluorescence loss in photobleaching approaches establish that negative charge at serine 193 through phosphorylation or point mutation both reduces IPO13 nuclear import and increases its nuclear export. Importantly, phosphorylation also appears to enhance cargo interaction on the part of IPO13, with significant impact on localization, as shown for the Pax6 homeobox-containing transcription partner. This is the first report that IPO13 can be phosphorylated at Ser193 and that this modification regulates IPO13 subcellular localization and nucleocytoplasmic transport function, with important implications for IPO13's role in development and other processes.

Interactome of the inhibitory isoform of the nuclear transporter Importin 13.

Importin 13 (Imp13) is a bidirectional nuclear transporter of proteins involved in a range of important cellular processes, with an N-terminally truncated inhibitory isoform (tImp13) specifically expressed in testis. To gain insight into tImp13 function, we performed a yeast-2-hybrid screen from a human testis cDNA library, identifying for the first time a suite of interactors with roles in diverse cellular process. We validated the interaction of tImp13 with Eukaryotic translation initiation factor 4γ2 (EIF4G2) and High mobility group containing protein 20A (HMG20A), benchmarking that with glucocorticoid receptor (GR), a known Imp13 interactor expressed in testis. Coimmunoprecipitation assays indicated association of both tImp13 and Imp13 with EIF4G2, HMG20A and GR. Quantitative confocal microscopic analysis revealed the ability of tImp13 to inhibit the nuclear localisation of EIF4G2, HMG20A and GR, as well as that of Imp13 to act as a nuclear exporter for both EIF4G2 and HMG20A, and as a nuclear importer for GR. The physiological relevance of these results was highlighted by the cytoplasmic localisation of EIF4G2, HMG20A and GR in pachytene spermatocytes/round spermatids in the murine testis where tImp13 is present at high levels, in contrast to the nuclear localisation of HMG20A and GR in spermatogonia, where tImp13 is largely absent. Interestingly, Imp13, EIF4G2, HMG20A and GR were found together in the acrosome vesicle of murine epididymal spermatozoa. Collectively, our findings show, for the first time, that tImp13 may have a functional role in the mature spermatozoa, in addition to that in the meiotic germ cells of the testis.

Biologic refractory disease in rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis.

OBJECTIVES: Biologic disease-modifying antirheumatic drugs (bDMARDs) have revolutionised treatment and outcomes for rheumatoid arthritis (RA). The expanding repertoire allows the option of switching bDMARD if current treatment is not effective. For some patients, even after switching, disease control remains elusive. This analysis aims to quantify the frequency of, and identify factors associated with, bDMARD refractory disease. METHODS: Patients with RA starting first-line tumour necrosis factor inhibitor in the British Society for Rheumatology Biologics Register for RA from 2001 to 2014 were included. We defined patients as bDMARD refractory on the date they started their third class of bDMARD. Follow-up was censored at last follow-up date, 30 November 2016, or death, whichever came first. Switching patterns and stop reasons of bDMARDs were investigated. Cox regression identified baseline clinical factors associated with refractory disease. Multiple imputation of missing baseline data was used. RESULTS: 867 of 13 502 (6%) patients were bDMARD refractory; median time to third bDMARD class of 8 years. In the multivariable analysis, baseline factors associated with bDMARD refractory disease included patients registered more recently, women, younger age, shorter disease duration, higher patient global assessment, higher Health Assessment Questionnaire score, current smokers, obesity and greater social deprivation. CONCLUSIONS: This first national study has identified the frequency of bDMARD refractory disease to be at least 6% of patients who have ever received bDMARDs. As the choice of bDMARDs increases, patients are cycling through bDMARDs quicker. The aetiopathogenesis of bDMARD refractory disease requires further investigation. Focusing resources, such as nursing support, on these patients may help them achieve more stable, controlled disease.

The relationship between depression and biologic treatment response in rheumatoid arthritis: An analysis of the British Society for Rheumatology Biologics Register.

