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Hydrothermal alteration and mineralization processes can affect the physical and chemical properties of volcanic rocks. Aggressive acidic degassing and fluid flow often also lead to changes in the appearance of a rock, such as changes in surface coloration or intense bleaching. Although hydrothermal alteration can have far-reaching consequences for rock stability and permeability, limited knowledge exists on the detailed structures, extent, and dynamic changes that take place near the surface of hydrothermal venting systems. By integrating drone-based photogrammetry with mineralogical and chemical analyses of rock samples and surface gas flux, we investigate the structure of the evolving volcanic degassing and alteration system at the La Fossa cone on the island of Vulcano, Italy. Our image analysis combines principal component analysis (PCA) with image classification and thermal analysis through which we identify an area of approximately 70 000 m(2) that outlines the maximum extent of hydrothermal alteration effects at the surface, represented by a shift in rock color from reddish to gray. Within this area, we identify distinct gradients of surface coloration and temperature that indicate a local variability in the degassing and alteration intensity and define several structural units within the fumarole field. At least seven such larger units of increased activity could be constrained. Through mineralogical and geochemical analysis of samples from the different alteration units, we define a relationship between surface appearance in drone imagery and the mineralogical and chemical composition. Gradients in surface color from reddish to gray correlate with a reduction in Fe2O3 from up to 3.2 % in the unaltered regime to 0.3 % in the altered regime, and the latter coincides with the area of increased diffuse acid gas flux. As the pixel brightness increases towards higher alteration gradients, we note a loss of the initial (igneous) mineral fraction and a change in t

Biofilms are problematic on Earth due to their ability to both degrade the materials upon which they grow and promote infections. Remarkably, 65% of infections and 80% of chronic diseases on Earth are associated with biofilms. The impact of biofilms is even greater in space, as the crew's lives and mission success depend on nominal operation of mechanical systems which can be interrupted by material damage associated with biofilm growth. Furthermore, the isolated confined environment nature of spaceflight may increase the rates of disease transmission. In the case of the International Space Station (ISS), biofilms are an identified problem on the Environmental Control and Life Support System (ECLSS), namely on the water processor assembly (WPA). In late 2019, the bacterial component of the Space Biofilms experiment launched to ISS to (i) characterize the mass, thickness, morphology, and gene expression of biofilms formed in space compared to matched Earth controls, (ii) interrogate the expression of antimicrobial resistance genes, and (iii) test novel materials as potential biofilm control strategies for future ECLSS components. For this, 288 bacterial samples were prepared prior to the launch of the Northrop Grumman CRS-12 mission from NASA's Wallops Flight Facility. The samples were integrated into the spaceflight hardware, BioServe's Fluid Processing Apparatus (FPA), packed in sets of eight in Group Activation Packs (GAP). Half of these samples were activated and terminated on orbit by NASA astronauts Jessica Meir and Christina Koch, while the remaining half were processed equivalently on Earth. The spaceflight bacterial samples of Space Biofilms returned on board the SpaceX CRS-19 Dragon spacecraft in early 2020. We here describe the test campaign implemented to verify the experiment design and confirm it would enable us to achieve the project's scientific goals. This campaign ended with the Experiment Verification Test (EVT), from which we present example morph

Land use is a key driver of the ongoing biodiversity crisis and therefore also a major opportunity for its mitigation. However, appropriately considering the diversity of land-use actors and activities in conservation assessments and planning is challenging. As a result, top-down conservation policy and planning are often criticized for a lack of contextual nuance widely acknowledged to be required for effective and just conservation action. To address these challenges, we have developed a conceptually consistent, scalable land system typology and demonstrated its usefulness for the world's tropical dry woodlands. Our typology identifies key land-use actors and activities that represent typical threats to biodiversity and opportunities for conservation action. We identified land systems in a hierarchical way, with a global level allowing for broad-scale planning and comparative work. Nested within it, a regionalized level provides social-ecological specificity and context. We showcase this regionalization for five hotspots of land-use change and biodiversity loss in dry woodlands in Argentina, Bolivia, Mozambique, India, and Cambodia. Unlike other approaches to present land use, our typology accounts for the complexity of overlapping land uses. This allows, for example, assessment of how conservation measures conflict with other land uses, understanding of the social-ecological co-benefits and trade-offs of area-based conservation, mapping of threats, or targeting area-based and actor-based conservation measures. Moreover, our framework enables cross-regional learning by revealing both commonalities and social-ecological differences, as we demonstrate here for the world's tropical dry woodlands. By bridging the gap between global, top-down, and regional, bottom-up initiatives, our framework enables more contextually appropriate sustainability planning across scales and more targeted and social-ecologically nuanced interventions.

BACKGROUND Research and clinical use of clinical pharmacology laboratories are limited in low- and middle-income countries. We describe our experience in building and sustaining laboratory capacity for clinical pharmacology at the Infectious Diseases Institute, Kampala, Uganda. INTERVENTION Existing laboratory infrastructure was repurposed, and new equipment was acquired. Laboratory personnel were hired and trained to optimise, validate, and develop in-house methods for testing antiretroviral, anti-tuberculosis and other drugs, including 10 high-performance liquid chromatography methods and four mass spectrometry methods. We reviewed all research collaborations and projects for which samples were assayed in the laboratory from January 2006 to November 2020. We assessed laboratory staff mentorship from collaborative relationships and the contribution of research projects towards human resource development, assay development, and equipment and maintenance costs. We further assessed the quality of testing and use of the laboratory for research and clinical care. LESSONS LEARNT Fourteen years post inception, the clinical pharmacology laboratory had contributed significantly to the overall research output at the institute by supporting 26 pharmacokinetic studies. The laboratory has actively participated in an international external quality assurance programme for the last four years. For clinical care, a therapeutic drug monitoring service is accessible to patients living with HIV at the Adult Infectious Diseases clinic in Kampala, Uganda. RECOMMENDATIONS Driven primarily by research projects, clinical pharmacology laboratory capacity was successfully established in Uganda, resulting in sustained research output and clinical support. Strategies implemented in building capacity for this laboratory may guide similar processes in other low- and middle-income countries.

