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PurposeResearch in acute care faces many challenges, including enrolment challenges, legal limitations in data sharing, limited funding and lack of singular ownership of the domain of acute care. To overcome these challenges, the Center of Acute Care of the University Medical Center Groningen in the Netherlands, has established a de novo data, image and biobank named ‘Acutelines’.ParticipantsClinical data, imaging data and biomaterials (ie, blood, urine, faeces, hair) are collected from patients presenting to the emergency department (ED) with a broad range of acute disease presentations. A deferred consent procedure (by proxy) is in place to allow collecting data and biomaterials prior to obtaining written consent. The digital infrastructure used ensures automated capturing of all bed-side monitoring data (ie, vital parameters, electrophysiological waveforms) and securely importing data from other sources, such as the electronic health records of the hospital, ambulance and general practitioner, municipal registration and pharmacy. Data are collected from all included participants during the first 72 hours of their hospitalisation, while follow-up data are collected at 3 months, 1 year, 2 years and 5 years after their ED visit.Findings to dateEnrolment of the first participant occurred on 1 September 2020. During the first month, 653 participants were screened for eligibility, of which 180 were approached as potential participants. In total, 151 (84%) provided consent for participation of which 89 participants fulfilled criteria for collection of biomaterials.Future plansThe main aim of Acutelines is to facilitate research in acute medicine by providing the framework for novel studies and issuing data, images and biomaterials for future research. The protocol will be extended by connecting with central registries to obtain long-term follow-up data, for which we already request permission from the participant.Trial registration numberNCT04615065.

Background:Chronic pain is common in rheumatic and musculoskeletal conditions, and a major driver of disability worldwide. Knowledge gaps exist with respect to correct estimates of chronic pain [1], what causes it and how best to manage it [2]. To address this, researchers need validated methods to measure pain in large, representative populations. Though many authors have recognised the potential benefits of paper-based and digital pain manikins [3]–[5], it is unknown to what extent studies have adopted digital manikins as a data collection tool.Objectives:The objective of our review was to identify and characterise published studies that have used digital pain manikins as a data collection tool.Methods:We systematically searched six electronic databases, including Medline, CINAHL, Embase, Scopus, IEEE Xplore digital library, ACM Digital Library, on 3-4 of November 2020 by using a pre-defined search strategy. We included a study in our review if it used a digital manikin for self-reporting any pain aspect (e.g., intensity, type) by people suffering from pain, and if its full text was published in English. We conducted this review by following the PRISMA reporting guidelines and conducted a descriptive synthesis of findings, including manikin-derived outcome measures.Results:Our search yielded 4,685 unique studies. After full text screening of 705 articles, we included 14 studies in our review. Most articles were excluded because they used either paper-based manikins or didn’t include enough details to determine that the manikin was digital (n=386). The majority of included studies were published in Europe (n=11). Most studies collected data on a manikin once (n=11); from people with pain conditions (n=9); and in clinical settings (n=9). There was only one study that collected digital pain manikin data in a large sized (i.e., ~20,000) population-based survey.In most studies participants shaded any painful area on manikin (n=9) and did not enable participants to record location-specific pain aspects (n=11). None of the manikins enabled participants to record location-specific pain intensity. Pain distribution (i.e. number or percentage of pre-defined body areas or locations experiencing pain) and pain extent (i.e. number or percentage of shaded pixels) were commonly used manikin-derived outcome measures. In six studies, a heat map was used to summarise the extent of pain across the population.Conclusion:Digital pain manikins have been available since the 1990s but their adoption in research has been slow. Few manikins enabled location-specific pain recording suggesting that the digital nature of the manikin is not yet fully utilised. Future development of a validated digital pain manikin supporting self-reporting of the location and intensity of pain, usable across any device and screen size, may increase uptake and value.References:[1]S. E. E. Mills, K. P. Nicolson, and B. H. Smith, “Chronic pain: a review of its epidemiology and associated factors in population-based studies,” Br. J. Anaesth., vol. 123, no. 2, pp. e273–e283, Aug. 2019.[2]D. B. Reuben et al., “National Institutes of Health Pathways to Prevention Workshop: The Role of Opioids in the Treatment of Chronic Pain,” Ann. Intern. Med., vol. 162, no. 4, p. 295, Feb. 2015.[3]R. Waller, P. Manuel, and L. Williamson, “The Swindon Foot and Ankle Questionnaire: Is a Picture Worth a Thousand Words?,” ISRN Rheumatol., vol. 2012, pp. 1–8, 2012.[4]M. Barbero et al., “Clinical Significance and Diagnostic Value of Pain Extent Extracted from Pain Drawings: A Scoping Review,” Diagnostics, vol. 10, no. 8, p. 604, Aug. 2020.[5]S. M. Ali, W. J. Lau, J. McBeth, W. G. Dixon, and S. N. van der Veer, “Digital manikins to self-report pain on a smartphone: A systematic review of mobile apps,” Eur. J. Pain, vol. 25, no. 2, pp. 327–338, Feb. 2021.Disclosure of Interests:None declared

