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Purpose of review Resilience is an adaptation process presented by an individual despite facing adversities. Epigenetic changes, such as histone acetylation/methylation and DNA methylation, have been demonstrated to mediate stress response. In this review, we summarize recent findings on epigenetic mechanisms contributing to stress resilience. Recent findings Epigenetic modifications of genes involved in synaptic plasticity, endocrine, immune, and vascular systems are linked to resilience. For instance, increased DNA methylation of the nonneuronal growth factor Gdnf in specific brain regions promotes stress resilience. Additionally, high DNA methylation at the glucocorticoid receptor gene was associated with resilience in both rodents and humans. At the immune level, chronic stress induces increased DNA methylation at IL6 gene, a mediator of stress vulnerability. Moreover, epigenetic adaptations of the blood--brain barrier have been recently associated with stress resilience, which could lead to innovative therapeutic approaches to treat depression. Summary Identification of both central and peripheral epigenetic changes promoting stress resilience represent promising novel targets in the development of preventive and personalized medicine. Nevertheless, more research is needed to establish sex specific differences and to identify novel epigenetic mechanisms, such as serotonylation and dopaminylation, that hold great promises for the field of psychiatry.

Opioids are effective analgesics in the management of severe pain. However, tolerance, leading to dose escalation and adverse effects are significant limiting factors in their use. The role of peripheral opioid receptors in analgesia has been discussed especially under inflammatory conditions. The results from pharmacological and conditional knockout studies together do not provide a clear picture of the contribution of peripheral opioid receptors on antinociceptive tolerance and this needs to be evaluated. Therefore, we studied whether the peripherally restricted opioid receptor antagonist, methylnaltrexone (MNTX), could prevent morphine tolerance without attenuating the antinociceptive effect of morphine. Male Sprague-Dawley rats were treated for 7 days with increasing subcutaneous doses of morphine (5-30 mg/kg) and were coadministered saline, MNTX (0.5 or 2 mg/kg), or naltrexone (NTX; 2 mg/kg). Nociception was assessed with tail-flick, hotplate, and von Frey tests. Morphine, MNTX, and NTX concentrations in the plasma, brain, and spinal cord were measured by liquid chromatography-tandem mass spectrometry. In acute coadministration, NTX, but not MNTX, abolished the acute antinociceptive effects of morphine in all nociceptive tests. The antinociceptive tolerance after repeated morphine administration was also prevented by NTX but not by MNTX. MNTX penetrated to the spinal cord and the brain to some extent after repeated administration. The results do not support the use of MNTX for preventing opioid tolerance and also suggest that morphine tolerance is mediated by central rather than peripheral opioid receptors in the rat.

Significance Thirty to fifty percent of depressed individuals are unresponsive to commonly prescribed antidepressant treatments, suggesting that biological mechanisms, such as stress-induced inflammation and blood vessel dysfunction, remain untreated. The blood–brain barrier is the ultimate frontier between the brain and harmful toxins or inflammatory signals circulating in the blood. Depression and vulnerability to chronic social stress are associated with loss of this barrier integrity; however, the mechanisms involved remain poorly understood. Identification of adaptations leading to resilience under stressful conditions could help develop novel treatments. Here we combined behavioral, pharmacological, and cell-specific gene profiling experiments in mice with epigenetic, molecular, and anatomical analysis of human samples to unravel mechanisms with therapeutic potential to protect the brain and promote resilience., Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood–brain barrier (BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Region- and endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressant-treated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.

The aim of this article is to analyze translation techniques used in the film translation of dialectically-marked proper names. Undoubtedly, the issue of rendering dialectical varieties constitutes one of the greatest challenges in interlingual translation. The applicable translation techniques, however, are frequently in conflict with the rules of reducing audiovisual target text to an indispensable minimum. The research material consists of the English subtitles to The Peasants (Chłopi, dir. Jan Rybkowski, Telewizja Polska S.A. 1973; English translation by Agata Deka, PolArt Video 2006). This article outlines the main theoretical approaches and translation techniques which can be used in the cases of dialects, proper names, and audiovisual translation. The research part aims at verifying the hypothesis’s claim that these translation methods which require implementation of more complex procedures than, for instance, omission (e.g. replacing the source language dialect with a target text variation) are not applicable in the case of audiovisual translation. The conclusion consists of the outline of the main translation tendencies as well as the verification of the aforementioned hypothesis.

Major depressive disorder (MDD) is a chronic and recurrent psychiatric condition characterized by depressed mood, social isolation and anhedonia. It will affect 20% of individuals with considerable economic impacts. Unfortunately, 30–50% of depressed individuals are resistant to current antidepressant treatments. MDD is twice as prevalent in women and associated symptoms are different. Depression's main environmental risk factor is chronic stress, and women report higher levels of stress in daily life. However, not every stressed individual becomes depressed, highlighting the need to identify biological determinants of stress vulnerability but also resilience. Based on a reverse translational approach, rodent models of depression were developed to study the mechanisms underlying susceptibility vs resilience. Indeed, a subpopulation of animals can display coping mechanisms and a set of biological alterations leading to stress resilience. The aetiology of MDD is multifactorial and involves several physiological systems. Exacerbation of endocrine and immune responses from both innate and adaptive systems are observed in depressed individuals and mice exhibiting depression‐like behaviours. Increasing attention has been given to neurovascular health since higher prevalence of cardiovascular diseases is found in MDD patients and inflammatory conditions are associated with depression, treatment resistance and relapse. Here, we provide an overview of endocrine, immune and vascular changes associated with stress vulnerability vs. resilience in rodents and when available, in humans. Lack of treatment efficacy suggests that neuron‐centric treatments do not address important causal biological factors and better understanding of stress‐induced adaptations, including sex differences, could contribute to develop novel therapeutic strategies including personalized medicine approaches., Endocrine, immune and vascular aspects contributing to depression and resilience. Evidence from mouse and human studies highlighted sex‐specific roles of these three different, but associated, systems in major depressive disorder and resilience.

Prevalence, symptoms, and treatment of depression all point toward major sex differences. Social stress-induced neurovascular pathology is associated with depressive symptoms in male mice however it remains unknown if it contributes to this sexual dimorphism. Here, we report that chronic social and subchronic variable stress promoted sex-specific blood-brain barrier (BBB) molecular and morphological alterations in mood-related brain regions. Viral-mediated functional manipulation leading to a targeted disruption of the BBB induced anxiety- and depression-like behaviors including social avoidance and anhedonia. Endothelium cell-specific transcriptomic profiling revealed key pathways and novel genes involved in maladaptive stress responses vs resilience. We also confirmed BBB leakiness in the brain of stressed females which led us to explore and identify circulating vascular biomarkers of chronic stress that could inform on diagnosis and treatment. Importantly, these pre-clinical findings were validated in human blood and postmortem brain samples from depressed women, thus highlighting their translational value. By revealing a sex-specific causal role of BBB dysfunction in stress responses and depression, our results implicate vascular impairment as a major factor underlying mood disorders.