Are individuals of higher socio-economic status less ethical than those of lower status? Highly popularised research findings claim that this is the case. This paper provides evidence against this claim, based on data from two large survey experiments with more than 11,000 participants. We prime social status in two heterogeneous samples of the German population and then elicit ethical behaviour in an incentivised experimental task. Thus, our data allows us to study both correlation (using demographic data) and causality (using the priming). Our study rejects the claim that higher social status individuals are less ethical on both accounts.

The auditory mismatch negativity (MMN) has been proposed as a biomarker of NMDA receptor (NMDAR) dysfunction in schizophrenia. Such dysfunction may be caused by aberrant interactions of different neuromodulators with NMDARs, which could explain clinical heterogeneity among patients. In two studies (N = 81 each), we used a double-blind placebo-controlled between-subject design to systematically test whether auditory mismatch responses under varying levels of environmental stability are sensitive to diminishing and enhancing cholinergic vs. dopaminergic function. We found a significant drug × mismatch interaction: while the muscarinic acetylcholine receptor antagonist biperiden delayed and topographically shifted mismatch responses, particularly during high stability, this effect could not be detected for amisulpride, a dopamine D2/D3 receptor antagonist. Neither galantamine nor levodopa, which elevate acetylcholine and dopamine levels, respectively, exerted significant effects on MMN. This differential MMN sensitivity to muscarinic versus dopaminergic receptor function may prove useful for developing tests that predict individual treatment responses in schizophrenia.

The Thirteenth Amendment to the United States Constitution prohibits involuntary servitude, except as a punishment for crime. But what if an agent voluntarily signs a contract to provide a service for a principal? Should such contracts always be enforceable? Or should the freedom of contract be restricted, such that the agent cannot waive his or her right to quit work? According to the Coase Theorem, restricting the freedom of two rational parties to contract with each other cannot A principal hires an agent to provide a verifiable service. Initially, the agent can exert unobservable effort to reduce his disutility from providing the service. If the agent is free to waive his right to quit, he may voluntarily sign a contract specifying an inefficiently large service level, while there are insufficient incentives to exert effort. If the agent's right to quit is inalienable, the underprovision of effort may be further aggravated, but the service level is ex post efficient. Overall, it turns out that the total surplus can be larger when agents are not permitted to contractually waive their right to quit work. Yet, we also study an extension of our model in which even the agent can be strictly better off when the parties have the contractual freedom to waive the agent's right to quit. (c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

The Thirteenth Amendment to the United States Constitution prohibits involuntary servitude, except as a punishment for crime. But what if an agent voluntarily signs a contract to provide a service for a principal? Should such contracts always be enforceable? Or should the freedom of contract be restricted, such that the agent cannot waive his or her right to quit work? According to the Coase Theorem, restricting the freedom of two rational parties to contract with each other cannot A principal hires an agent to provide a verifiable service. Initially, the agent can exert unobservable effort to reduce his disutility from providing the service. If the agent is free to waive his right to quit, he may voluntarily sign a contract specifying an inefficiently large service level, while there are insufficient incentives to exert effort. If the agent's right to quit is inalienable, the underprovision of effort may be further aggravated, but the service level is ex post efficient. Overall, it turns out that the total surplus can be larger when agents are not permitted to contractually waive their right to quit work. Yet, we also study an extension of our model in which even the agent can be strictly better off when the parties have the contractual freedom to waive the agent's right to quit. (c) 2021 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

Purpose: Several risk factors and causes of adjacent segment disease have been debated; however, no quantitative relationship to spino-pelvic parameters has been established so far. A retrospective case-control study was carried out to investigate spino-pelvic alignment in patients with adjacent segment disease compared to a control group. Methods: 45 patients (ASDis) were identified that underwent revision surgery for adjacent segment disease after on average 49months (7-125), 39 patients were selected as control group (CTRL) similar in the distribution of the matching variables, such as age, gender, preoperative degenerative changes, and numbers of segments fused with a mean follow-up of 84months (61-142) (total n=84). Several radiographic parameters were measured on pre- and postoperative radiographs, including lumbar lordosis measured (LL), sacral slope, pelvic incidence (PI), and tilt. Results: Significant differences between ASDis and CTRL groups on preoperative radiographs were seen for PI (60.9±10.0° vs. 51.7±10.4°, p=0.001) and LL (48.1±12.5° vs. 53.8±10.8°, p=0.012). Pelvic incidence was put into relation to lumbar lordosis by calculating the difference between pelvic incidence and lumbar lordosis (∆PILL=PI−LL, ASDis 12.5±16.7° vs. CTRL 3.4±12.1°, p=0.001). A cutoff value of 9.8° was determined by logistic regression and ROC analysis and patients classified into a type A (∆PILL <10°) and a type B (∆PILL ≥10°) alignment according to pelvic incidence-lumbar lordosis mismatch. In type A spino-pelvic alignment, 25.5% of patients underwent revision surgery for adjacent segment disease, whereas 78.3% of patients classified as type B alignment had revision surgery. Classification of patients into type A and B alignments yields a sensitivity for predicting adjacent segment disease of 71%, a specificity of 81% and an odds ratio of 10.6. Conclusion: In degenerative disease of the lumbar spine a high pelvic incidence with diminished lumbar lordosis seems to predispos

A Ni-catalyzed reductive carboxylation of N-substituted aziridines with CO2 at atmospheric pressure is disclosed. The protocol is characterized by its mild conditions, experimental ease, and exquisite chemo- and regioselectivity pattern, thus unlocking a new catalytic blueprint to access beta-amino acids, important building blocks with considerable potential as peptidomimetics.