The poly‐ADP‐ribose polymerase (PARP) is a protein from the family of ADP‐ribosyltransferases that catalyzes polyadenosine diphosphate ribose (ADPR) formation in order to attract the DNA repair machinery to sites of DNA damage. The inhibition of PARP activity by olaparib can cause cell death, which is of clinical relevance in some tumor types. This demonstrates that quantification of PARP activity in the context of living cells is of great importance. In this work, we present the design, synthesis and biological evaluation of photo‐activatable affinity probes inspired by the olaparib molecule that are equipped with a diazirine for covalent attachment upon activation by UV light and a ligation handle for the addition of a reporter group of choice. SDS‐PAGE, western blotting and label‐free LC‐MS/MS quantification analysis show that the probes target the PARP‐1 protein and are selectively outcompeted by olaparib; this suggests that they bind in the same enzymatic pocket. Proteomics data are available via ProteomeXchange with identifier PXD018661., Impair the repair: Olaparib is a PARP inhibitor (PARPi) of clinical relevance because it causes cell death in certain tumor types. By using a substructure of olaparib and adding a photo‐activatable linker, a proteomics assay is presented for visualizing PARP1 with in‐gel fluorescence and MS/MS analysis.

Interpreting evidence in the arteriovenous (AV) access literature is challenged by the heterogeneity in terminology and the lack of standardization in outcomes. Below some of the terms used in this guideline are listed and how they have been interpreted in the context of this document. Because guideline development necessarily relies on aggregate data from systematic reviews and other individual studies, we can only hope to provide the user with conceptual definitions for certain concepts and outcome domains. At present, there is insufficient consensus to go beyond that point and define specific outcome measures or measurements. [...]

AIM: Six Phase III randomized trials have determined the effectiveness of chemoradiotherapy as primary treatment for anal squamous cell carcinoma (ASCC), but outcomes reported in these trials varied widely, hindering evidence synthesis. To improve reporting in all future trials, we aim to develop a core outcomes set (COS). As the first stage of COS development, we undertook a systematic review to summarize the outcomes reported in studies evaluating chemoradiotherapy for ASCC.METHOD: Systematic literature searches identified studies evaluating radiotherapy or chemoradiotherapy for ASCC. Outcomes and accompanying definitions were extracted verbatim and categorized into domains.RESULTS: From 5170 abstracts, we identified 95 eligible studies, reporting 1192 outcomes and 533 unique terms. We collapsed these terms into 86 standardized outcomes and five domains: survival; disease activity; life impact [including quality of life (QoL)]; delivery of care; and toxicity. The most commonly reported domains were survival and disease activity, reported in 74 (86%) and 54 (62%) studies, respectively. No outcome was reported in every publication. Over half (43/86) of the standardized outcome terms were reported in fewer than five studies, and 21 (25%) were reported in a single study only. There was wide variation in definitions of disease-free survival, colostomy-free survival and progression-free survival (PFS). Anal continence was reported in only 35 (41%) studies.CONCLUSION: Outcomes reported in studies evaluating chemoradiotherapy for ASCC were heterogenous and definitions varied widely. Outcomes likely to be important to patients, such as ano-rectal function, toxicity and QoL, have been neglected. A COS for future trials will address these issues.

