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Environmental monitoring (EM) is the cornerstone for the assurance of sterility during aseptic manufacturing. In this study, the EM quality aspects in the radiopharmaceutical cleanrooms of the University Medical Center Groningen (UMCG), The Netherlands, were evaluated. Hereto, data obtained from EM over the period 2010–2022 were analyzed. The data were sorted according to the Good Manufacturing Practice (GMP) classification of the respective premises with their corresponding limits, and frequencies of excursions were determined per location. The frequency of conducted measurements gradually increased between the start and end of the assessed period. There was a trend of increased action limit excursions observed between 2010–2022. We found that EM in grade A areas appeared to be significantly less compliant with GMP specifications than the combined data from all sampled premises at the facility (p < 0.00001; two-sided Fisher’s exact test). A trend was found for reduced action limit excursions for passive air sampling and particle counting, suggesting improved GMP compliance over time for this specific type of EM. The contamination recovery rate (CRR) found for cleanroom conditions, around 10%, was considered sufficient. From this comprehensive data analysis, we learn that, in order to be fully compliant with the requirements set in the recent revision of EU (European Union)-GMP Annex 1 ‘Manufacture of sterile medicinal products’ (in force as of 25 August 2023), strategies to further improve product protection are justified. For example, improved cleaning and disinfection procedures, more efficient working methods as well as optimization of the conditions under which aseptic manufacturing is performed are to be considered.

Objectives To follow up four previously identified classes ‘pure axial spondyloarthritis’ (axSpA) (‘axial’), ‘axSpA with peripheral signs’ (‘inflammatory back pain+peripheral’), ‘axSpA at risk’ and ‘no spondyloarthritis’ (‘no SpA’). They reflect the expert-opinion-free construct or ‘Gestalt’ of chronic back pain suspicious of axSpA. The aim was to assess participants’ transitions between these classes over time.Methods Participants with chronic back pain of ≤2 years duration, suspicious of axSpA from the SPondyloArthritis Caught Early cohort were analysed. Latent class (LCA) and latent transition analysis (LTA) using clinical, laboratory and imaging data at baseline and 2 years were calculated. Conditional and marginal probabilities were obtained, reflecting the probability of a spondyloarthritis feature in a class and the probability of the participant’s class membership, respectively. Transitional probabilities were extracted revealing potential switches across classes. The analyses were performed in all participants using imputations for missing data and in participants with full data at baseline and 2 years.Results Baseline and 2 years LCA models were constructed for 702 participants, resulting in the same four-class model as previously described. LTA revealed only a 3% transition from the ‘no SpA’ to the ‘at-risk’ class from baseline to 2 years with all other participants remaining in their initially assigned class. Sensitivity analysis on 384 participants with complete data at both baseline and 2 years showed similar results, underlining the model’s robustness.Conclusions Transitions between the four classes over 2 years were basically inexistent, highlighting the unlikelihood of developing new class-defining features of axSpA after an initial clinical workup.

Summary: Monoclonal antibodies are important cancer medicines. The European Medicines Agency (EMA) approved 48 and the Food and Drug Administration (FDA) 56 anticancer monoclonal antibody-based therapies. Their high prices burden healthcare systems and hamper global drug access. Biosimilars could retain costs and expand the availability of monoclonal antibodies. In Europe, five rituximab biosimilars, six trastuzumab biosimilars, and eight bevacizumab biosimilars are available as anti-cancer drugs. To gain insight into the biosimilar landscape for cancer treatment, we performed a literature search and analysis. In this review, we summarize cancer monoclonal antibodies’ properties crucial for the desired pharmacology and point out sources of variability. The analytical assessment of all EMA-approved bevacizumab biosimilars is highlighted to illustrate this variability. The global landscape of investigational and approved biosimilars is mapped, and the challenges for access to cancer biosimilars are identified.

Objective European Alliance of Associations for Rheumatology (EULAR) task forces (TF) requires participation of ≥2 junior members, a health professional in rheumatology (HPR) and two patient research partners for the development of recommendations or points to consider. In this study, participation of these junior and representative members was compared with the one of traditional TF members (convenor, methodologist, fellow and expert TF members).Methods An online survey was developed and emailed to previous EULAR TF members. The survey comprised multiple-choice, open-ended and 0–100 rating scale (fully disagree to fully agree) questions.Results In total, 77 responded, 48 (62%) women. In total, 46 (60%) had participated as a junior or representative TF member. Most junior/representative members reported they felt unprepared for their first TF (10/14, 71%). Compared with traditional members, junior/representative members expressed a significantly higher level of uncertainty about their roles within the TF (median score 23 (IQR 7.0–52.0) vs 7 (IQR 0.0–21.0)), and junior/representative members felt less engaged by the convenor (54% vs 71%). Primary factors that facilitated interaction within a TF were experience, expertise and preparation (54%), a supportive atmosphere (42%) and a clear role (12%).Conclusion Juniors, patients and HPR experience various challenges when participating in a EULAR TF. These challenges differ from and are generally less pronounced than those experienced by traditional TF members. The convenor should introduce the participants to the tasks, emphasise the value of their contributions and how to prepare accordingly for the TF meeting.