To block the transmission of severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) a number of non-pharmaceutical interventions (NPIs) are being implemented. Taiwan successfully controlled coronavirus disease of 2019 (COVID-19) mainly by NPIs that were centered on facial masking, enhanced hand hygiene, social distancing, international travel controls, effective quarantine and contact-tracing policy [1, 2]. After the first case of COVID-19 was detected on January 21 2020, a rise in local demand for surgical masks and N95 respirators was observed and at least 50% of people spontaneously wore a facial mask in public places since early February 2020 [3, 4]. Among the total 799 COVID-19 cases reported in 2020, annual incidence rate of COVID-19 in Taiwan was remarkably low (0.238/100,000; n=56) for locally acquired (local) cases and high (3.153/100,000; n=743) for internationally acquired (imported) cases (Taiwan CDC, https://data.cdc.gov.tw/en/dataset). It is perceived that NPIs that are currently being implemented to reduce the COVID-19 should also prevent both acquisition and transmission of other viral and bacterial respiratory tract infections [5‒9]. In this observational study we examined the monthly incidence rates of invasive pneumococcal disease (IPD) and serotype distribution in age groups at high risk and from high pneumococcal transmission settings between January 2020 and February 2021. The differential serotype transmission dynamics revealed by various level of reduction in IPD caused by different serotypes was discussed., Significant reduction in the incidence rates of both vaccine and non-vaccine serotype invasive pneumococcal disease among children and adults during the COVID-19 pandemic were observed after the implementation of non-pharmaceutical interventions.

Objective To compare the safety and efficacy of switching from reference adalimumab to adalimumab biosimilar CT-P17 with continuing reference adalimumab/CT-P17 in active RA. Methods This double-blind, phase III study randomized (1:1) subjects with active RA to receive 40 mg (100 mg/ml) CT-P17 or European Union-sourced reference adalimumab subcutaneously every 2 weeks (Q2W) until week (W) 24 [treatment period (TP) 1]. Thereafter, subjects receiving reference adalimumab were randomized (1:1) to continue reference adalimumab or switch to CT-P17 from W26 (both Q2W until W48; TP2). Subjects receiving CT-P17 in TP1 continued CT-P17. W0–W24 results were previously reported; we present W26–W52 findings. End points were efficacy (including joint damage progression), pharmacokinetics, safety and immunogenicity. Results Of 607 subjects who initiated TP2 treatment, 303 continued CT-P17, 153 continued reference adalimumab and 151 switched to CT-P17. Efficacy improvements up to W24 were maintained during TP2; efficacy was comparable among groups. At W52, 20% improvement in ACR response rates were 80.5% (continued CT-P17), 77.8% (continued reference adalimumab) and 82.2% (switched to CT-P17). Joint damage progression was minimal. Mean trough serum adalimumab concentrations were similar among groups. CT-P17 and reference adalimumab safety profiles were numerically similar and switching did not affect immunogenicity. At W52, 28.4% (continued CT-P17), 27.0% (continued reference adalimumab) and 28.3% (switched to CT-P17) of subjects were anti-drug antibody-positive. Conclusion Efficacy, pharmacokinetics, safety and immunogenicity of CT-P17 and reference adalimumab were comparable after 1 year of treatment, including after switching from reference adalimumab to CT-P17. Trial registration ClinicalTrials.gov, http://clinicaltrials.gov, NCT03789292.

Background/Purpose Acinetobacter baumannii is an important nosocomial pathogen. To better understand the role of CsuA/BABCDE pilus of A. baumannii in virulence, bacterial biofilm formation, adherence and carbohydrate-mediated inhibition were conducted. Methods CsuA/BABCDE pilus-producing (abbreviated Csu pilus) operon of A. baumannii ATCC17978 was cloned for analysis of biofilm formation on an abiotic plastic plate, bacterial adherence to respiratory epithelial human A549 cells and carbohydrate-mediated inhibition. The carbohydrates used for inhibition of biofilm formation and adherence to A549 cells included monosaccharides, pyranosides, and mannose-polymers. Results The Csu pilus of A. baumannii ATCC17978 was cloned and expressed into a non-pilus-producing Escherichia coli JM109, and was knocked out as well. The recombinant Csu (rCsu) pilus on E. coli JM109/rCsu pilus-producing clone observed by both electro-microscopy and atomic force microscopy showed abundant, while Csu-knockout A. baumannii ATCC17978 mutant appeared less or no pilus production. The E. coli JM109/rCsu pilus-producing clone significantly increased biofilm formation and adherence to A549 cells; however, the Csu-knockout mutant dramatically lost biofilm-making ability but, in contrast, increased adherence. Moreover, both of biofilm formation and adherence could be significantly inhibited by d -mannose and methyl-α- d- mannopyranoside in Csu pilus-producing E. coli JM109, whereas in A. baumannii ATCC17978, high concentration of carbohydrates was required for the inhibition, suggesting that Csu pilus is sensitive to d- mannose. Conclusion This is the first study confirming that Csu pilus of A. baumannii belongs to mannose-sensitive type 1 pilus family and contributes to biofilm formation and bacterial adherence to human epithelial cells.

Objective.To evaluate the efficacy and safety of poseltinib (formerly LY3337641/HM71224), an irreversible covalent inhibitor of Bruton’s tyrosine kinase in a 2-part, phase II trial (RAjuvenate; ClinicalTrials.gov: NCT02628028) in adults with active rheumatoid arthritis (RA).Methods.In Part A, 36 patients with mildly active RA were randomized 1:1:1:1 to oral poseltinib 5, 10, or 30 mg or placebo once daily for 4 weeks to assess safety and tolerability. No safety signals precluded moving to Part B, where 250 patients with moderate-to-severe RA were randomized 1:1:1:1 to oral poseltinib 5 mg (n = 63), 10 mg (n = 62), or 30 mg (n = 63), or placebo (n = 62) once daily for 12 weeks. Parts A and B permitted stable doses of background disease-modifying antirheumatic drugs. The primary endpoint in Part B was proportion of patients achieving 20% improvement in American College of Rheumatology criteria (ACR20) at Week 12. Logistic regression compared each poseltinib dose to placebo for primary and secondary endpoints. Nonresponder imputation was used for missing data.Results.After interim analysis showed low likelihood of demonstrating significant efficacy, the sponsor discontinued Part B of the study. One hundred and eighty-nine (76%) patients completed 12 weeks in Part B; 61 discontinued study treatment (27 [44%] due to study termination by sponsor). There was no statistically significant difference in ACR20 response between any dose of poseltinib and placebo at Week 12 (P > 0.05 for all comparisons). Five serious adverse events occurred (n = 2, placebo; n = 3, 30 mg); there was 1 death due to a fall.Conclusion.While no safety findings precluded continuation, the study was terminated after interim data demonstrated low likelihood of benefit in RA.