Background:Patients with long-term conditions (LTCs), including many RMDs, often require continuous management of care. Patient-generated health data (PGHD) collected between visits could inform ongoing care management and provide important insights into patient health and well-being. There is increasing interest in integrating PGHD in electronic health records (EHRs). However, integration is still largely aspirational with limited evidence of successful systems.Objectives:To map the landscape of EHR-integrated remote symptom monitoring systems in the field of LTCs. The objectives were to 1) characterise state of the art systems, 2) describe their clinical use, and 3) outline anticipated and realized benefits for clinical practice.Methods:A systematic search was conducted in three electronic databases up until November 2019. Titles and abstracts were independently screened by two reviewers. One reviewer screened full-text articles, identified those relevant for review and extracted data. Inclusion criteria included 1) symptom reporting systems in adult patients suffering a LTC, 2) integration of data into the EHR, 3) symptom data collected remotely, 4) evidence of use in clinical care. We did not exclude studies based on study design, quality, or sample size. Synthesis focused on describing system specifications and their use. For objective three we adopted a list of outcome indicators [1], which each of the studies were assessed against.Results:The initial search yielded 2040 articles. Only 12 studies reporting on ten unique systems were identified. Two systems were used in rheumatology, but the majority were used in oncology. Systems were highly heterogeneous in terms of technical and functional specifications. Nine systems were fully integrated (data viewable in the EHR) while the remaining system represented a partial integration (data viewable via link in the EHR). Five systems allowed repeated data collection at pre-defined intervals between visits with frequencies varying from daily to monthly. The remaining five made a single request before a scheduled clinic visit. The number of items requested from patients ranged from 9-48 per session. We identified three different clinical workflows: Simple (data only used during consultation, n=5), moderate (real-time alerts for providers when severe symptoms were reported, n=4) and on-demand (patient-initiated visits, n=1). Benefits of symptom reporting from each of the studies were categorised as anticipated, realized quantitative, and realized qualitative. We present summarised counts of these benefits in Figure 1. The most common anticipated benefits were better communication, changes to patient management and improved health outcomes. Most common realized benefits were detecting unrecognised problems and changes to patient management.Figure 1.Summarized counts of benefits from each included study assessed against Chen et al.’s 10 outcome indicators. Categorized in anticipated (orange), realized quantitative (light purple), and realized qualitative benefits (dark purple).Conclusion:There is growing interest and urge for integrating symptom data in the EHR and clinical care. Yet, this review has illustrated that there are limited published efforts to learn from. The heterogeneity in approaches underpins the need for a common framework. There is growing evidence from qualitative work in support of remote symptom-reporting in enabling better and patient-centred care in LTCs. The next step will be for robust, quantitative studies to provide evidence of benefits.References:[1]Chen J, Ou L, Hollis SJ. A systematic review of the impact of routine collection of patient reported outcome measures on patients, providers and health organisations in an oncologic setting. BMC Health Serv Res. 2013 Jun 11;13:211.Disclosure of Interests:Julie de Fonss Gandrup: None declared, Syed Mustafa Ali: None declared, Sabine van der Veer: None declared, John McBeth: None declared, William Dixon Consultant of: Bayer and Google

In the STEPWISE project, the Sorption Enhanced Water-Gas Shift (SEWGS) CO2 capture technology is brought to TRL6 by means of design, construction, operation and modelling a pilot installation in the Iron and Steel industry using actual Blast Furnace Gas (BFG). This advanced CO2 removal technology makes use of regenerative solid adsorbents. The STEPWISE project represents the essential demonstration step within the research, development and demonstration trajectory of the SEWGS technology. This project will further reduce the risks associated with scaling up of the technology. The pilot has been constructed and the initial pilot campaigns have been performed. Major achievements are the demonstration of sorbent production at tonnage scale, robust operation of the pre-shift section at lowered steam conditions, and SEWGS performance at >90% H2S removal efficiency and >90% CO2 capture rate at 90% product purity. Emphasis is currently on 2nd pilot campaign to complete the techno-economic analysis and the life-cycle- assessment studies, costing of a full-size installation and the business plan. The preliminary technical evaluation illustrates that the SPECCA coefficient, illustrating the energy requirement for capture, is below 2 which is around 30% lower than the amine-based case. The LCA indicates that all impact parameters are lower for the STEPWISE cases compared to post combustion amine scrubbing reference case.