Immuno-positron emission tomography (immunoPET) enables imaging of specific targets that play a role in targeted therapy and immunotherapy, such as antigens on cell membranes, targets in the disease microenvironment, or immune cells. The most common immunoPET applications use a monoclonal antibody labeled with a relatively long-lived positron emitter such as 89Zr (T1/2 = 78.4 h), but smaller antibody-based constructs labeled with various other positron emitting radionuclides are also being investigated. This molecular imaging technique can thus guide the development of new drugs and may have a pivotal role in selecting patients for a particular therapy. In early phase immunoPET trials, multiple imaging time points are used to examine the time-dependent biodistribution and to determine the optimal imaging time point, which may be several days after tracer injection due to the slow kinetics of larger molecules. Once this has been established, usually only one static scan is performed and semi-quantitative values are reported. However, total PET uptake of a tracer is the sum of specific and nonspecific uptake. In addition, uptake may be affected by other factors such as perfusion, pre-/co-administration of the unlabeled molecule, and the treatment schedule. This article reviews imaging methodologies used in immunoPET studies and is divided into two parts. The first part summarizes the vast majority of clinical immunoPET studies applying semi-quantitative methodologies. The second part focuses on a handful of studies applying pharmacokinetic models and includes preclinical and simulation studies. Finally, the potential and challenges of immunoPET quantification methodologies are discussed within the context of the recent technological advancements provided by long axial field of view PET/CT scanners.

Background: The Computed Tomography Syndesmophyte Score (CTSS) was developed as a reliable and sensitive tool to assess syndesmophytes in low-dose CT images of the entire spine in patients with axial spondyloarthritis (axSpA). The original paper provided sparce examples of the CTSS grades.Objectives: Provide an atlas tailored to assist readers in understanding and employing the CTSS method.Methods: In this paper, illustrations of the different grades and views of the CTSS are presented. CTSS is used to measure bone formation in the spine of patients with axial spondyloarthritis (axSpA), in the form of syndesmophytes. In both the sagittal and coronal planes, syndesmophytes can be graded from 0 to 3 over 23 vertebral units starting at C2 and ending at S1. The CTSS ranges from 0 (absence of axSpA-related syndesmophytes) to 552 (total ankylosis of the spine).Results: The current atlas contains low-dose CT images of the spine without lesions (for reference) and all grades of syndesmophytes in different planes used in the CTSS. Examples are arranged per spinal segment (cervical, thoracic and lumbar).Conclusions: These images can be used to assist any reader in the assessment of syndesmophytes on (low-dose) CT in patients with axSpA.

Abstract Objectives To analyse whether time-varying treatment with tumour necrosis factor inhibitors (TNFi) in radiographic axial spondyloarthritis (r-axSpA) has a differential impact on structural damage progression on different spinal segments (cervical versus lumbar spine). Methods Patients with r-axSpA in the Swiss Clinical Quality Management cohort were included if cervical and lumbar radiographs were available at intervals of 2 years for a maximum of 10 years. Paired radiographs were scored by two calibrated readers according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The relationship between TNFi use and progression in the cervical and the lumbar spine was analysed using generalised estimating equation models and adjustment for potential confounding. Radiographic progression per spinal segment was defined as an increase of ≥ 1 mSASSS unit or by the formation of ≥ 1 new syndesmophyte over 2 years. Results Mean ± SD symptom duration was 13.8 ± 9.8 years. Mean ± SD mSASSS progression per radiographic interval was 0.41 ± 1.69 units in the cervical spine and 0.45 ± 1.45 units in the lumbar spine (p = 0.66). Prior use of TNFi significantly reduced the odds of progression in the cervical spine by 68% (OR 0.32, 95% CI 0.14–0.72), but not in the lumbar spine (OR 0.99, 95% CI 0.52–1.88). A more restricted inhibition of progression in the lumbar spine was confirmed after multiple imputation of missing covariate data (OR 0.43, 95% CI 0.24–0.77 and 0.85, 95% CI 0.51–1.41, for the cervical and lumbar spine, respectively). It was also confirmed with progression defined as formation of ≥ 1 syndesmophyte (OR 0.31, 95% CI 0.12–0.80 versus OR 0.56, 95% CI 0.26–1.24 for the cervical and lumbar spine, respectively). Conclusion Disease modification by treatment with TNFi seems to more profoundly affect the cervical spine in this r-axSpA population with longstanding disease. Site-specific analysis of spinal progression might, therefore, improve detection of disease modification in clinical trials in axSpA.