Objective To evaluate fenebrutinib, an oral and highly selective noncovalent inhibitor of Bruton's tyrosine kinase (BTK), in patients with active rheumatoid arthritis (RA). Methods Patients with RA and an inadequate response to methotrexate (MTX) (cohort 1; n = 480) were randomized to receive fenebrutinib (50 mg once daily, 150 mg once daily, or 200 mg twice daily), adalimumab (40 mg every other week), or placebo. Patients with RA and an inadequate response to tumor necrosis factor inhibitors (cohort 2; n = 98) received fenebrutinib (200 mg twice daily) or placebo. Both cohorts continued MTX therapy. Results In cohort 1, the percentages of patients in whom American College of Rheumatology 50% improvement criteria (ACR50) was achieved at week 12 were similar in the fenebrutinib 50 mg once daily and placebo groups, and were higher in the fenebrutinib 150 mg once daily group (28%) and 200 mg twice daily group (35%) than in the placebo group (15%) (P = 0.016 and P = 0.0003, respectively). Fenebrutinib 200 mg twice daily and adalimumab (36%) were comparable (P = 0.81). In cohort 2, ACR50 was achieved in more patients receiving fenebrutinib 200 mg twice daily (25%) than placebo (12%) (P = 0.072). The most common adverse events in the fenebrutinib groups included nausea, headache, anemia, and upper respiratory tract infections. Fenebrutinib had significant effects on myeloid and B cell biomarkers (CCL4 and rheumatoid factor). Fenebrutinib and adalimumab caused overlapping as well as distinct changes in B cell and myeloid biomarkers. Conclusion Fenebrutinib demonstrates efficacy comparable to adalimumab in patients with an inadequate response to MTX, and safety consistent with existing immunomodulatory therapies for RA. These data support targeting both B and myeloid cells via this novel mechanism for potential efficacy in the treatment of RA.

The aim of this research is to estimate the degree of dialect untranslatability in audiovisual translation AVT. Polish regiolects may constitute a significant barrier to interlingual transfer. The problems with non-standard varieties of a language, which are frequently incomprehensible even to native speakers of their standard counterparts, can be overcome by means of, inter alia, explanatory periphrastic substitution added to the translated text. In the method of subtitling examined in this research, however, a translation of this kind is nearly impossible due to the broadly defined aesthetics of film e.g. time and space constraints frequently applied to the mode of AVT. Therefore, this article examines the hypothesis of dual constraint, which assumes a two-fold hindrance to a successful AV dialect transfer i.e. the lack of equivalents in the target language and the aforementioned aesthetic requirements of film. The corpus of the material researched here is based on the English subtitles for the screen adaptation of Chlopi — a Nobel Prize-winning novel written by Wladyslaw Stanislaw Reymont The Peasants; PolArt Video 2006. This article provides the theoretical background for the subsequent study as well as introduces its own classification of the translation techniques applicable to this particular piece of research as well as to other AV dialect transfers. The research part focuses on the research proper. The findings are briefly summarised and conclusions are drawn.

Background:Therapeutic equivalence of CT-P17 to reference adalimumab (ref-adalimumab) has been shown in patients with moderate-to-severe active rheumatoid arthritis (RA) through primary 24-week results [1]. Here, efficacy, pharmacokinetics (PK), safety and immunogenicity results up to 52-week, including transition data from ref-adalimumab to CT-P17 are presented.Objectives:To evaluate efficacy, PK, safety and immunogenicity when switched from ref-adalimumab to CT-P17 compared to maintaining CT-P17 or ref-adalimumab.Methods:In this study, 648 moderate-to-severe active RA patients despite methotrexate treatment were randomized (1:1) to either CT-P17 or ref-adalimumab and treated with doses of 40 mg every 2 weeks up to Week 24. Prior to dosing at Week 26, 608 patients were randomized again to either maintaining their treatments or being switched from ref-adalimumab to CT-P17. Efficacy, PK, safety, and immunogenicity were assessed up to Week 52.Results:After the second randomization, 303 patients continued with CT-P17, 153 patients continued with ref-adalimumab and 151 patients switched from ref-adalimumab to CT-P17 treatments, up to Week 48. Demographics and baseline characteristics were similar among the 3 groups. Sustained and comparable efficacy in terms of ACR20/50/70 response rates was achieved not only in the maintenance groups (CT-P17 or ref-adalimumab) but also in the switched from ref-adalimumab to CT-P17 group up to Week 52 (Figure 1).Figure 1.ACR 20/50/70 Response Rates up to 1 YearAbbreviation: ref-adalimumab, reference adalimumab.Note. There were patients who could not visit the study site due to COVID-19 pandemic and were counted as nonresponder for ACR response at Week 52.In terms of PK, mean trough serum concentration (Ctrough) were maintained after Week 24 in all 3 groups. The observed mean Ctrough were within the reported therapeutic ranges of ref-adalimumab trough levels in RA patients (5-8 μg/mL).The safety profile after transition was comparable among the 3 groups (Table 1). The most common treatment-emergent adverse events (TEAEs) was neutropenia. Similar proportions of patients in all 3 groups experienced at least 1 TEAE: injection site reactions, hypersensitivity/allergic reactions and infections. One malignancy (basal cell carcinoma; unrelated) was reported in the ref-adalimumab maintenance group. Safety data accumulated over 1 year also showed comparable results among the 3 groups. Anti-drug antibody (ADA) and neutralizing antibody (NAb) results were similar among the 3 groups. At Week 52, the proportions of patients who had ADA/NAbs were 28.4%/24.8% patients in CT-P17 maintenance, 27.0%/24.3% patients in ref-adalimumab maintenance and 28.3%/26.3% patients in switched to CT-P17 groups.Conclusion:Single transition from ref-adalimumab to CT-P17 was efficacious and safe without increase in immunogenicity. Also, efficacy, PK, safety and immunogenicity profiles were comparable between CT-P17 and ref-adalimumab up to Week 52.References:[1]J Kay et al, 2020. Poster Presented at ACR Convergence 2020.Table 1.Overview of TEAEs from Weeks 26 to 52 (Safety Population – second random subset)Patients, n (%)Second RandomizationCT-P17 Maintenance(N=303)Ref-ada Maintenance(N=152)Switched to CT-P17 (N=152)≥1 TEAE121 (39.9)69 (45.4)73 (48.0)≥1 TESAE6 (2.0)3 (2.0)5 (3.3)≥1 TEAE leading to study drug discontinuation3 (1.0)2 (1.3)5 (3.3)≥1 TEAE classified as hypersensitivity/allergic reactions2 (0.7)1 (0.7)0 (0)≥1 TEAE classified as injection site reactions1 (0.3)4 (2.6)1 (0.7)≥1 TEAE classified as infection54 (17.8)41 (27.0)28 (18.4)≥1 TEAE classified as malignancy0 (0)1 (0.7)0 (0)Abbreviations: Ref-ada, reference adalimumab; TEAE, treatment-emergent adverse event; TESAE, treatment-emergent serious adverse event.Disclosure of Interests:Daniel Furst Speakers bureau: CME, Consultant of: Amgen, Corbus, Galapagos, Horizon, Kadmon, Pfizer, Talaris, Grant/research support from: Corbus, CSL Behring, Galapagos, Gilead, GSK, Horizon, Kadmon, Novartis, Pfizer, Roche/Genetech, Talaris, Edward Keystone Speakers bureau: Amgen, AbbVie, F. Hoffmann-La Roche Inc., Janssen Inc., Merck, Novartis, Pfizer Pharmaceuticals, Sanofi Genzyme, Consultant of: AbbVie, Amgen, Bristol-Myers Squibb Company, Celltrion Inc., Myriad Autoimmune, F. Hoffmann-La Roche Inc, Gilead, Janssen Inc., Lilly Pharmaceuticals, Merck, Pfizer Pharmaceuticals, Sandoz, Sanofi-Genzyme, Samsung Bioepis, Grant/research support from: Amgen, Merck, Pfizer Pharmaceuticals, PuraPharm, Jonathan Kay Consultant of: AbbVie, Inc., Boehringer Ingelheim GmbH, Celltrion Healthcare Co. Ltd., Jubilant Radiopharma, Merck & Co., Inc., Pfizer Inc., Samsung Bioepis, Sandoz Inc., Scipher Medicine, UCB, Inc., Grant/research support from: Paid to the University of Massachusetts Medical School: Gilead Sciences Inc., Novartis Pharmaceuticals Corp., Pfizer Inc., Janusz Jaworski: None declared, Rafal Wojciechowski: None declared, Piotr Wiland Speakers bureau: Eli Lilly, Sanofi Aventis, Novartis, Sandoz, Consultant of: Eli Lilly, Novartis, Sandoz, Anna Dudek: None declared, Marek Krogulec: None declared, Sławomir Jeka Speakers bureau: Novartis, Pfizer, Roche, Lilly, Teva, MSD, Abbvie, Sandoz, Egis, Medac, Consultant of: Novartis, Pfizer, Roche, Lilly, Teva, MSD, Abbvie, Sandoz, Egis, Medac, Agnieszka Zielinska: None declared, Jakub Trefler: None declared, Katarzyna Bartnicka-Masłowska: None declared, Magdalena Krajewska-Wlodarczyk Speakers bureau: Abbvie, Eli Lilly, Novartis, Roche, Piotr Klimiuk: None declared, Sang Joon Lee Employee of: Celltrion, Inc., Sung Hyun Kim Employee of: Celltrion, Inc., YunJu Bae Employee of: Celltrion, Inc., GoEun Yang Employee of: Celltrion, Inc., JaeKyoung Yoo Employee of: Celltrion, Inc., TaeKyung Kim Employee of: Celltrion, Inc.