Background People living with rheumatoid arthritis (RA) experience continuous, daily symptoms that fluctuate over time. Clinical decisions made by healthcare professionals at intermittent consultations rely upon history taking, which is subject to pitfalls including recall bias, variable help-seeking behaviours and difficulty in summarising fluctuating symptoms. Objectives REmote MOnitoring in Rheumatoid Arthritis (REMORA) was a pilot study to design, implement and evaluate a system of remote data collection for RA patients, for health and research purposes. A unique feature was its aim to integrate patient-generated data from a smartphone app into the electronic health record (EHR). Methods Semi-structured interviews with key stakeholders informed project design and evaluation, comprising three stages: 1) co-design of smartphone app prototype and integration into the electronic patient record (EHR); 2) end-to-end prototype testing (1 month); 3) evaluation of feasibility and acceptability (3 months). Qualitative data from audio-recorded interviews and ‘routine’ consultations, following app use, were coded using a priori and emergent themes, and triangulated. Results Daily, weekly and monthly question sets were developed. Patients tracked daily symptoms for one month (n=8) and three months (n=20). Patients submitted daily scores on most days (median 91% of days; IQR 78%>95%) with 4/20 patients submitting on Data from interviews with 16 patients, 2 clinician-researchers (WD and CAS) and 17 clinical consultations were analysed. Patients and clinicians found remote monitoring acceptable and easy to use. Three themes emerged with REMORA data providing the ‘bigger picture’ by highlighting episodes that might otherwise have been missed, for example short-lived flares and gradual changes in disease; empowering patients through increased self-awareness and improved understanding of RA; and changing the nature of consultations with graphs integrated into the EHR facilitating shared conversations and leading to more personalised care. Conclusions This study demonstrates the acceptability and feasibility of the REMORA system. Novel integration of patient-generated data into the EHR positively impacted consultations and was felt to empower patients. The system generated a unique, temporally-rich research dataset. The next challenge is to scale-up and spread the adoption of this innovation across a range of clinical contexts. Reference [1] Van Der Veer S, Austin L, Sanders C, Dixon W. FRI0175 Using smartphones to improve remote monitoring of rheumatoid arthritis: completeness of patients’ symptom reports. BMJ Publishing Group Ltd2017. Disclosure of Interest None declared

Background Smartphones can facilitate collection of temporally-rich self-reported data, and have proven to enable large recruitment. However, their viability to support epidemiological research is uncertain due to concerns about selection bias and unsustained engagement. Objectives To examine the characteristics and engagement of participants in the first six months of Cloudy with a Chance of Pain, a UK smartphone-based study investigating the link between the weather and chronic pain. Methods Between 20th of January and 29th of February 2016, we recruited UK residents 17 years or older with chronic pain (≥3 months) who owned a smartphone. Participants received prompts from an app developed by uMotif, which they used to daily report the severity of ten pain-related symptoms. Of those who enrolled, those eligible for analysis provided sufficient baseline data to confirm they were ≥17 years old, and at least one symptom. The characteristics of those who were eligible were examined. Engagement per day was defined based on whether participants had completed any of the ten symptoms. Participants were then clustered by their engagement over time using a first-order hidden Markov models. Participant characteristics were then compared between the clusters. Results Of 7972 people who registered to participate, 6370 were eligible. 81% of participants were female, with a mean age of 49 years (SD 12.9). The most common diagnosis was arthritis (40% type unspecified, 19% rheumatoid arthritis), followed by fibromyalgia/chronic widespread pain (24%) and “other pain diagnosis” (23%). We identified four clusters of engagement: high (14%), moderate (22%), low (39%) and tourists (25%). Median days of data entry ranged from 1 (1–1) to 175 (IQR: 152–177) for the tourist and high engagement clusters respectively. Those in the high and moderate clusters (n=2249, 35%) engaged on at least 50% of days in the study (high: 79%; moderate: 50%). Highly engaged participants were older (median 56 (47–63)) when compared to those who were low engagers (47 (39–57)) or tourists (49 (40–58)). A lower proportion of tourists were women (76% (95% CI: 74–78), than in any other cluster (high: 82% (80–85), moderate: 84% (82–86), low: 81% (79–82)). Conclusions Cloudy with a Chance of Pain recruited a large sample of people with chronic pain, of whom over one in three participants engaged in smartphone-based symptom reporting for at least 50% of days in the first six months. Smartphone studies enable quick mass participation with sustained daily data entry, providing unprecedented volumes of daily data. While there may be selection bias towards older females in our study, younger men are also less likely to participate in studies using traditional data collection methods. Our study suggests that smartphones could provide a viable alternative to traditional data collection methods. Disclosure of Interest None declared