Background To examine radiographic axial damage of the sacroiliac joints and spine in patients with psoriatic arthritis (PsA) and spondyloarthritis (SpA) in private and academic Belgian practices.Methods Patients with PsA with clinical diagnosis of PsA and fulfilling the Classification Criteria for Psoriatic Arthritis from the prospective Belgian Epidemiological Psoriatic Arthritis Study and patients with SpA fulfilling the Assessment of SpondyloArthritis international Society classification criteria for SpA originate from the Ghent and BelGian Inflammatory Arthritis and spoNdylitis cohorTs were included in this study. Baseline pelvic and spinal radiographs were analysed by two calibrated readers. Blinded for the origin of the cohort or clinical data readers assessed the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) and modified New York criteria on spinal and pelvic radiographs, respectively. Data were compared between both patient groups.Results Of the 525 patients included (312 PsA and 213 SpA), most patients showed normal spinal radiographs: 87.5% of the patients with PsA and 92.0% of the patients with SpA. Patients with SpA with spinal damage show higher mSASSS than the patients with PsA (p

Abstract [177Lu]Lu-DOTA-NNV003, a radioimmunoconjugate targeting CD37, is developed as novel radioimmunotherapy (RIT) treatment for patients with B cell non-Hodgkin’s lymphoma (NHL). Since patients are at risk for developing hematological toxicities due to CD37 expression on normal B cells, we aimed to develop 89Zr-labeled NNV003 for positron emission tomography (PET) imaging as a surrogate tool to predict [177Lu]Lu-DOTA-NNV003 RIT whole-body distribution and tumor uptake. NNV003 antibody was first radiolabeled with 89Zr. [89Zr]Zr-N-sucDf-NNV003 tumor uptake was evaluated by PET imaging of mice bearing human CD37-expressing REC1 B cell NHL or RAMOS Burkitt’s lymphoma xenograft tumors followed by ex vivo analysis. Finally, CD37-targeting of [89Zr]Zr-N-sucDf-NNV003 and [177Lu]Lu-DOTA-NNV003 RIT were compared. [89Zr]Zr-N-sucDf-NNV003 accumulated in REC1 tumors over time, which was not observed for non-specific, 111In-labeled IgG control molecule. In RAMOS tumor-bearing mice, [89Zr]Zr-N-sucDf-NNV003 tumor uptake was higher than [111In]In-DTPA-IgG at all tested tracer protein doses (10 µg, 25 µg and 100 µg; P

BackgroundThe use of social media in health care may serve as a beneficial tool for education, information dissemination, telemedicine, research, networking, and communications. To better leverage the benefits of social media, it is imperative to understand the patterns of its use and potential barriers to its implementation in health care. A previous study in 2016 that investigated social media use among young clinical rheumatologists (≤45 years) and basic scientists showed that there was substantial social media use among them for social and professional reasons. However, there is a limited inquiry into social media use in different areas of rheumatology, such as spondyloarthritis. ObjectiveWe aimed to explore the motivations, barriers, and patterns of social media use among an international group of experts in spondyloarthritis. MethodsWe distributed a web-based survey via email from March 2021 to June 2021 to 198 members of the Assessment of Spondyloarthritis International Society. It contained 24 questions about demographic characteristics, patterns of current social media use, and perceptions of utility. Univariable and multivariable logistic regression analyses were performed to identify the characteristics associated with use trends. ResultsThe response rate was 78.8% (156/198). Of these, 93.6% (146/156) of participants used at least one social media platform. Apart from internet-based shopping and entertainment, the use of social media for clinical updates (odds ratio [OR] 6.25, 95% CI 2.43-16.03) and research updates (OR 3.45, 95% CI 1.35-8.78) were associated with higher social media consumption. Among the respondents, 66% (103/156) used social media in a work-related manner. The use of social media for new web-based resources (OR 6.55, 95% CI 2.01-21.37), interaction with international colleagues (OR 4.66, 95% CI 1.21-17.90), and establishing a web-based presence (OR 4.05, 95% CI 1.25-13.13) were associated with higher levels of consumption for work-related purposes. Time investment, confidentiality concerns, and security concerns were the top 3 challenges to a wider adoption of social media. ConclusionsMost respondents (103/156, 66%) use social media in a work-related manner. Professional development, establishing a web-based presence, and international collaboration were associated with higher use. Challenges to social media adoption should be addressed to maximize its benefits.