BackgroundTo assess the effect of baricitinib on patient-reported outcomes (PROs) in patients with active rheumatoid arthritis and an inadequate response to methotrexate (MTX).MethodsIn this double-blind phase 3 study, patients were randomised 3:3:2 to placebo (n=488), baricitinib 4 mg once daily (n=487), or adalimumab 40 mg biweekly (n=330) with background MTX. PROs included the SF-36, EuroQol 5-D (EQ-5D) index scores and visual analogue scale, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Health Assessment Questionnaire-Disability Index (HAQ-DI), Patient’s Global Assessment of Disease Activity (PtGA), patient’s assessment of pain and Work Productivity and Activity Impairment Questionnaire-Rheumatoid Arthritis (WPAI-RA), and measures collected in electronic patient daily diaries: duration and severity of morning joint stiffness (MJS), Worst Ttiredness and Worst Joint Pain. The primary study endpoint was at week 12. Treatment comparisons were assessed with logistic regression for categorical measures or analysis of covariance for continuous variables.ResultsCompared with placebo and adalimumab, baricitinib showed statistically significant improvements (p≤0.05) in HAQ-DI, PtGA, pain, FACIT-F, SF-36 physical component score, EQ-5D index scores and WPAI-RA daily activity at week 12. Improvements were maintained for measures assessed to week 52. Statistically significant improvement in patient diary measures (MJS duration and severity), worst tiredness and worst joint pain were observed for baricitinib versus placebo and adalimumab at week 12 (p≤0.05).ConclusionsBaricitinib provided significantly greater improvement in most PROs compared with placebo and adalimumab, including physical function MJS, pain, fatigue and quality of life. Improvement was maintained to the end of the study (week 52).Trial registrationNCT01710358.

Summary Background Ixekizumab, a high-affinity interleukin-17A (IL-17A) monoclonal antibody, has previously shown efficacy in radiographic axial spondyloarthritis (also known as ankylosing spondylitis). We aimed to evaluate the efficacy and safety of ixekizumab, an IL-17 inhibitor, in non-radiographic axial spondyloarthritis. Here, we report the primary results of COAST-X. Methods COAST-X was a 52-week, randomised, double-blind, placebo-controlled, parallel-group study done at 107 sites in 15 countries in Europe, Asia, North America, and South America. Eligible participants were adults (aged ≥18 years) with active axial spondyloarthritis without definite radiographic sacroiliitis (non-radiographic axial spondyloarthritis), objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). Patients were randomly assigned (1:1:1) to receive subcutaneous 80 mg ixekizumab every 4 weeks (Q4W) or every 2 weeks (Q2W), or placebo. Changing background medications or switching to open-label ixekizumab Q2W, or both, was allowed after week 16 at investigator discretion. Primary endpoints were Assessment of SpondyloArthritis international Society-40 (ASAS40) response (defined as an improvement of 40% or more and an absolute improvement from baseline of 2 units or more [range 0–10] in at least three of the four domains [patient global, spinal pain, function, and inflammation] without any worsening in the remaining one domain) at weeks 16 and 52. Patients who switched to open-label ixekizumab were imputed as non-responders in logistic regression analysis. This trial is registered with ClinicalTrials.gov , number NCT02757352 . Findings Between Aug 2, 2016, and Jan 29, 2018, 303 patients were enrolled (105 to placebo, 96 to ixekizumab Q4W, and 102 to ixekizumab Q2W). Both primary endpoints were met: ASAS40 at week 16 (ixekizumab Q4W: 34 [35%] of 96, p=0·0094 vs placebo; ixekizumab Q2W: 41 [40%] of 102, p=0·0016; placebo: 20 [19%] of 105) and ASAS40 at week 52 (ixekizumab Q4W: 29 [30%] of 96, p=0·0045; ixekizumab Q2W: 32 [31%] of 102, p=0·0037; placebo: 14 [13%] of 105). 60 (57%) of 104 patients in the placebo group, 63 (66%) of 96 in the ixekizumab Q4W group, and 79 (77%) of 102 in the ixekizumab Q2W group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events in the ixekizumab groups were nasopharyngitis and injection site reaction. Of the treatment-emergent adverse events of special interest, there was one case of serious infection in the ixekizumab Q4W group. The frequency of serious adverse events was low (four [1%] of 302) and similar across the three groups. There were no malignancies or deaths. No new safety signals were identified. Interpretation Ixekizumab was superior to placebo for improving signs and symptoms in patients with non-radiographic axial spondyloarthritis at weeks 16 and 52. Reports of adverse events were similar to those of previous ixekizumab studies. Ixekizumab offers a potential therapeutic option for patients with non-radiographic axial spondyloarthritis who had an inadequate response or were intolerant to NSAID therapy. Funding Eli Lilly and Company.