Objective. Anti-citrullinated protein antibodies (ACPAs) are a hallmark of seropositive rheumatoid arthritis (RA). Yet, the precise disease-relevant autoantigens that are targeted by ACPAs remains a matter of debate. This study utilized patient-derived monoclonal ACPAs, rather than serum autoantibody analysis, to characterize the multireactivity to different protein modifications and to reveal autoantibody subsets in patients with RA. Methods. Twelve human monoclonal ACPAs (positive by the second-generation cyclic citrullinated peptide test) were generated from 6 RA patients, and a head-to-head comparison of their reactivities was performed. For profiling, we used a complementary DNA-based protein array (Engine GmbH) and 3 peptide-screening platforms with RA autoantigens (Thermo Fisher Scientific), citrullinated and carbamylated peptides (NimbleGen/Roche), or histonederived peptides with different posttranslational modifications (JPT Histone Code), covering >207,000 peptides (>7,800 gene products). Results. The fine-specificity profiles of the investigated ACPAs varied, but all of the monoclonal ACPAs displayed multireactivity to a large number of citrullinated peptides/proteins, each characterized by specific binding properties. ACPA subsets could be defined by clone-distinct consensus binding motifs (e.g., Cit-Gly, Gly-Cit, or Arg-Cit-Asp), with the most common ACPA recognition being that of a Gly in the +1 flanking position, but with additional amino acid preferences. For ACPA protein recognition, we observed a preference for citrullinated RNA-binding proteins with high Arg/Gly content. Six of the 12 ACPA clones also bound acetylated-lysine (KAc) or homocitrulline peptide motifs, displaying a similar affinity or higher apparent affinity than that for Cit peptides. Conclusion. ACPAs and anti-modified protein autoantibodies represent overlapping facets of RA autoimmunity and bind to a wide variety of modified proteins, extending well beyond the historically r, QC 20201201

PURPOSE To analyze and correlate preinterventional magnetic resonance (MR) imaging findings with clinical symptoms after percutaneous sclerotherapy of venous malformations (VMs) adjacent to the knee. MATERIALS AND METHODS Twenty-five patients (mean age, 24 y; range, 7-55 y; 11 female) with 26 VMs adjacent to the knee undergoing sclerotherapy (direct puncture, diagnostic angiography, sclerosant injection) were identified, and MR imaging findings were analyzed. The VM involved the synovium of the knee joint in 19 of 26 cases (76%). These lesions were associated with joint effusion (3 of 19; 16%), hemarthrosis (4 of 19; 21%), or synovial thickening (16 of 19; 84%). Follow-up ended 6-8 weeks after the first or second sclerotherapy session if complete pain relief was achieved or 3 months after the third sclerotherapy session. Treatment outcomes were categorized as symptom improvement (complete or partial pain relief) or poor response (unchanged or increased pain). RESULTS Forty-nine percutaneous sclerotherapy sessions were performed. Despite the absence of signs of knee osteoarthritis, patients with a VM involving the synovium (8 of 14; 57%) showed a poor response to sclerotherapy (1 of 8 [13%] pain-free after 1 sclerotherapy session). Among patients with VMs with no associated joint alteration and no synovial involvement (6 of 14; 43%), 5 of 6 (83%) showed improvement of symptoms after 1 sclerotherapy session (P < .05). CONCLUSIONS Juxta-articular VMs of the knee are frequently associated with hemarthrosis and synovial thickening. Patients with signs of osteoarthritis and synovial involvement of the VM on presclerotherapy MR imaging deserve special consideration, as these findings predict worse clinical symptoms after sclerotherapy.

Background: Schizophrenic psychoses are severe mental disorders. Despite advances in treatment, outcomes are still unsatisfactory. Pharmacological treatments are still limited, in particular regarding improvements in psychosocial functioning and neuro-cognitive impairment. In recent years new psychological therapies have been developed, demonstrating promising results. However, most of these interventions have been designed for and studied in outpatients; their efficacy and feasibility for patients requiring hospitalization is still unknown. Therefore, we have designed a clinical trial to compare a neuro-cognitive (Integrated Neuro-cognitive Treatment INT); a cognitive-behavioral (Integrated Psychological Therapy IPT); and a control (Cogpack CGP) intervention for patients with a schizophrenic psychosis hospitalized for treatment. Methods: In a three-parallel-arm, single-blind, randomized, controlled study, we compare INT, IPT, and CGP. Participants will take part in two weekly sessions of one intervention for at least 16 sessions. If due to randomization, participants are allocated to a treatment arm not suitable for them, they are allowed to switch intervention after four sessions. Based on a sample size calculation, recruitment will continue until 30 participants have completed the intervention for each treatment arm. Outcome Measurement: Primary outcomes are: change in symptom as measured by the Positive and Negative Syndrome Scale (PANSS), change in psychosocial functioning as assessed by the mini ICF-APP and neuro-cognitive performance, assessed by the Matrics Cognitive Consensus Battery (MCCB). Other outcomes of interest are the Brief Symptom Inventory (BSI) and the Health of the Nation Outcome Scales (HoNOS); together with prescribed medication, treatment retention and completion rates. Outcomes will be measured at baseline, 2 weeks into treatment (prior to a potential switch of intervention arm), post-treatment and at 6 and 12-month post-treatment follow-ups

Objective: Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross-reactivity. Methods: IgG-secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full-length mAb (n = 93) and also as germline-reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mAb to promote osteoclastogenesis were investigated. Results: Four unrelated anti-citrullinated protein autoantibodies (ACPAs), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA. The ACPAs recognized >3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients. The plasma cell-derived mAb were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay. Conclusion: These findings suggest that the high level of cross-reactivity among RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that RA is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints.