The advent of immune checkpoint inhibitors has reinvigorated the field of immuno-oncology. These monoclonal antibody-based therapies allow the immune system to recognize and eliminate malignant cells. This has resulted in improved survival of patients across several tumor types. However, not all patients respond to immunotherapy therefore predictive biomarkers are important. There are only a few Food and Drug Administration-approved biomarkers to select patients for immunotherapy. These biomarkers do not consider the heterogeneity of tumor characteristics across lesions within a patient. New molecular imaging tracers allow for whole-body visualization with positron emission tomography (PET) of tumor and immune cell characteristics, and drug distribution, which might guide treatment decision making. Here, we summarize recent developments in molecular imaging of immune checkpoint molecules, such as PD-L1, PD-1, CTLA-4, and LAG-3. We discuss several molecular imaging approaches of immune cell subsets and briefly summarize the role of FDG-PET for evaluating cancer immunotherapy. The main focus is on developments in clinical molecular imaging studies, next to preclinical studies of interest given their potential translation to the clinic.

Purpose: As one of the five concrete actions recommended for implementing sustainable development at universities (internal operations, institutional framework, research, education and capacity building), capacity building has received the least research attention. Although capacity building can be a tangible implementation of outreach that offers empowerment to universities, it is currently unclear how capacity building can be operationalised in concrete activities and which parties represent the university and the community. The purpose of this study is to provide the idea that capacity building can be organised through student training projects. Design/methodology/approach: To provide support for our suggestion that student training projects can act as an implementation method for capacity building, an illustrative case study is presented. The case study concerns an academic consultancy training project for students in the domain of sustainable development. Findings: The case study analysis reveals that, as an implementation method, student training projects can provide benefits for both universities and communities. It appears that student training projects do not depend on individual engagement, on individual university staff members or on research grants and that they provide community members with access to resources, expertise and experiences of academics. Moreover, student training projects overcome the major challenges of both power distance and continuity. Originality/value: To summarise, student training projects may provide a new, promising avenue as an implementation method for capacity building that provides substantial benefits and overcomes the challenges of other methods mentioned in the existing literature.

(1) Introduction: Pharmacokinetic boosting of kinase inhibitors can be a strategy to enhance drug exposure and to reduce dose and associated treatment costs. Most kinase inhibitors are predominantly metabolized by CYP3A4, enabling boosting using CYP3A4 inhibition. Kinase inhibitors with food enhanced absorption can be boosted using food optimized intake schedules. The aim of this narrative review is to provide answers to the following questions: Which different boosting strategies can be useful in boosting kinase inhibitors? Which kinase inhibitors are potential candidates for either CYP3A4 or food boosting? Which clinical studies on CYP3A4 or food boosting have been published or are ongoing? (2) Methods: PubMed was searched for boosting studies of kinase inhibitors. (3) Results/Discussion: This review describes 13 studies on exposure boosting of kinase inhibitors. Boosting strategies included cobicistat, ritonavir, itraconazole, ketoconazole, posaconazole, grapefruit juice and food. Clinical trial design for conducting pharmacokinetic boosting trials and risk management is discussed. (4) Conclusion: Pharmacokinetic boosting of kinase inhibitors is a promising, rapidly evolving and already partly proven strategy to increase drug exposure and to potentially reduce treatment costs. Therapeutic drug monitoring can be of added value in guiding boosted regimens.

Abstract Background Limited information is available on the impact of treatment with a tumor necrosis factor inhibitor (TNFi) on structural lesions in patients with recent-onset axial spondyloarthritis (axSpA). We compared 2-year structural lesion changes on magnetic resonance imaging (MRI) in the sacroiliac joints (SIJ) of patients with recent-onset axSpA receiving etanercept in a clinical trial (EMBARK) to similar patients not receiving biologics in a cohort study (DESIR). We also evaluated the relationship between the Ankylosing Spondylitis Disease Activity Score (ASDAS) and change in MRI structural parameters. Methods The difference between etanercept (EMBARK) and control (DESIR) in the net percentage of patients with structural lesion change was determined using the SpondyloArthritis Research Consortium of Canada SIJ Structural Score, with and without adjustment for baseline covariates. The relationship between sustained ASDAS inactive disease, defined as the presence of ASDAS