Background The most severe form of pneumococcal disease is invasive pneumococcal disease (IPD), including empyema, sepsis and meningitis. Thomsen-Friedenreich antigen (TA; Galβ1-3GalNAc) activation is known to be a predictor of Streptococcus pneumoniae-associated hemolytic uremic syndrome (Sp-HUS). There have been limited data to correlate TA activation and overall disease severity of IPD in children. The study aimed to prove the positive correlation between TA activation and disease severity and to demonstrate the trend of TA level during the disease course. Methods We retrospectively reviewed the medical records from 38 pediatric patients aged from 0 to 18 years with microbiologically-confirmed IPD between 2010 and 2015 at a medical center in Taiwan. All cases underwent TA activation testing by the fluorescence-labeled peanut lectin agglutination method. Medical information including demographic data, laboratory findings, co-morbidities, and outcome was collected and reviewed. We compared the clinical manifestations and associated co-morbidities between TA-positive and TA-negative patients. Results Among the 38 patients, 25 (66%) showed TA activation. Compared to TA-negative patients, patients with TA activation had a statistically higher rate of prolonged anemia, thrombocytopenia, and acute kidney injury. TA-positive patients also had a longer intensive care unit stay and overall hospitalization days. The TA levels usually peaked 5–10 days after disease onset. Twenty-one pneumococcal isolates were recovered from the patients and serotyping was determined in 11 isolates: 10 serotype 19A and 1 serotype 3. Conclusions TA determination not only helps to diagnose Sp-HUS but also is a predictor for IPD severity. Among hospitalized patients with severe pneumococcal disease, the peak of TA level usually appeared 5–10 days after disease onset.

Background LY3337641 is an irreversible covalent inhibitor of Bruton’s tyrosine kinase (BTK), a key signaling molecule in the B-cell-receptor and Fc-receptor pathways and mediator of B-cell– and myeloid-cell–dependent inflammatory arthritis.1,2 RA-JUVENATE was a multicenter, randomized, double-blind, placebo-controlled, 2-part Phase 2 trial with long-term extension (LTE) in adult patients (pts) with rheumatoid arthritis (RA). Objectives The objective of this analysis is to present the primary results from Part B of the study. Methods In Part A, 36 pts with at least mildly active RA were randomized 1:1:1:1 to receive oral LY3337641 5, 10, or 30 mg or placebo (PBO) once daily (QD) for 4 weeks (wks) with the primary objective of safety and tolerability. There were no safety signals to preclude moving to Part B; pts in Part A were not eligible to participate in Part B. In Part B, 250 pts with active moderate to severe RA were randomized 1:1:1:1 receive oral LY3337641 5 (N=63), 10 (N=62), or 30 mg (N=63) or PBO (N=62) QD for 12 wks. The primary endpoint of Part B was the proportion of pts achieving ≥20% improvement in American College of Rheumatology criteria (ACR20) at Wk 12. A logistic regression model was used to compare each LY3337641 dose to PBO for primary and secondary endpoints. Nonresponder imputation was used to impute missing data. After an interim analysis showed a low likelihood of demonstrating significant efficacy at the conclusion of the trial, the sponsor discontinued Part B of the study, including the LTE. Efficacy results (except analysis of low disease activity and remission) included pts who completed through Wk 12 at the time of study discontinuation; safety was results included all pts who received ≥1 dose of study drug. Results Of the 250 pts (mean age 51.0 years; 86.4% female; mean disease duration 11.2 years) randomized in Part B, 189 (75.6%) completed 12 weeks and 180 entered the LTE (72.0%); 61 discontinued study treatment in Part B.. The most common reasons for discontinuation were study terminated by sponsor (27 [10.8%]), withdrawal by subject (8 [3.2%]), adverse event (8 [3.2%]), and lack of efficacy (4 [1.6%]). There was no statistically significant difference in the ACR20 response between any treatment group of LY3337641 and PBO at Wk 12 (p>0.05 for all comparisons; Table); a high placebo rate was noted, but no underlying reason was identified in post hoc analyses. There were 5 serious adverse events: 2 in PBO pts (joint dislocation and cholecystitis acute) and 3 in 30-mg pts (foot fracture, multiple injuries, and venous thrombosis). There was 1 death (30-mg pt, multiple injuries after 4-story fall down elevator shaft). There were no safety findings that precluded continuation of the study. Conclusion Although there were no safety findings that precluded continuation of the study, the study sponsor determined that the observed benefit-risk profile of LY3337641 in the study did not warrant its continuation. References [1] Di Paolo JA, et al. Nat Chem Biol. 2011;7:41-50 [2] Chakravarty SD, et al. Clin Immunol. 2013;148:66-78. Disclosure of Interests Mark C. Genovese Grant/research support from: Sanofi/Genzyme, Genentech/Roche, RPharm, Consultant for: Sanofi/Genzyme, Genentech/Roche, RPharm, Alberto Spindler: None declared, Akira Sagawa Paid instructor for: ONO Pharmaceutical co., ltd, Eli Lilly Japan K.K., Takeda Pharmaceutical Company Limited, AYUMI Pharmaceutical, ISSEI PHARMACEUTICAL CO., LTD., CHUGAI PHARMACEUTICAL CO.,LTD., Asahi Kasei Pharma Corporation, Janssen Pharmaceutical, Won Park Consultant for: Celltrion, Inc, Anna Dudek: None declared, Alan Kivitz Shareholder of: Novartis, Consultant for: Abbvie, Janssen, Pfizer, UCB, Genzyme, Sanofi, Regeneron, Boehringer Ingelheim, Sun Pharma Advanced Research, Flexion., Paid instructor for: Celgene, Horizon, Merck, Novartis, Pfizer, Genzyme, Sanofi, Regeneron, Speakers bureau: Celgene, Horizon, Merck and Genetech, Flexion, Jeannie Chao Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Lai Shan (Melanie) Chan Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, William Barchuk Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Ajay Nirula Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company