Rheumatoid arthritis (RA) associated anti-citrullinated protein autoantibodies (ACPA) target a wide range of modified proteins. Citrullination occurs during physiological processes such as apoptosis, yet little is known about the interaction of ACPA with nuclear antigens or apoptotic cells. Since uncleared apoptotic cells and neutrophil extracellular trap (NET) products have been postulated to be central sources of autoantigen and immunostimulation in autoimmune disease, we sought to characterize the anti-nuclear and anti-neutrophil reactivities of ACFA. Serology showed that a subset of anti-CCP2 seropositive RA patients had high reactivity to full-length citrullinated histones. In contrast, seronegative RA patients displayed elevated IgG reactivity to native histone compared to controls, but no citrulline-specific reactivity. Screening of 10 single B-cell derived monoclonal AGFA from RA patients revealed that four ACPA exhibited strong binding to apoptotic cells and three of these had anti-nuclear (ANA) autoantibody reactivity. Modified histones were confirmed to be the primary targets of this anti-nuclear ACPA subset following immunoprecipitation from apoptotic cell lysates. Monoclonal ACPA were also screened for reactivities against stimulated murine and human neutrophils, and all the nuclear-reactive monoclonal ACPA bound to NETs. Intriguingly, one ACPA mAb displayed a contrasting cytoplasmic perinuclear neutrophil binding and may represent a different NET-reactive ACPA subset. Notably, studies of CRISPR-Cas9 PAD4 KO cells and cells from PAD KO mice showed that the cytoplasmic NET-binding was fully dependent on PAD4, whilst nuclear- and histone-mediated NEI reactivity was largely PAD-independent. Our further analysis revealed that the nuclear binding could be explained by consensus-motif driven ACPA cross-reactivity to acetylated histones. Specific acetylated histone peptides targeted by the monoclonal antibodies were identified and the anti-modified protein aut

QC 20190822

Objective Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross-reactivity. Methods IgG-secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full-length mAb (n = 93) and also as germline-reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mAb to promote osteoclastogenesis were investigated. Results Four unrelated anti-citrullinated protein autoantibodies (ACPAs), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA. The ACPAs recognized >3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients. The plasma cell-derived mAb were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay. Conclusion These findings suggest that the high level of cross-reactivity among RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that RA is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints., QC 20190404

Objective: Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross-reactivity. Methods: IgG-secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full-length mAb (n = 93) and also as germline-reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mAb to promote osteoclastogenesis were investigated. Results: Four unrelated anti-citrullinated protein autoantibodies (ACPAs), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA. The ACPAs recognized >3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients. The plasma cell-derived mAb were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay. Conclusion: These findings suggest that the high level of cross-reactivity among RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that RA is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints.

Rheumatoid arthritis (RA) associated anti-citrullinated protein autoantibodies (ACPA) target a wide range of modified proteins. Citrullination occurs during physiological processes such as apoptosis, yet little is known about the interaction of ACPA with nuclear antigens or apoptotic cells. Since uncleared apoptotic cells and neutrophil extracellular trap (NET) products have been postulated to be central sources of autoantigen and immunostimulation in autoimmune disease, we sought to characterize the anti-nuclear and anti-neutrophil reactivities of ACFA. Serology showed that a subset of anti-CCP2 seropositive RA patients had high reactivity to full-length citrullinated histones. In contrast, seronegative RA patients displayed elevated IgG reactivity to native histone compared to controls, but no citrulline-specific reactivity. Screening of 10 single B-cell derived monoclonal AGFA from RA patients revealed that four ACPA exhibited strong binding to apoptotic cells and three of these had anti-nuclear (ANA) autoantibody reactivity. Modified histones were confirmed to be the primary targets of this anti-nuclear ACPA subset following immunoprecipitation from apoptotic cell lysates. Monoclonal ACPA were also screened for reactivities against stimulated murine and human neutrophils, and all the nuclear-reactive monoclonal ACPA bound to NETs. Intriguingly, one ACPA mAb displayed a contrasting cytoplasmic perinuclear neutrophil binding and may represent a different NET-reactive ACPA subset. Notably, studies of CRISPR-Cas9 PAD4 KO cells and cells from PAD KO mice showed that the cytoplasmic NET-binding was fully dependent on PAD4, whilst nuclear- and histone-mediated NEI reactivity was largely PAD-independent. Our further analysis revealed that the nuclear binding could be explained by consensus-motif driven ACPA cross-reactivity to acetylated histones. Specific acetylated histone peptides targeted by the monoclonal antibodies were identified and the anti-modified protein aut

Objective: Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross-reactivity. Methods: IgG-secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full-length mAb (n = 93) and also as germline-reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mAb to promote osteoclastogenesis were investigated. Results: Four unrelated anti-citrullinated protein autoantibodies (ACPAs), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA. The ACPAs recognized >3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients. The plasma cell-derived mAb were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay. Conclusion: These findings suggest that the high level of cross-reactivity among RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that RA is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints.