Background: Hypertension is a prevalent problem with huge impact on health and health care budgets. Several guidelines on how to manage blood pressure have been published, and it is unclear which one should be preferred.Methods: Eight guidelines dealing with blood pressure management of chronic kidney disease patients were evaluated for methodological quality by the AGREE II instrument by 4 appraisers. They were also analysed for consistency in their recommendations.Results: Most problematic domains were “applicability”, “stakeholder involvement” and “editorial independence”. Three guidelines scored below 50% for 5, and one for 4 of the 6 AGREE II domains. The guideline produced by Canadian Hypertension Education Program was preferred most, followed by KDIGO. There were discrepancies between the different guidelines with regard to blood pressure targets and thresholds, with the best and most recent advocating 140/90 mmHg. There was a consensus on the use of ACE-I/ARB‘s in patients with but not for...

In the STEPWISE project, the Sorption Enhanced Water-Gas Shift (SEWGS) technology for CO 2 capture is brought to TRL6 by means of design, construction, operation and modelling a pilot installation in the Iron and Steel industry using Blast Furnace Gas (BFG). This advanced CO 2 removal technology makes use of regenerative solid adsorbents. The STEPWISE project represents the essential demonstration step within the research, development and demonstration trajectory of the SEWGS technology. This project will further reduce the risks associated with scaling up the process.

Background: In our efforts to develop novel effective treatment regimens for multiple myeloma we evaluated the potential benefits of combining the immunomodulatory drug lenalidomide with daratumumab. Daratumumab is a novel human CD38 monoclonal antibody which kills CD38+ multiple myeloma cells via antibody-dependent cell-mediated cytotoxicity, complement-dependent cytotoxicity and apoptosis. Design and Methods To explore the effect of lenalidomide combined with daratumumab, we first carried out standard antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity assays in which the CD38+ multiple myeloma cell line UM-9 and primary multiple myeloma cells isolated from patients were used as target cells. We also tested the effect of lenalidomide on daratumumab-dependent cell-mediated-cytotoxicity and complement-dependent cytotoxicity of multiple myeloma cells directly in the bone marrow mononuclear cells of multiple myeloma patients. Finally, we determined the daratumumab-dependent cell-mediated cytotoxicity using peripheral blood mononuclear cells of multiple myeloma patients receiving lenalidomide treatment. Results Daratumumab-dependent cell-mediated cytotoxicity of purified primary multiple myeloma cells, as well as of the UM-9 cell line, was significantly augmented by lenalidomide pre-treatment of the effector cells derived from peripheral blood mononuclear cells from healthy individuals. More importantly, we demonstrated a clear synergy between lenalidomide and daratumumab- induced antibody-dependent cell-mediated cytotoxicity directly in the bone marrow mononuclear cells of multiple myeloma patients, indicating that lenalidomide can also potentiate the daratumumab-dependent lysis of myeloma cells by activating the autologous effector cells within the natural environment of malignant cells. Finally, daratumumab-dependent cellmediated cytotoxicity was significantly up-regulated in peripheral blood mononuclear cells derived from 3 multiple myeloma patients during lenalidomide treatment. Conclusions Our results indicate that powerful and complementary effects may be achieved by combining lenalidomide and daratumumab in the clinical management of multiple myeloma

The 13,636 bp mitochondrial (mt) genome sequence of the trichostrongylid nematode Cooperia oncophora was determined. Like the mt genomes of other nematodes it is AT rich (76.75%) and cytidine is the least common nucleoside in the coding strand. There are 2 ribosomal RNA (rrn) genes, 22 transfer RNA (trn) genes and 12 protein coding genes. The relatively short AT-rich region (304 bp) and the lack of a non-coding region between two of the NADH dehydrogenase genes, nad3 and nad5, makes the mt genome of C. oncophora one of the smallest known to date, having only 525 bp of non-coding regions in total. The majority of the C. oncophora protein encoded genes are predicted to end in an abbreviated stop codon like T or TA. In total, 426 single nucleotide polymorphisms (SNP) were mapped on the mt genome of C. oncophora, which is an average of 1 polymorphism per 32 bp. The most common SNPs in the mt genome of C. oncophora were G/A (59.2%) and C/T (28.4%) transitions. Synonymous substitutions (86.4%) were favoured over non-synonymous substitutions. However, the degree of sequence conservation between individual protein genes of different parasitic nematode species did not always correspond to the relative number of non-synonymous SNPs. The mt genome sequence of C. oncophora presents the first mt genome of a member of the Trichostrongyloidea and will be of importance in refining phylogenetic relationships between nematodes. The, still limited, SNP map presented here provides a basis for obtaining insight into the genetic diversity present in the different protein coding genes, trn, rrn and non-coding regions. A more detailed study of the more variable regions will be of use in determining the population genetic structure of C. oncophora. Ultimately this knowledge will add to the understanding of the host-parasite relationship.