Author(s): Deodhar, Atul; Gensler, Lianne S; Sieper, Joachim; Clark, Michael; Calderon, Cesar; Wang, Yuhua; Zhou, Yiying; Leu, Jocelyn H; Campbell, Kim; Sweet, Kristen; Harrison, Diane D; Hsia, Elizabeth C; van der Heijde, Desiree | Abstract: ObjectiveTo evaluate the efficacy and safety of ustekinumab in 3 randomized, placebo-controlled studies in patients with axial spondyloarthritis (SpA). Studies 1 and 2 included patients with radiographic axial SpA (anti-tumor necrosis factor [anti-TNF]-naive patients and patients with inadequate response or intolerance to anti-TNF, respectively); study 3 patients had nonradiographic axial SpA.MethodsIn all 3 studies, patients were randomly assigned (1:1:1) to receive subcutaneous ustekinumab at 45 mg or 90 mg or placebo up to 24 weeks, after which placebo-treated patients were rerandomized to receive ustekinumab at 45 mg or 90 mg. The primary end point in studies 1 and 2 was the proportion of patients who met the Assessment of SpondyloArthritis international Society criteria for 40% improvement in disease activity (achieved an ASAS40 response). The primary end point in study 3 was the proportion of patients who achieved an ASAS20 response. Other disease activity and safety measures were also evaluated. A week 24 analysis of study 1 was preplanned to determine continuation of studies 2 and 3.ResultsFor study 1, the primary and major secondary end points were not met, and the study was discontinued. As a result, studies 2 and 3 were prematurely discontinued before they were fully enrolled. For all 3 studies, neither ustekinumab dose group demonstrated clinically meaningful improvement over placebo on key efficacy end points. The proportion of patients experiencing adverse events in the ustekinumab groups was consistent with that in previous studies.ConclusionIn these 3 placebo-controlled trials, efficacy of ustekinumab in the treatment of axial SpA was not demonstrated. The safety profile was consistent with that of studies in other indications.

The Janus kinase 1 (JAK1) pathway has been implicated in the pathogenesis of psoriatic arthritis. We aimed to investigate the efficacy and safety of filgotinib, a selective JAK1 inhibitor, for the treatment of psoriatic arthritis.The EQUATOR trial was a randomised, double-blind, placebo-controlled phase 2 trial that enrolled adults from 25 sites in seven countries (Belgium, Bulgaria, Czech Republic, Estonia, Poland, Spain, and Ukraine). Patients (aged ≥18 years) had active moderate-to-severe psoriatic arthritis (defined as at least five swollen joints and at least five tender joints) fulfilling Classification for psoriatic arthritis (CASPAR) criteria, active or a documented history of plaque psoriasis, and an insufficient response or intolerance to at least one conventional synthetic disease-modifying anti-rheumatic drug (csDMARD). Patients continued to take csDMARDs during the study if they had received this treatment for at least 12 weeks before screening and were on a stable dose for at least 4 weeks before baseline. Using an interactive web-based system, we randomly allocated patients (1:1) to filgotinib 200 mg or placebo orally once daily for 16 weeks (stratified by current use of csDMARDs and previous use of anti-tumour necrosis factor). Patients, study team, and sponsor were masked to treatment assignment. The primary endpoint was proportion of patients achieving 20% improvement in American College of Rheumatology response criteria (ACR20) at week 16 in the full analysis set (patients who received at least one dose of study drug), which was compared between groups with the Cochran-Mantel-Haenszel test and non-responder imputation method. This trial is registered with ClincalTrials.gov, number NCT03101670.Between March 9, and Sept 27, 2017, 191 patients were screened and 131 were randomly allocated to treatment (65 to filgotinib and 66 to placebo). 60 (92%) patients in the filgotinib group and 64 (97%) patients in the placebo group completed the study; five patients (8%) in the filgotinib group and two patients (3%) in the placebo group discontinued treatment. 52 (80%) of 65 patients in the filgotinib group and 22 (33%) of 66 in the placebo group achieved ACR20 at week 16 (treatment difference 47% [95% CI 30·2-59·6], p0·0001). 37 (57%) patients who received filgotinib and 39 (59%) patients who received placebo had at least one treatment-emergent adverse event. Six participants had an event that was grade 3 or worse. The most common events were nasopharyngitis and headache, occurring at similar proportions in each group. One serious treatment-emergent adverse event was reported in each group (pneumonia and hip fracture after a fall), one of which (pneumonia) was fatal in the filgotinib group.Filgotinib is efficacious for the treatment of active psoriatic arthritis, and no new safety signals were identified.Galapagos and Gilead Sciences.

Background: Filgotinib (FIL) is an orally administered, selective inhibitor of Janus Kinase 1 (JAK1) in Phase 3 development for the treatment of rheumatoid arthritis (RA). Objectives: Assess the long-term safety and efficacy of FIL in the DARWIN 3 open-label extension study. Methods: Two 24-week Phase 2b studies were completed in patients (pts) with moderately to severely active RA (DARWIN 1, DARWIN 2; Ref 1, 2). Following study completion, pts were offered FIL in the ongoing DARWIN 3 extension study: 100 mg QD (US males), 200 mg QD, or 100 mg BID. This report summarizes safety data from the first dose of FIL in the DARWIN program to 11 Oct 2017 and efficacy data from the DARWIN 3 baseline visit to Week 108, which all ongoing pts have completed. Results: Of 877 pts, 790 (90%) completed DARWIN 1/2, and 739 (84%) enrolled in DARWIN 3; 603 (82%) were female, mean age 53 years. At analysis, 491/739 (66%) were on study. Cumulative patient years of exposure (PYE) was 1931, median time on study drug was 1072 days. Key data are summarized in table 1. 87%, 68%, and 48% of pts achieved ACR20/50/70, respectively, and 72% achieved DAS28-CRP≤3.2 (by observed case analysis). Conclusions: Filgotinib long-term RA data demonstrates an acceptable safety and durable efficacy profile. References [1]Westhovens R, et al. Ann Rheum Dis2017;76:998–1008. [2]Kavanaugh A, et al. Ann Rheum Dis2017;76:1009–1019. Disclosure of Interest: R. Westhovens Grant/research support from: Galapagos and Celltrion, Roche and BMS, Consultant for: Galapagos and Celltrion, Roche and BMS, R. Alten Grant/research support from: Galapagos/Gilead, K. Winthrop Consultant for: Pfizer, Lilly, Galapagos, Gilead, AbbVie, M. Greenwald Grant/research support from: Gilead, L. Ponce: None declared, F. Enriquez-Sosa: None declared, M. Stanislavchuk: None declared, M. Mazur: None declared, A. Spindler: None declared, R. Cseuz: None declared, N. Nikulenkova: None declared, M. Glowacka-Kulesz: None declared, I. Szombati: None declared, A. Dudek: None declared, N. Mozaffarian Shareholder of: Gilead, Employee of: Gilead, J. Greer Shareholder of: Gilead, Employee of: Gilead, R. Kunder Shareholder of: Gilead, Employee of: Gilead, D. An Shareholder of: Gilead, Employee of: Gilead, P. Harrison Shareholder of: Galapagos, Employee of: Galapagos, A. Van der Aa Shareholder of: Galapagos, Employee of: Galapagos, A. Kavanaugh Consultant for: Galapagos, M. Genovese Consultant for: Gilead, Galapagos, Abbvie, Lilly, Pfizer