Rheumatoid arthritis (RA) associated anti-citrullinated protein autoantibodies (ACPA) target a wide range of modified proteins. Citrullination occurs during physiological processes such as apoptosis, yet little is known about the interaction of ACPA with nuclear antigens or apoptotic cells. Since uncleared apoptotic cells and neutrophil extracellular trap (NET) products have been postulated to be central sources of autoantigen and immunostimulation in autoimmune disease, we sought to characterize the anti-nuclear and anti-neutrophil reactivities of ACFA. Serology showed that a subset of anti-CCP2 seropositive RA patients had high reactivity to full-length citrullinated histones. In contrast, seronegative RA patients displayed elevated IgG reactivity to native histone compared to controls, but no citrulline-specific reactivity. Screening of 10 single B-cell derived monoclonal AGFA from RA patients revealed that four ACPA exhibited strong binding to apoptotic cells and three of these had anti-nuclear (ANA) autoantibody reactivity. Modified histones were confirmed to be the primary targets of this anti-nuclear ACPA subset following immunoprecipitation from apoptotic cell lysates. Monoclonal ACPA were also screened for reactivities against stimulated murine and human neutrophils, and all the nuclear-reactive monoclonal ACPA bound to NETs. Intriguingly, one ACPA mAb displayed a contrasting cytoplasmic perinuclear neutrophil binding and may represent a different NET-reactive ACPA subset. Notably, studies of CRISPR-Cas9 PAD4 KO cells and cells from PAD KO mice showed that the cytoplasmic NET-binding was fully dependent on PAD4, whilst nuclear- and histone-mediated NEI reactivity was largely PAD-independent. Our further analysis revealed that the nuclear binding could be explained by consensus-motif driven ACPA cross-reactivity to acetylated histones. Specific acetylated histone peptides targeted by the monoclonal antibodies were identified and the anti-modified protein aut

Objective: Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross-reactivity. Methods: IgG-secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full-length mAb (n = 93) and also as germline-reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mAb to promote osteoclastogenesis were investigated. Results: Four unrelated anti-citrullinated protein autoantibodies (ACPAs), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA. The ACPAs recognized >3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients. The plasma cell-derived mAb were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay. Conclusion: These findings suggest that the high level of cross-reactivity among RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that RA is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints.

Rheumatoid arthritis (RA) associated anti-citrullinated protein autoantibodies (ACPA) target a wide range of modified proteins. Citrullination occurs during physiological processes such as apoptosis, yet little is known about the interaction of ACPA with nuclear antigens or apoptotic cells. Since uncleared apoptotic cells and neutrophil extracellular trap (NET) products have been postulated to be central sources of autoantigen and immunostimulation in autoimmune disease, we sought to characterize the anti-nuclear and anti-neutrophil reactivities of ACFA. Serology showed that a subset of anti-CCP2 seropositive RA patients had high reactivity to full-length citrullinated histones. In contrast, seronegative RA patients displayed elevated IgG reactivity to native histone compared to controls, but no citrulline-specific reactivity. Screening of 10 single B-cell derived monoclonal AGFA from RA patients revealed that four ACPA exhibited strong binding to apoptotic cells and three of these had anti-nuclear (ANA) autoantibody reactivity. Modified histones were confirmed to be the primary targets of this anti-nuclear ACPA subset following immunoprecipitation from apoptotic cell lysates. Monoclonal ACPA were also screened for reactivities against stimulated murine and human neutrophils, and all the nuclear-reactive monoclonal ACPA bound to NETs. Intriguingly, one ACPA mAb displayed a contrasting cytoplasmic perinuclear neutrophil binding and may represent a different NET-reactive ACPA subset. Notably, studies of CRISPR-Cas9 PAD4 KO cells and cells from PAD KO mice showed that the cytoplasmic NET-binding was fully dependent on PAD4, whilst nuclear- and histone-mediated NEI reactivity was largely PAD-independent. Our further analysis revealed that the nuclear binding could be explained by consensus-motif driven ACPA cross-reactivity to acetylated histones. Specific acetylated histone peptides targeted by the monoclonal antibodies were identified and the anti-modified protein aut

Objective: Antibodies against posttranslationally modified proteins are a hallmark of rheumatoid arthritis (RA), but the emergence and pathogenicity of these autoantibodies are still incompletely understood. The aim of this study was to analyze the antigen specificities and mutation patterns of monoclonal antibodies (mAb) derived from RA synovial plasma cells and address the question of antigen cross-reactivity. Methods: IgG-secreting cells were isolated from RA synovial fluid, and the variable regions of the immunoglobulins were sequenced (n = 182) and expressed in full-length mAb (n = 93) and also as germline-reverted versions. The patterns of reactivity with 53,019 citrullinated peptides and 49,211 carbamylated peptides and the potential of the mAb to promote osteoclastogenesis were investigated. Results: Four unrelated anti-citrullinated protein autoantibodies (ACPAs), of which one was clonally expanded, were identified and found to be highly somatically mutated in the synovial fluid of a patient with RA. The ACPAs recognized >3,000 unique peptides modified by either citrullination or carbamylation. This highly multireactive autoantibody feature was replicated for Ig sequences derived from B cells from the peripheral blood of other RA patients. The plasma cell-derived mAb were found to target distinct amino acid motifs and partially overlapping protein targets. They also conveyed different effector functions as revealed in an osteoclast activation assay. Conclusion: These findings suggest that the high level of cross-reactivity among RA autoreactive B cells is the result of different antigen encounters, possibly at different sites and at different time points. This is consistent with the notion that RA is initiated in one context, such as in the mucosal organs, and thereafter targets other sites, such as the joints.