Macrophages can promote tumor development. Preclinically, targeting macrophages by colony-stimulating factor 1 (CSF1)/CSF1 receptor (CSF1R) monoclonal antibodies (mAbs) enhances conventional therapeutics in combination treatments. The physiological distribution and tumor uptake of CSF1R mAbs are unknown. Therefore, we radiolabeled a murine CSF1R mAb and preclinically visualized its biodistribution by PET. CSF1R mAb was conjugated to N-succinyl-desferrioxamine (N-suc-DFO) and subsequently radiolabeled with zirconium-89 (89Zr). Optimal protein antibody dose was first determined in non-tumor-bearing mice to assess physiological distribution. Next, biodistribution of optimal protein dose and 89Zr-labeled isotype control was compared with PET and ex vivo biodistribution after 24 and 72 h in mammary tumor-bearing mice. Tissue autoradiography and immunohistochemistry determined radioactivity distribution and tissue macrophage presence, respectively. [89Zr]Zr-DFO-N-suc-CSF1R-mAb optimal protein dose was 10 mg/kg, with blood pool levels of 10 ± 2% injected dose per gram tissue (ID/g) and spleen and liver uptake of 17 ± 4 and 11 ± 4%ID/g at 72 h. In contrast, 0.4 mg/kg of [89Zr]Zr-DFO-N-suc-CSF1R mAb was eliminated from circulation within 24 h; spleen and liver uptake was 126 ± 44% and 34 ± 7%ID/g, respectively. Tumor-bearing mice showed higher uptake of [89Zr]Zr-DFO-N-suc-CSF1R-mAb in the liver, lymphoid tissues, duodenum, and ileum, but not in the tumor than did 89Zr-labeled control at 72 h. Immunohistochemistry and autoradiography showed that 89Zr was localized to macrophages within lymphoid tissues. Following [89Zr]Zr-DFO-N-suc-CSF1R-mAb administration, tumor macrophages were almost absent, whereas isotype-group tumors contained over 500 cells/mm2. We hypothesize that intratumoral macrophage depletion by [89Zr]Zr-DFO-N-suc-CSF1R-mAb precluded tumor uptake higher than 89Zr-labeled control. Translation of molecular imaging of macrophage-targeting therapeutics to humans may support macrophage-directed therapeutic development.

Various lines of research have hinted at the existence of multiple forms of self-conscious emotion pride. Thus far, it is unclear whether forms, such as self-pride, group-pride, or vicarious-pride are characterized by a similar feeling of pride, and what the communal and unique aspects are of their subjective experiences. The current research addressed this issue and examined the communal and unique characteristics of the subjective experiences of self-pride, group-pride, and vicarious-pride. Using recalled experiences, two experiments demonstrated that self-pride, group-pride, and vicarious-pride could be separated on the basis of their subjective experiences. More specifically, Experiment 2 demonstrated how self-pride, group-pride, and vicarious-pride were related to feelings of self-inflation, other-distancing vs. approaching, and other-devaluation vs. valuation. Finally, Experiment 3 showed that not only the responsibility for the achievement but also the number of people who had contributed to the achievement could influence the experience of other-oriented forms of pride. The current findings revealed that self-pride, group-pride, and vicarious-pride were all forms of pride with distinct subjective experiences. These findings provided valuable insights into the emotion of pride and might lead to divergent consequences for sociality, self-consciousness, and behavior.

To reduce food waste, it is essential to motivate consumers to purchase and consume products that deviate from optimality on the basis of only cosmetic specifications (also called suboptimal products). Previous research has shown it to be challenging to motivate consumers to buy such suboptimal products. Sustainability or authenticity positioning of suboptimal products may be a promising avenue, but no research to date has examined their effects on consumer behaviour. The current research examines whether sustainability and/or authenticity positioning increase the sales of suboptimal products and whether these strategies increase suboptimal product perceptions up to the level of optimal products. Two field experiments examined whether sustainability and authenticity positioning could increase the sales of suboptimal products in two settings: a daily market and a supermarket. They reveal that both types of positioning can increase the sales of suboptimal products. Moreover, in an online experiment, consumers were presented with suboptimal and optimal products with sustainability, authenticity, information, or no positioning, and consumers indicated their perceptions of and purchase intentions for suboptimal and optimal products. It demonstrates that the strategies motivate consumers to perceive suboptimal products as more similar to optimal products and can increase purchase intentions for suboptimal products. Together, these findings suggest that sustainability and authenticity positioning of suboptimal products can support the fight against food waste.

Abstract Background Molecular imaging of immune cells might be a potential tool for response prediction, treatment evaluation and patient selection in inflammatory diseases as well as oncology. Targeting interleukin-2 (IL2) receptors on activated T-cells using positron emission tomography (PET) with N-(4-[18F]fluorobenzoyl)-interleukin-2 ([18F]FB-IL2) could be such a strategy. This paper describes the challenging translation of the partly manual labeling of [18F]FB-IL2 for preclinical studies into an automated procedure following Good Manufacturing Practices (GMP), resulting in a radiopharmaceutical suitable for clinical use. Methods The preclinical synthesis of [18F]FB-IL2 was the starting point for translation to a clinical production method. To overcome several challenges, major adaptations in the production process were executed. The final analytical methods and production method were validated and documented. All data with regards to the quality and safety of the final drug product were documented in an investigational medicinal product dossier. Results Restrictions in the [18F]FB-IL2 production were imposed by hardware configuration of the automated synthesis equipment and by use of disposable cassettes. Critical steps in the [18F]FB-IL2 production comprised the purification method, stability of recombinant human IL2 and the final formulation. With the GMP compliant production method, [18F]FB-IL2 could reliably be produced with consistent quality complying to all specifications. Conclusions To enable the use of [18F]FB-IL2 in clinical studies, a fully automated GMP compliant production process was developed. [18F]FB-IL2 is now produced consistently for use in clinical studies.