The Bunjevci are an South Slavic ethnic minority living on the territory of four countries: Serbia, Croatia, Bosnia and Hercegovina and Hungary. Originally they were recognized as a part of the Croatian nation, however because of a specific political situation in Serbia shortly after the breakup of Yugoslavia they were given an opportunity to declare themselves as a separate minority group in the 1991 census. After gaining a minority status, they have started to standardize their own language. In 2014, after a long years of work, the textbooks for teaching Bunjevian ethnolect were published. The aim of the article is to present the complex sociolinguistic situation of Bunjevci and analyze grammatical and orthographical content of textbooks as well as the metalanguage used to describe the language processes.

Background: Biological disease-modifying anti-rheumatic drugs (bDMARDs) are recommended for radiographic axial spondyloarthritis, otherwise known as ankylosing spondylitis, when conventional therapies are not effective. We report efficacy and safety data on ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin-17A (IL-17A), in patients with radiographic axial spondyloarthritis who have not previously been treated with bDMARDs. Methods: In this phase 3, randomised, double-blind, placebo-controlled superiority study of ixekizumab, adult patients with inadequate response or intolerance to non-steroidal anti-inflammatory drugs, an established diagnosis of radiographic axial spondyloarthritis, radiographic sacroiliitis centrally defined by modified New York criteria, and at least one spondyloarthritis feature according to the Assessment of SpondyloArthritis international Society (ASAS) criteria, were recruited from 84 sites (12 countries) in Europe, Asia, and North America. By use of a computer-generated random sequence, patients were randomly assigned (1:1:1:1) to 80 mg subcutaneous ixekizumab every two (Q2W) or four (Q4W) weeks, 40 mg adalimumab Q2W (active reference group), or placebo. The primary objective was to compare the proportion of patients achieving an ASAS40 response, a composite measure of clinical improvement in axial spondyloarthritis, at week 16 for both ixekizumab treatment groups versus the placebo group. The adalimumab reference group was included as an in-study active reference for comparison with placebo to provide additional context to interpretation of the ixekizumab study results. Findings: Between June 20, 2016, and Aug 22, 2017, 341 patients were randomly assigned to either the placebo group (n=87), adalimumab group (n=90), ixekizumab Q2W (n=83), or ixekizumab Q4W (n=81). At week 16, compared with placebo (16 [18%] of 87), more patients achieved ASAS40 with ixekizumab Q2W (43 [52%] of 83; p

Mesoporous ordered carbons were obtained from two precursors, sucrose and phloroglucinol/formaldehyde, using a hard-template and a soft-template method, respectively. The surface of the materials was modified with the –NH 2 groups via nitration and subsequent reduction of the resulting –NO 2 groups. The modified carbon materials were investigated by elemental analysis, Boehm titration, nitrogen sorption, XRD, TEM, thermal analysis including TPD, as well as XPS and Raman spectroscopy. Apart from the –NO 2 groups, the nitration step resulted in formation of the oxygen-rich surface species, the concentration of which decreased after reduction. This concerned especially the carboxylic groups, a part of which transformed into the amino acetate type of species. The sucrose-based method resulted in the materials with more abounding acidic groups then in the case of the phloroglucinol-based route. The number of the acidic groups decreased after the nitration in the following order: CMK-1 > CMK-3 >> CMK-8. On the contrary, the resistance of the carbon structures to the nitration/reduction processes conformed to the order of CMC-1 > CMK-3 >> CMK-1 ∼ CMK-8. The nitrogen content after the amination step exceeded slightly 2 wt.%. Such surface modifications provided attachment of the TCPP ligands, the amount of which ranged between ca. 30–60 wt.%.