Rheumatoid arthritis (RA) associated anti-citrullinated protein autoantibodies (ACPA) target a wide range of modified proteins. Citrullination occurs during physiological processes such as apoptosis, yet little is known about the interaction of ACPA with nuclear antigens or apoptotic cells. Since uncleared apoptotic cells and neutrophil extracellular trap (NET) products have been postulated to be central sources of autoantigen and immunostimulation in autoimmune disease, we sought to characterize the anti-nuclear and anti-neutrophil reactivities of ACFA. Serology showed that a subset of anti-CCP2 seropositive RA patients had high reactivity to full-length citrullinated histones. In contrast, seronegative RA patients displayed elevated IgG reactivity to native histone compared to controls, but no citrulline-specific reactivity. Screening of 10 single B-cell derived monoclonal AGFA from RA patients revealed that four ACPA exhibited strong binding to apoptotic cells and three of these had anti-nuclear (ANA) autoantibody reactivity. Modified histones were confirmed to be the primary targets of this anti-nuclear ACPA subset following immunoprecipitation from apoptotic cell lysates. Monoclonal ACPA were also screened for reactivities against stimulated murine and human neutrophils, and all the nuclear-reactive monoclonal ACPA bound to NETs. Intriguingly, one ACPA mAb displayed a contrasting cytoplasmic perinuclear neutrophil binding and may represent a different NET-reactive ACPA subset. Notably, studies of CRISPR-Cas9 PAD4 KO cells and cells from PAD KO mice showed that the cytoplasmic NET-binding was fully dependent on PAD4, whilst nuclear- and histone-mediated NEI reactivity was largely PAD-independent. Our further analysis revealed that the nuclear binding could be explained by consensus-motif driven ACPA cross-reactivity to acetylated histones. Specific acetylated histone peptides targeted by the monoclonal antibodies were identified and the anti-modified protein aut

Background: We evaluated the analytical and clinical performance of the new Lumipulse® G 25-OH vitamin D assay from Fujirebio, and compared it to a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method and three other commercial automated assays. Methods: Total 25 hydroxy vitamin D (25(OH)D) levels were measured in 100 selected serum samples from our routine analysis with Fujirebio 25(OH)D assay. The results were compared with those obtained with LC-MS/MS and three other automated 25(OH)D assays (Abbott, Beckman, and Roche). The accuracy of each assay tested was evaluated against a Labquality reference serum panel for 25(OH)D (Ref!25OHD; University of Ghent). Results: Intra- and inter-day imprecision of the Fujirebio 25(OH)D assay was <5%. Fujirebio 25(OH)D assay showed the highest correlation among the assays tested with the LC-MS/MS method (R=0.986). The mean relative bias obtained was -15.6% (Fujirebio), -12.7% (Beckman), -2.1% (Abbott) and 9.7% (Roche) as compared to LC-MS/MS. Comparison with the Labquality certified reference serum panel yielded a mean bias of -11.8% (Fujirebio), -14.1% (Beckman), 4.4% (Abbott) and 3.2% (Roche), respectively. Compared to LC-MS/MS, the sensitivity of different methods in detecting vitamin D insufficiency (<50 nmol/L) varied from 100% for the Fujirebio assay to 72.7% for Roche, and specificity ranged from 94.4% for Roche to 87.6% for Beckman. Conclusions: The Lumipulse G 25-OH vitamin D assay from Fujirebio demonstrated a good correlation with LC-MS/MS and some immunoassays. The performance of the assay is well-suited for routine 25(OH)D measurement in clinical serum samples. A correction for the observed negative bias vs. LC-MS/MS could be considered.

[EN] At the 2015 International Hospital Federation (IHF) World Congress in Chicago, Illinois, USA, the Global Consortium for Healthcare Management Professionalization presented a call to action to professionalize the field of healthcare management. Governments and organizations that seek to realize the benefits of professional healthcare managers may meet this challenge by providing educational opportunities to established executives who are positioned to lead and ultimately mentor future managers. This paper introduces a case example of an executive graduate program in health administration, delivered by a university in the United States in partnership with the Ministry of Health in Saudi Arabia, with the aim of developing Saudi healthcare professionals as healthcare leaders. We share challenges, experiences and insights related to adapting a US curriculum for the Saudi working executives during a time of transformation in the Kingdom. We also provide a detailed description of the Executive Management Study, an applied synthesis activity required for all executive learners in the program. Results of an alumni survey are incorporated to demonstrate graduates’ perceptions of the effectiveness of the learning experience.

[EN] Wurster granulation with external product classification can be used for stable continuous coating or layering processes. It has been ascertained from recent population balance simulations that the ratio of the spray rate to the nuclei feed rate can be used to control the thickness of the sprayed product layer. However, thermal conditions are not considered by population balances regarding the particle size as distributed property. For this reason, heat and mass transfer is investigated in the present contribution by modelling of several subprocesses. The results can be used to discuss the cause of fluidized bed destabilization due to over-wetting.

[EN] At the 2015 International Hospital Federation (IHF) World Congress in Chicago, Illinois, USA, the Global Consortium for Healthcare Management Professionalization presented a call to action to professionalize the field of healthcare management. Governments and organizations that seek to realize the benefits of professional healthcare managers may meet this challenge by providing educational opportunities to established executives who are positioned to lead and ultimately mentor future managers. This paper introduces a case example of an executive graduate program in health administration, delivered by a university in the United States in partnership with the Ministry of Health in Saudi Arabia, with the aim of developing Saudi healthcare professionals as healthcare leaders. We share challenges, experiences and insights related to adapting a US curriculum for the Saudi working executives during a time of transformation in the Kingdom. We also provide a detailed description of the Executive Management Study, an applied synthesis activity required for all executive learners in the program. Results of an alumni survey are incorporated to demonstrate graduates’ perceptions of the effectiveness of the learning experience.