Abstract Objective The aim of this study was to compare radiographic progression in patients with ankylosing spondylitis (AS) treated for up to 2 years with secukinumab (MEASURE 1) with a historical cohort of biologic-naïve patients treated with NSAIDs (ENRADAS). Methods Baseline and 2-year lateral cervical and lumbar spine radiographs were independently evaluated using mSASSS by two readers, who were blinded to the chronology and cohort of the radiographs. The primary endpoint was the proportion of patients with no radiographic progression (mSASSS change ≤ 0 from baseline to year 2). The Primary Analysis Set included patients with baseline (≤ day 30) and post-baseline day 31–743 radiographs. Sensitivity analyses were performed to assess the robustness of the comparison between the two cohorts, as follows: Sensitivity Analysis Set 1 included all patients with baseline (≤ day 30) and year 2 (days 640–819) radiographs; Sensitivity Analysis Set 2 included all patients with baseline and post-baseline (> day 30) radiographs. Results A total of 168 patients (84%) from the MEASURE 1 cohort and 69 (57%) from the ENRADAS cohort qualified for the Primary Analysis Set. Over 2 years, the LS (SE) mean change from baseline in mSASSS for the primary analysis was 0.55 (0.139) for MEASURE 1 vs 0.89 (0.216) for ENRADAS (p = 0.1852). Mean changes from baseline in mSASSS were lower in MEASURE 1 vs ENRADAS for the primary and sensitivity analyses. The proportion of patients with no radiographic progression was consistently higher in the MEASURE 1 vs ENRADAS cohort across all cutoffs for no radiographic progression (change in mSASSS from baseline to year 2 of ≤ 0, ≤ 0.5, ≤ 1, and ≤ 2), but the differences were not statistically significant. Conclusion Secukinumab-treated patients demonstrated a numerical, but statistically non-significant, higher proportion of non-progressors and lower change in mSASSS over 2 years versus a cohort of biologic-naïve patients treated with NSAIDs.

Due to ethical and practical reasons, a knowledge gap exists on the pharmacokinetics (PK) of inflammatory bowel disease (IBD)-related drugs in pregnant women with IBD. Before evidence-based dosing can be proposed, insight into the PK has to be gained to optimize drug therapy for both mother and fetus. This systematic review aimed to describe the effect of pregnancy and IBD on the PK of drugs used for IBD. One aminosalicylate study, two thiopurine studies and twelve studies with biologicals were included. Most drugs within these groups presented data over multiple moments before, during and after pregnancy, except for mesalazine, ustekinumab and golimumab. The studies for mesalazine, ustekinumab and golimumab did not provide enough data to demonstrate an effect of pregnancy on concentration and PK parameters. Therefore, no evidence-based dosing advice was given. The 6-thioguanine nucleotide levels decreased during pregnancy to 61% compared to pre-pregnancy levels. The potentially toxic metabolite 6-methylmercaptopurine (6-MMP) increased to maximal 209% of the pre-pregnancy levels. Although the PK of the thiopurines changed throughout pregnancy, no evidence-based dosing advice was provided. One study suggested that caution should be exercised when the thiopurine dose is adjusted, due to shunting 6-MMP levels. For the biologicals, infliximab levels increased, adalimumab stayed relatively stable and vedolizumab levels tended to decrease during pregnancy. Although the PK of the biologicals changed throughout pregnancy, no evidence-based dosing advice for biologicals was provided. Other drugs retrieved from the literature search were mesalazine, ustekinumab and golimumab. We conclude that limited studies have been performed on PK parameters during pregnancy for drugs used in IBD. Therefore, more extensive research to determine the values of PK parameters is warranted. After gathering the PK data, evidence-based dosing regimens can be developed.