Background Filgotinib (GLPG0634, GS-6034) is an oral JAK1 selective inhibitor with a favorable safety and efficacy profile in two 24-week Phase 2b studies as add-on to methotrexate (DARWIN 1) or as monotherapy (DARWIN 2) in patients with active rheumatoid arthritis (RA). Three daily doses were tested (50mg, 100mg or 200mg) in comparison to placebo. Objectives To assess long term safety and efficacy of filgotinib 200mg daily in patients from the DARWIN 3 Phase 2 open-label extension study. Methods Patients who completed DARWIN 1 or 2 and enrolled in DARWIN 3 received filgotinib 200mg once daily or 100mg twice daily, depending on prior treatment assignment. The DARWIN 3 data cut off was when the last patient reached extension Week 60. For safety, all data from the first intake of filgotinib in DARWIN 1/2/3 were analysed (up to 144 weeks). Results 877 patients participated in DARWIN 1 or 2, 790 completed and 739 entered DARWIN 3 from 22 countries (82% females, mean age 53y). 559 patients (75.6%) completed Week 60, 9.3% discontinued due to positive Quantiferon, 7.8% due to other adverse events, 6.8% for other reasons and 0.3% due to insufficient response. Overall exposure to filgotinib was 1314 patient-years (PYE). Treatment-emergent adverse events (157.7/100PYE), serious adverse events (5.3/100PYE) and serious infections (1.9/100PYE) occurred at similar rates compared to the core studies, however infections decreased on a percentage basis from 15% (109/739, W0–12) to 5% (25/549, W85–96). 16 cases of Herpes zoster were reported (1.2/100PYE), 6 cases of malignancy (excl. NMSC) (0.5/100PYE) and 1 case of MACE (0.1/100PYE). There was no active case of tuberculosis. Three fatalities were reported (0.2/100PYE). Mean change from baseline (CFB) at Week 96 and CTCAE toxicity grading in lab parameters of special interest are shown in table 1. Based on an observed case analysis 84% (505/601), 65% (389/601), 44% (267/601) and 51% (299/587) of patients reached ACR20, ACR50, ACR70 and DAS28(CRP) remission at Week 60 respectively. Conclusions With 1314 patient-years of exposure, the safety profile of filgotinib appears consistent with that of previously reported double-blind studies and the clinical response appears durable. References Westhovens R et al. Ann Rheum Dis 2016;0:1–11. Kavanaugh A et al. Ann Rheum Dis 2016;0:1–11. Disclosure of Interest R. Alten Grant/research support from: Galapagos, R. Westhovens Grant/research support from: Roche, Consultant for: Galapagos, Speakers bureau: BMS, A. Kavanaugh Consultant for: Galapagos, Pfizer, AbbVie, Amgen, Celgene, Janssen, Novartis, Eli Lilly, UCB, M. Genovese Grant/research support from: Abbvie, Eli Lilly, Pfizer, Astellas, Vertex, Consultant for: Galapagos, Gilead, Abbvie, Eli Lilly, Pfizer, Astellas, Vertex, K. Winthrop Grant/research support from: BMS, Pfizer, Consultant for: pfizer, BMS, lilly, Abbvie, Roche, UCB, Galapagos, Amgen, M. Greenwald Grant/research support from: Abbvie,Amgen, Bristol Myers Squibb, Celgene, Galapagos, Gilead, Lilly, Merck, Pfizer, UCB, Consultant for: Lilly, Pfizer, L. Ponce: None declared, F. Enriquez: None declared, M. Stanislavchuk: None declared, M. Mazur: None declared, A. Spindler: None declared, R. Cseuz: None declared, N. Nikulenkova: None declared, M. Glowacka-Kulesz: None declared, I. Szombati: None declared, A. Dudek: None declared, L. Meuleners Employee of: Galapagos NV, C. Tasset Employee of: Galapagos NV, P. Harrison Employee of: Galapagos NV, A. Van der Aa Employee of: Galapagos NV

This paper presents a case report of an infant, with a prenatally diagnosed congenital lung malformation, which proved to be pulmonary sequestration and congenital cystic adenomatoid malformation. The authors discuss current knowledge on diagnosis, clinical course and suggestions of ante- and postnatal management of patients with pulmonary sequestration or/and congenital cystic lung malformation.

BACKGROUND Biotrickling filtration is one of the most promising biotechnologies for off-gas treatment. However, gas–liquid mass transfer limitations constitute the most important drawback of biotrickling filters (BTFs) when treating hydrophobic pollutants. Oxygen limitations might also arise when treating soluble pollutants at high loading rates. In the present study, an easy-to-implement method for mass transfer characterization in BTFs based on dissolved oxygen measurements was investigated. RESULTS kLa values for oxygen in the range 30–300 h−1 were obtained by fitting the experimental data to a mathematical model with high correlation coefficients (average r2 = 0.995). In addition, the kLa values for other gas pollutants of industrial and environmental interest (NH3, H2S, toluene and hexane) were estimated by means of an empirical correlation, which allowed calculation of their mass transfer rates in order to identify potential mass transfer limiting scenarios. CONCLUSIONS The methodology proposed allowed for a rapid, easy and accurate determination of the kLa for oxygen under varied operational conditions, the mass transfer data obtained being in agreement with previous literature. The experimental kLa data obtained for oxygen and the methodology applied for the estimation of kLa for the target gaseous pollutants selected constitutes a valuable tool for the optimization, design and operation of BTFs. © 2013 Society of Chemical Industry

Pulmonary functions such as rapid adsorption, respreading, and hysteresis behavior of pulmonary surfactants are very important for respiratory movement. The interfacial behavior of pulmonary preparations containing an amphiphilic peptide (Hel 13-5) has recently investigated. An orientation of hydrophobic chains in a dipalmitoylphosphatidylcholine (DPPC) with or without palmitic acid (PA) is associated with a collapse of alveoli during respiration process. Therefore, the present study focused on the acyl chain orientation in model pulmonary surfactants (DPPC/Hel 13-5 and DPPC/PA/Hel 13-5). A successive change in the orientation during cyclic compression and expansion of films at the air-water interface can be probed directly by an infrared reflection-absorption spectrometry (IRRAS) technique. The hysteresis behavior, one of very important pulmonary functions, was previously observed in surface pressure (pi)-molecular area (A) isotherms for the both model pulmonary surfactant systems (Langmuir 22(2006)1182-1192 and Langmuir 22(2006)5792-5803). In addition, it was reported that Hel 13-5 was squeezed-out of the surface on compression like native pulmonary surfactant proteins. The data obtained for the binary and ternary systems were compared with those of the equivalent pure DPPC and DPPC/PA mixtures, respectively. For an asymmetric methylene stretching vibration (nu(a)-CH(2)) RA intensity, the absolute RA values increased with shifting to small surface area, monotonously. For the corresponding wavenumber, on the other hand, the values gradually decreased into approximately 2920cm(-1). However, they were kept constant in the squeeze-out region in spite of a further decrease of surface area. These results suggested that the orientation of hydrophobic chains in DPPC and DPPC/PA mixtures became in the most packed state soon after emergence of the squeeze-out process of Hel 13-5 and then the packed orientation was retained up to the collapse state. This indicated that the squeezed-out Hel 13-5 stabilized monolayers left at the interface. For the DPPC/PA/Hel 13-5 system, in particular, dissociated PA molecules were excluded together with Hel 13-5 and the surface monolayers were refined to DPPC and undissociated PA components during the compression process. And the similar behavior in the second and third cycles supported the good respreading ability of the monolayers containing Hel 13-5.

Polystyrenesulfonate acid (PSS) and alkyltrimethylammonium bromide (CnTAB, n = 8, 14, or 18) were dissolved in a chloroform/methanol solution and cospread on an air/water interface. The surfactant−...

From an economic point of view, protected areas do not bring in high profits, in comparison to other possible ways of land usage. National parks and nature reserves are costly in their creation, as well as in their subsequent upkeep and management. In developing countries, their operation can be the source of many political and economic problems. Usually, local communities neighboring protected areas perceive the existence of a protected zone negatively, although they are often able to avail themselves of park resources in various ways. Besides being given the opportunity to rationally make use of certain park resources, community members may be employed as park attendants, which is a practice that is widespread. A part of the profits obtained from the developing tourist industry may be allocated towards local development programs, e.g. the building of a new hospital or school. Some national parks, while lacking the adequate infrastructure necessary for tourism, grapple with a lack of funds. The lack of earning opportunities in connection with the development of tourism results in the local community’s over-exploitation of park resources. This often manifests itself in an increased incidence of poaching in the protected area.