Introduction: This is a prospective study of adolescent patients in whom idiopathic thoracic scoliosis was corrected by short anterior fusion through a mini-open thoracotomy approach. Clinical, radiological and pulmonary function results of minimal 2-year (2-6) follow-up are presented. Materials and methods: Consecutive 62 patients with Lenke 1 and 2 curves, having main thoracic scoliosis of up to 75°, were prospectively included. The shoulder imbalance in Lenke 2 patients was less than 20mm. Thoracic scoliosis was corrected by short anterior fusion. The thoracic spine was exposed by an 8-cm mini-open thoracotomy incision. The operation technique and choosing of fusion levels are thoroughly described. Complete 360° discectomies and convex side vertebral endplates osteotomies are essential for deformity corrections with short fusions. Single-rod 5.5-mm titanium implants were used. The age at the time of operation was mean 15.2 years; 56 patients had a single thoracic curve and 6 patients had a double thoracic curve. There were almost equal numbers of patients with lumbar modifier A, B or C. The average length of fusion was 5.5 (4-7) vertebrae. The average length of fusion was 3.5 (2-6) vertebrae shorter than the average curve length. Results: The instrumented thoracic curves improved by 58.3% at 6 weeks and 56.3% at the last follow-up. Apex thoracic vertebral rotation improved by 73.78% at 6 weeks and 76.24% at the last follow-up. The non-instrumented upper thoracic curve improved by 25% in double thoracic scoliosis, where the mid-thoracic curve was selectively fused, and the non-instrumented lumbar curves improved by 33.9% at the last follow-up. The radiological changes from 6 weeks to the last follow-up were statistically not significant. The clinical rib hump improved by 54% at the last follow-up. There were no significant changes in the pulmonary function. FVC% was 81.04% preoperatively, 76.41% at 6 months and 80.38% at the 2-year follow-up. The results of SRS 24

Human liver microsomes (HLMs) are used to simulate human xenobiotic metabolism in vitro. In forensic and clinical toxicology, HLMs are popularly used to study the metabolism of new designer drugs for example. In this work, we present an automated online extraction system we developed for HLM experiments, which was compared to a classical offline approach. Furthermore, we present studies on the metabolism of 11 cathinones; for eight of these, the metabolism has not previously been reported. Metabolites were identified based on MS2 and MS3 scans. Fifty-three substances encompassing various classes of drugs were employed to compare the established offline and the new online methods. The metabolism of each of the following 11 cathinones was studied using the new method: 3,4-methylenedioxy-N-benzylcathinone, benzedrone, butylone, dimethylcathinone, ethylone, flephedrone, methedrone, methylone, methylethylcathinone, naphyrone, and pentylone. The agreement between the offline and the online methods was good; a total of 158 metabolites were identified. Using only the offline method, 156 (98.7%) metabolites were identified, while 151 (95.6%) were identified using only the online method. The metabolic pathways identified for the 11 cathinones included the reduction of the keto group, desalkylation, hydroxylation, and desmethylenation in cathinones containing a methylenedioxy moiety. Our method provides a straightforward approach to identifying metabolites which can then be added to the library utilized by our clinical toxicological screening method. The performance of our method compares well with that of an established offline HLM procedure, but is as automated as possible

In clinical toxicology, fast and specific methods are necessary for the screening of different classes of drugs. Therefore, an online extraction high-performance liquid chromatography coupled to mass spectrometry (LC-MSn) screening method using a MS2 and MS3 spectral library for the identification of xenobiotic substances has been developed and validated. Samples were run twice, once native and once after enzymatic hydrolysis. Internal standards and buffer were added to the urine samples. Following centrifugation, the supernatant was injected into the system. Extraction was performed by online turbulent flow chromatography. The chromatographic separation was achieved using a Phenyl/Hexyl column. For detection, a linear ion trap, equipped with an APCI interface, was used and the different compounds were identified using a MS2 and MS3 spectral library containing 356 compounds. The turnaround time to report the results of the screening including hydrolysis was approximately 2h. About 92% of the 356 substances could be identified with a limit of identification below 100ng/ml. The recovery and matrix effect experiments showed suitable results, and in six drug-free urine samples of healthy volunteers analyzed for selectivity, no substances have been identified. Carryover could be well controlled, and the method had a good reproducibility. The comparison of the results of 103 real patient urine samples showed a good agreement between the existing GC-MS and LC-MS methods with offline extraction and the new online extraction LC-MSn screening method. The presented method allows a fast and sensitive analysis of a broad range of compounds

[EN] Wurster granulation with external product classification can be used for stable continuous coating or layering processes. It has been ascertained from recent population balance simulations that the ratio of the spray rate to the nuclei feed rate can be used to control the thickness of the sprayed product layer. However, thermal conditions are not considered by population balances regarding the particle size as distributed property. For this reason, heat and mass transfer is investigated in the present contribution by modelling of several subprocesses. The results can be used to discuss the cause of fluidized bed destabilization due to over-wetting.

[EN] At the 2015 International Hospital Federation (IHF) World Congress in Chicago, Illinois, USA, the Global Consortium for Healthcare Management Professionalization presented a call to action to professionalize the field of healthcare management. Governments and organizations that seek to realize the benefits of professional healthcare managers may meet this challenge by providing educational opportunities to established executives who are positioned to lead and ultimately mentor future managers. This paper introduces a case example of an executive graduate program in health administration, delivered by a university in the United States in partnership with the Ministry of Health in Saudi Arabia, with the aim of developing Saudi healthcare professionals as healthcare leaders. We share challenges, experiences and insights related to adapting a US curriculum for the Saudi working executives during a time of transformation in the Kingdom. We also provide a detailed description of the Executive Management Study, an applied synthesis activity required for all executive learners in the program. Results of an alumni survey are incorporated to demonstrate graduates’ perceptions of the effectiveness of the learning experience.

[EN] At the 2015 International Hospital Federation (IHF) World Congress in Chicago, Illinois, USA, the Global Consortium for Healthcare Management Professionalization presented a call to action to professionalize the field of healthcare management. Governments and organizations that seek to realize the benefits of professional healthcare managers may meet this challenge by providing educational opportunities to established executives who are positioned to lead and ultimately mentor future managers. This paper introduces a case example of an executive graduate program in health administration, delivered by a university in the United States in partnership with the Ministry of Health in Saudi Arabia, with the aim of developing Saudi healthcare professionals as healthcare leaders. We share challenges, experiences and insights related to adapting a US curriculum for the Saudi working executives during a time of transformation in the Kingdom. We also provide a detailed description of the Executive Management Study, an applied synthesis activity required for all executive learners in the program. Results of an alumni survey are incorporated to demonstrate graduates’ perceptions of the effectiveness of the learning experience.