Background To better predict response to immune checkpoint therapy and toxicity in healthy tissues, insight in the in vivo behavior of immune checkpoint targeting monoclonal antibodies is essential. Therefore, we aimed to study in vivo pharmacokinetics and whole-body distribution of zirconium-89 (89Zr) labeled programmed cell death protein-1 (PD-1) targeting pembrolizumab with positron-emission tomography (PET) in humanized mice.Methods Humanized (huNOG) and non-humanized NOG mice were xenografted with human A375M melanoma cells. PET imaging was performed on day 7 post 89Zr-pembrolizumab (10 µg, 2.5 MBq) administration, followed by ex vivo biodistribution studies. Other huNOG mice bearing A375M tumors received a co-injection of excess (90 µg) unlabeled pembrolizumab or 89Zr-IgG4 control (10 µg, 2.5 MBq). Tumor and spleen tissue were studied with autoradiography and immunohistochemically including PD-1.Results PET imaging and biodistribution studies showed high 89Zr-pembrolizumab uptake in tissues containing human immune cells, including spleen, lymph nodes and bone marrow. Tumor uptake of 89Zr-pembrolizumab was lower than uptake in lymphoid tissues, but higher than uptake in other organs. High uptake in lymphoid tissues could be reduced by excess unlabeled pembrolizumab. Tracer activity in blood pool was increased by addition of unlabeled pembrolizumab, but tumor uptake was not affected. Autoradiography supported PET findings and immunohistochemical staining on spleen and lymph node tissue showed PD-1 positive cells, whereas tumor tissue was PD-1 negative.Conclusion 89Zr-pembrolizumab whole-body biodistribution showed high PD-1-mediated uptake in lymphoid tissues, such as spleen, lymph nodes and bone marrow, and modest tumor uptake. Our data may enable evaluation of 89Zr-pembrolizumab whole-body distribution in patients.

Background Bispecific antibodies redirecting T cells to the tumor obtain increasing interest as potential cancer immunotherapy. ERY974, a full-length bispecific antibody targeting CD3ε on T cells and glypican 3 (GPC3) on tumors, has been in clinical development However, information on the influence of T cells on biodistribution of bispecific antibodies, like ERY974, is scarce. Here, we report the biodistribution and tumor targeting of zirconium-89 (89Zr) labeled ERY974 in mouse models using immuno-positron emission tomography (PET) imaging.Methods To study both the role of GPC3 and CD3 on the biodistribution of [89Zr]Zr-N-suc-Df-ERY974, 89Zr-labeled control antibodies targeting CD3 and non-mammalian protein keyhole limpet hemocyanin (KLH) or KLH only were used. GPC3 dependent tumor targeting of [89Zr]Zr-N-suc-Df-ERY974 was tested in xenograft models with different levels of GPC3 expression. In addition, CD3 influence on biodistribution of [89Zr]Zr-N-suc-Df-ERY974 was evaluated by comparing biodistribution between tumor-bearing immunodeficient mice and mice reconstituted with human immune cells using microPET imaging and ex vivo biodistribution. Ex vivo autoradiography was used to study deep tissue distribution.Results In tumor-bearing immunodeficient mice, [89Zr]Zr-N-suc-Df-ERY974 tumor uptake was GPC3 dependent and specific over [89Zr]Zr-N-suc-Df-KLH/CD3 and [89Zr]Zr-N-suc-Df-KLH/KLH. In mice engrafted with human immune cells, [89Zr]Zr-N-suc-Df-ERY974 specific tumor uptake was higher than in immunodeficient mice. Ex vivo autoradiography demonstrated a preferential distribution of [89Zr]Zr-N-suc-Df-ERY974 to T cell rich tumor tissue. Next to tumor, highest specific [89Zr]Zr-N-suc-Df-ERY974 uptake was observed in spleen and lymph nodes.Conclusion [89Zr]Zr-N-suc-Df-ERY974 can potentially be used to study ERY974 biodistribution in patients to support drug development.

OBJECTIVE:To investigate whether spinal radiographic progression relates to structural damage at the sacroiliac level in axial spondyloarthritis (axSpA). METHODS:Patients classified as nonradiographic (nr-) and radiographic (r-) axSpA in the Swiss Clinical Quality Management cohort with radiographs performed every 2 years, scored according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), were included. The relationship between classification status and spinal progression during 2 years was investigated using binomial generalized estimating equations models with adjustment for sex, ankylosing spondylitis disease activity score (ASDAS) and tumour necrosis factor inhibitor treatment. Baseline spinal damage was considered an intermediate variable and included in sensitivity analyses. RESULTS:In total, 88 nr-axSpA and 418 r-axSpA patients contributed to data for 725 radiographic intervals. R-axSpA patients were more frequently male, had a longer disease duration and higher structural damage at baseline. Mean (SD) mSASSS change over 2 years was 0.16 (0.62) units in nr-axSpA and 0.92 (2.78) units in r-axSpA, p = 0.01. Nr-axSpA was associated with a significantly lower progression in 2 years (defined as an increase in ≥2 mSASSS units) in adjusted analyses (OR 0.33, 95%CI 0.13; 0.83), confirmed with progression defined as the formation of ≥1 syndesmophyte. Mediation analyses revealed that sacroiliitis exerted its effect on spinal progression indirectly by being associated with the appearance of a first syndesmophyte (OR 0.09, 95%CI 0.02; 0.36 for nr-axSpA vs r-axSpA). Baseline syndesmophytes were predictors of further progression. CONCLUSION:Spinal structural damage is mainly restricted to patients with r-axSpA, leading to relevant prognostic and therapeutic implications.