Objective: To investigate the relationship between depressive symptoms and treatment response and disease activity in RA over a 1-year follow-up. Methods: Data from the British Society for Rheumatology Biologics Register were used, representing 18 421 RA patients receiving biologic treatment. Depressive symptoms were identified through one of three assessments: reporting a history of depression, the Medical Outcomes Survey 36-item Short Form or the EuroQol five-dimension scale. Logistic regression analyses examined the relationship between baseline depressive symptoms and odds of good treatment response by 1 year. Multilevel models addressed the association between baseline depressive symptoms and disease activity outcomes over 1-year follow-up, adjusting for age, gender, disease duration, comorbidities and baseline disease activity and physical disability. Results: Depression symptoms at biologic treatment initiation were associated with 20-40% reduced odds of achieving a good treatment response at 1 year. Depressive symptoms at baseline also associated with reduced improvement in disease activity over the course of follow-up. Patients with a history of depression or reporting symptoms of depression according to the EuroQol five-dimension scale showed reduced improvement in tender and swollen joints, patient global assessment and ESR over 1-year follow-up. Patients with depression symptoms according to the 36-item Short Form showed reduced improvement in tender and swollen joints, but not ESR or patient global assessment. Conclusion: Experiencing symptoms of depression at the start of biologics treatment may reduce the odds of achieving a good treatment response, and reduce improvement in disease activity over time. Depression should be managed as part of routine clinical care to optimize treatment outcomes.

Risk of lymphoma in patients exposed to antitumour necrosis factor therapy: results from the British Society for Rheumatology Biologics Register for Rheumatoid Arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of lymphoma compared with the general population. There are concerns that tumour necrosis factor inhibitors (TNFi) may exacerbate this risk. However, since the excess risk of lymphoma in RA is related to the cumulative burden of inflammation, TNFi may conversely reduce the risk of lymphoma by decreasing the burden of inflammation. The aim of this study was to compare the risk of lymphoma in subjects with RA treated with TNFi with those treated with non-biological therapy. METHODS: Subjects diagnosed by a rheumatologist with RA enrolled in the British Society for Rheumatology Rheumatoid Arthritis Register (BSRBR-RA), a prospective cohort study, were followed until first lymphoma, death or until 30 November 2013. Rates of lymphoma in the TNFi and non-biological-treated cohorts were compared using Cox regression. RESULTS: 11 931 TNFi-treated patients were compared with 3367 biological-naive patients. 84 lymphomas (88 (95% CI 70 to 109) per 100 000 person-years) were reported in the TNFi cohort and 30 lymphomas (154 (95% CI 104 to 220)) in the biological-naive cohort. After adjusting for differences in baseline characteristics, there was no difference in the risk of lymphoma for the TNFi versus the biological-naive group: HR 1.00 (95% CI 0.56 to 1.80). No risk differences were observed for individual TNFi. CONCLUSIONS: In medium-term follow-up, there is no evidence that tumour necrosis factor inhibition influences the risk of lymphoma over the background risk in subjects with RA.

Cross-validation of commercial enzyme-linked immunosorbent assay and radioimmunoassay for porcine C-peptide concentration measurements in non-human primate serum.

BACKGROUND: C-peptide concentration is widely used as a marker of insulin secretion and is especially relevant in evaluating islet graft function following transplantation, because its measurement is not confounded by the presence of exogenous insulin. To address the shortage of human islet donors, the use of porcine islets has been proposed as a possible solution and the stringent pig-to-non-human primate (NHP) model is often the most relevant for pre-clinical evaluation of the potential for diabetes reversal resulting from an islet xenograft. The Millipore radioimmunoassay (RIA) was exclusively used to measure porcine C-peptide (PCP) until 2013 when the assay was discontinued and subsequently a commercially available enzyme-linked immunosorbent assay (ELISA) from Mercodia has been widely adopted. Both assays have been used in pre-clinical trials evaluating the therapeutic potential of xenograft products in reversing diabetes in the pig-to-NHP model, to interpret data in a comparable way it may be useful to perform a harmonization of C-peptide measurements. METHODS: We performed a method comparison by determining the PCP concentration in 620 serum samples collected from 20 diabetic cynomolgus macaques transplanted with adult porcine islets. All analyses were performed according to manufacturer instructions. RESULTS: With both assays, we demonstrated an acceptable detection limit, precision, and recovery. Linearity of the ELISA met acceptance criteria at all concentrations tested while linearity of the RIA only met acceptance criteria at five of the eight concentrations tested. The RIA had a detection limit of 0.16 ng/mL, and recovery ranged from 82% to 96% and met linearity acceptance criteria at 0.35 ng/mL and from 0.78 to 2.33 ng/mL. The ELISA had a detection limit of 0.03 ng/mL, and recovery ranged from 81% to 115% and met linearity acceptance criteria from 0.08 to 0.85 ng/mL. Both assays had intra-assay precision <11% and inter-assay precision <14%. PCP concentration measured by ELISA demonstrated a significant correlation with RIA (R2 =.9721, P<.0001). This strong correlation supports use of the regression equation y=2.029x+0.0897 to transform ELISA data to RIA or inversely y=0.4930x-0.0456 to convert RIA data to ELISA for direct comparison between assays in the concentration range of 0-3.0 ng/mL. Measured C-peptide concentration was lower with the ELISA than with the RIA; individual measurements plotted against the averages of the pair demonstrated that the variability from the mean strongly depended on increasing concentration. CONCLUSIONS: Porcine C-peptide can be reliably measured in NHP serum using the Mercodia ELISA, making this assay interchangeable with the Millipore RIA. Inherent differences in antibody affinity and calibration factors may explain the lower ELISA values as compared to the RIA; however without access to a traceable reference standard, it is not possible to determine which assay is most accurate. Regression modeling resulted in a correction factor appropriate for conversion of ELISA data to RIA-equivalent data facilitating comparison of assay results longitudinally and between groups.