[EN] Wurster granulation with external product classification can be used for stable continuous coating or layering processes. It has been ascertained from recent population balance simulations that the ratio of the spray rate to the nuclei feed rate can be used to control the thickness of the sprayed product layer. However, thermal conditions are not considered by population balances regarding the particle size as distributed property. For this reason, heat and mass transfer is investigated in the present contribution by modelling of several subprocesses. The results can be used to discuss the cause of fluidized bed destabilization due to over-wetting.

[EN] At the 2015 International Hospital Federation (IHF) World Congress in Chicago, Illinois, USA, the Global Consortium for Healthcare Management Professionalization presented a call to action to professionalize the field of healthcare management. Governments and organizations that seek to realize the benefits of professional healthcare managers may meet this challenge by providing educational opportunities to established executives who are positioned to lead and ultimately mentor future managers. This paper introduces a case example of an executive graduate program in health administration, delivered by a university in the United States in partnership with the Ministry of Health in Saudi Arabia, with the aim of developing Saudi healthcare professionals as healthcare leaders. We share challenges, experiences and insights related to adapting a US curriculum for the Saudi working executives during a time of transformation in the Kingdom. We also provide a detailed description of the Executive Management Study, an applied synthesis activity required for all executive learners in the program. Results of an alumni survey are incorporated to demonstrate graduates’ perceptions of the effectiveness of the learning experience.

[EN] Wurster granulation with external product classification can be used for stable continuous coating or layering processes. It has been ascertained from recent population balance simulations that the ratio of the spray rate to the nuclei feed rate can be used to control the thickness of the sprayed product layer. However, thermal conditions are not considered by population balances regarding the particle size as distributed property. For this reason, heat and mass transfer is investigated in the present contribution by modelling of several subprocesses. The results can be used to discuss the cause of fluidized bed destabilization due to over-wetting.

[EN] Wurster granulation with external product classification can be used for stable continuous coating or layering processes. It has been ascertained from recent population balance simulations that the ratio of the spray rate to the nuclei feed rate can be used to control the thickness of the sprayed product layer. However, thermal conditions are not considered by population balances regarding the particle size as distributed property. For this reason, heat and mass transfer is investigated in the present contribution by modelling of several subprocesses. The results can be used to discuss the cause of fluidized bed destabilization due to over-wetting.

[EN] At the 2015 International Hospital Federation (IHF) World Congress in Chicago, Illinois, USA, the Global Consortium for Healthcare Management Professionalization presented a call to action to professionalize the field of healthcare management. Governments and organizations that seek to realize the benefits of professional healthcare managers may meet this challenge by providing educational opportunities to established executives who are positioned to lead and ultimately mentor future managers. This paper introduces a case example of an executive graduate program in health administration, delivered by a university in the United States in partnership with the Ministry of Health in Saudi Arabia, with the aim of developing Saudi healthcare professionals as healthcare leaders. We share challenges, experiences and insights related to adapting a US curriculum for the Saudi working executives during a time of transformation in the Kingdom. We also provide a detailed description of the Executive Management Study, an applied synthesis activity required for all executive learners in the program. Results of an alumni survey are incorporated to demonstrate graduates’ perceptions of the effectiveness of the learning experience.

Self-organization is a property of dissipative nonlinear processes that are governed by an internal driver and a positive feedback mechanism, which creates regular geometric and/or temporal patterns and decreases the entropy, in contrast to random processes. Here we investigate for the first time a comprehensive number of 16 self-organization processes that operate in planetary physics, solar physics, stellar physics, galactic physics, and cosmology. Self-organizing systems create spontaneous {\sl order out of chaos}, during the evolution from an initially disordered system to an ordered stationary system, via quasi-periodic limit-cycle dynamics, harmonic mechanical resonances, or gyromagnetic resonances. The internal driver can be gravity, rotation, thermal pressure, or acceleration of nonthermal particles, while the positive feedback mechanism is often an instability, such as the magneto-rotational instability, the Rayleigh-B\'enard convection instability, turbulence, vortex attraction, magnetic reconnection, plasma condensation, or loss-cone instability. Physical models of astrophysical self-organization processes involve hydrodynamic, MHD, and N-body formulations of Lotka-Volterra equation systems., Comment: 61 pages, 38 Figures

Railway crew scheduling deals with generating duties for train drivers to cover all train movements of a given timetable while taking into account a set of work regulations. The objective is to minimize the overall costs associated with a crew schedule, which includes workforce costs and hotel costs. A cost minimal schedule often contains duties that are unpopular to train drivers, and these unpopular duties are often unevenly distributed among crew depots. At the company that motivated our research, for example, train drivers dislike duties that start in the early morning hours. Currently, some crew depots operate large numbers of these unpopular duties, while others do not have any unpopular duties at all. The train drivers perceive this situation as unfair. They prefer schedules with fewer and more evenly distributed unpopular duties across crew depots. In this paper, we define and measure unpopularity and (un)fairness in a railway crew scheduling context. We integrate fairness conditions into a column generation-based solution algorithm and analyze the effect of increased fairness on cost. We also show how increased fairness affects the unpopularity of a schedule. Our method has been applied to test instances at a large European railway freight carrier. Compared to a standard approach that penalizes only the number of unpopular duties in a schedule, we were able to significantly improve schedule fairness with only marginal increases in schedule cost.