This review describes acetaminophen pharmacokinetics (PK) throughout pregnancy, as analyzed by three methods (non-compartmental analyses (NCA), population PK, and physiologically based PK (PBPK) modelling). Eighteen studies using NCA were reported in the scientific literature. These studies reported an increase in the volume of distribution (3.5–60.7%) and an increase in the clearance (36.8–84.4%) of acetaminophen in pregnant women compared to non-pregnant women. Only two studies using population PK modelling as a technique were available in the literature. The largest difference in acetaminophen clearance (203%) was observed in women at delivery compared to non-pregnant women. One study using the PBPK technique was found in the literature. This study focused on the formation of metabolites, and the toxic metabolite N-acetyl-p-benzoquinone imine was the highest in the first trimester, followed by the second and third trimester, compared with non-pregnant women. In conclusion, this review gave an overview on acetaminophen PK changes in pregnancy. Also, knowledge gaps, such as fetal and placenta PK parameters, have been identified, which should be explored further before dosing adjustments can be suggested on an evidence-based basis.

Employing an epistemology of situated knowledges, I analyze Aspie (from: Asperger's) supremacy. This ideology consists of an interplay between anti-autistic ableism, and the frame of the Aspie subject as superior, both to other autistics and to non-autistics. This superiority is defined in terms of whiteness, masculinity and economic worthiness. I link this ideology to recent research into the collaboration of Hans Asperger with a Nazi program that involved the killing of disabled individuals. I also discuss contemporary (media) manifestations of Aspie supremacy. Furthermore, I draw a parallel between this ideology and a Lyotardian postmodernism. This type of postmodernism has been criticized for its inability to justify itself on its own terms. Through analyzing Aspie supremacy, I work through this paradox, as it relates to posthumanism.

En la siguiente investigación se construyó una propuesta metodológica para facilitar la socialización de un estu diante con síndrome de Asperger con sus compañeros de clase en una sección de octavo año de un colegio del circuito 01 de heredia. Para ello, se comenzó por indagar bibliográficamente sobre las características de dicho síndrome, así como posibles métodos para mejorar la calidad de vida de estas personas. Se realizaron varias observaciones para conocer el comportamiento del estudiante con síndrome de Asperger, así como las técnicas utilizadas por la educadora de ciencias de octavo año para identificar cómo éstas motivan la participación de dicho estudiante. Además, se aplicaron entrevistas hacia la psicóloga de la institución educativa y hacia estudiantes de dicha sección de octavo año, incluyendo al estudiante con síndrome de Asperger, para crear un perfil de éste. Con los datos bibliográficos, de las observaciones y de las entrevistas se elaboró la propuesta metodológica.

15-Deoxy-Δ12,14-prostaglandin-J2 (15d-PGJ2), a peroxisome proliferator-activated receptor γ (PPARγ) agonist, induces cell death in tumor cells in vitro; however, no study showed its in vivo effect on tumors. Here, we report that 15d-PGJ2 shows antitumor effects in vivo in mice. However, its effects correlate with tumor uptake of albumin, to which it reversibly binds. 15d-PGJ2 induces cell death in B16F10 melanoma and C26 colon carcinoma cells in vitro. These effects were not elicited through PPARγ-dependent pathways because an irreversible PPARγ antagonist GW9662 did not inhibit these effects. Caspase- and nuclear factor κB- (NF-κB) dependent pathways were found to be involved as determined with caspase-3/7 fluorescent assay and NF-κB containing plasmid transfection assay, respectively. Noticeably, 15d-PGJ2 had significantly stronger effects in C26 cells compared with B16 cells in all assays. However, in vivo, there was no effect on C26 tumors, yet it significantly inhibited the B16 tumor growth in mice by 75%. We found that 15d-PGJ2 rapidly bound to albumin and in vivo albumin greatly distributed to B16 tumors compared with C26 tumors, shown with γ-camera imaging and immunohistochemical staining. Albumin accumulation can be attributed to the large blood vessel diameter in B16 tumors and an enhanced permeability and retention effect. These findings suggest that 15d-PGJ2 can be an effective therapeutic agent for cancer, although its effects seem to be limited to the tumors allowing albumin penetration.