Factors associated with improvement in disease activity following initiation of etanercept in children and young people with Juvenile Idiopathic Arthritis: results from the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study.

OBJECTIVES: The objectives of this study were to investigate change in disease activity, and explore factors associated with response, in children with JIA over the initial year of etanercept treatment. METHODS: This analysis included children with JIA starting etanercept in the British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study. Response was assessed using change in juvenile arthritis disease activity score-71 (JADAS-71), an excellent response (ACR Pedi 90), and achieving minimal disease activity (MDA) at 1 year. Change in JADAS-71 was evaluated over time. Multivariable backward stepwise logistic regression was performed to identify factors associated with ACR Pedi 90 and MDA. RESULTS: A total of 496 children were included. Over the first year, 17 stopped due to inefficacy, 9 due to adverse events and 7 for other reasons. One child stopped for remission. At 1 year, 74, 69 and 38% reached ACR Pedi 30, 50 and 90, respectively, and 48% had achieved MDA. Independent predictors of achieving ACR Pedi 90 at 1 year included shorter disease duration [odds ratio (OR) 0.91; 95% CI: 0.85, 0.97)], no concurrent oral corticosteroid use (OR 0.48; 95% CI: 0.29, 0.80) and history of uveitis (OR 2.26; 95% CI: 1.08, 4.71). Independent predictors of achieving MDA at 1 year included younger patients (OR 0.60; 95% CI: 0.38, 0.95), and disease not treated with concurrent oral corticosteroids (OR 0.57; 95% CI: 0.35, 0.93). CONCLUSION: Among this real-world cohort of children with severe JIA, a significant proportion of children achieved an excellent ACR Pedi response and MDA within 1 year of starting etanercept, although few clinical factors could predict this outcome.

Factors associated with choice of biologic among children with Juvenile Idiopathic Arthritis: results from two UK paediatric biologic registers.

OBJECTIVE: The objectives of this study were to describe patients starting first-line biologics for JIA, to describe characteristics over time among patients starting etanercept, and to describe patterns of second biologic prescribing. METHODS: The British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study, and the Biologics for Children with Rheumatic Diseases study are ongoing prospective observational cohorts, collecting data on patients starting biologic therapy for JIA. Patients registered from 1 January 2010 starting their first biologic were compared between therapies. Patients starting etanercept before 2010 were included to analyse changes in etanercept prescribing. The pathway of patients starting a second biologic was recorded in all patients. RESULTS: To 26 August 2014, 931 patients were recruited starting a first-line biologic (142 Biologics for Children with Rheumatic Diseases; 789 British Society for Paediatric and Adolescent Rheumatology Etanercept Cohort Study). From 2010, patients with systemic JIA (sJIA) were almost exclusively prescribed anakinra or tocilizumab. Choice between anti-TNF therapies was largely driven by history of chronic anterior uveitis (CAU). When investigating trends in patients starting etanercept over time, disease duration at etanercept start, patients with sJIA, a history of CAU, and those who received concomitant oral corticosteroids decreased over time. Patients who started a second biologic from 1 January 2010 showed a similar stratification. CONCLUSION: Although etanercept remains the most common biologic prescribed for JIA, there has been a clear shift towards the use of alternative biologics, largely driven by disease subtype and history of CAU. This channelling of children towards specific therapies should be considered carefully in future studies and in clinical guidelines and ongoing research.