After primary infection with 100,000 third stage larvae of the intestinal nematode Cooperia oncophora in 3-month-old calves, a high variability in egg output and worm counts is observed. Based on this variability, infected animals can be divided in different responder types. The three major phenotypes can be classified as high, intermediate and low responder animals. We investigated whether calves classified into different responder types show different immune responses during infection. Peripheral blood eosinophil counts and flow cytometric analysis of different lymphocyte subsets of the blood did not reveal major differences between infected and control animals, nor between responder types. However, the levels of Cooperia-specific immunoglobulin (Ig)G1 and IgA during primary infection were significantly higher in intermediate responders than in low responders. In the intermediate responders, isotype specific responses were negatively correlated with parasitological parameters expressing worm expulsion and influence on worm fecundity. Total serum IgE levels were elevated in most of the infected animals. A quantitative positive relationship between worm counts and total serum IgE levels was observed. Based on the observed correlations, we propose a role for the humoral response against the maintenance of the infection in the gut.

Multiple myeloma (MM) is an incurable malignancy of antibody-producing clonal plasma cells. The mean life expectancy of patients has remained at

CD38, a type II transmembrane glycoprotein highly expressed in hematological malignancies including multiple myeloma (MM), represents a promising target for mAb-based immunotherapy. In this study, we describe the cytotoxic mechanisms of action of daratumumab, a novel, high-affinity, therapeutic human mAb against a unique CD38 epitope. Daratumumab induced potent Ab-dependent cellular cytotoxicity in CD38-expressing lymphoma- and MM-derived cell lines as well as in patient MM cells, both with autologous and allogeneic effector cells. Daratumumab stood out from other CD38 mAbs in its strong ability to induce complement-dependent cytotoxicity in patient MM cells. Importantly, daratumumab-induced Ab-dependent cellular cytotoxicity and complement-dependent cytotoxicity were not affected by the presence of bone marrow stromal cells, indicating that daratumumab can effectively kill MM tumor cells in a tumor-preserving bone marrow microenvironment. In vivo, daratumumab was highly active and interrupted xenograft tumor growth at low dosing. Collectively, our results show the versatility of daratumumab to effectively kill CD38-expressing tumor cells, including patient MM cells, via diverse cytotoxic mechanisms. These findings support clinical development of daratumumab for the treatment of CD38-positive MM tumors.

Lenalidomide alone or in combination with dexamethasone is highly effective in patients with relapsed multiple myeloma following allogeneic stem cell transplantation and increases the frequency of CD4 + Foxp3 + T cells

Chemical or physical modification of DNA may cause an increase in genomic mutations or other genetic alterations, which may ultimately result in the onset of cancer. To avoid these deleterious effects of DNA damage, humans possess DNA repair mechanisms. Decreased DNA repair, induced ex vivo by UV light or ionizing radiation in human peripheral blood lymphocytes (PBLs), has been associated with aging. The aim of this study was to investigate whether repair of DNA damage, after ex vivo exposure of PBLs obtained from smokers (n = 20) to (+/-)-anti-benzo(a)pyrene diolepoxide [(+/-)-anti-BPDE], which is a mixture of reactive metabolites from the environmental carcinogen benzo(a)pyrene, is also associated with age. Furthermore, age-related associations between ex vivo (+/-)-anti-BPDE-induced DNA repair and the frequency of endogenous cytogenetic damage (sister chromatid exchange frequencies and micronuclei frequencies) in PBLs were evaluated. A statistically significant negative association was observed between ex vivo (+/-)-anti-BPDE-induced unscheduled DNA synthesis and age of the donors. Also, parameters of endogenous lymphocytic cytogenetic damage were negatively associated with ex vivo (+/-)-anti-BPDE-induced unscheduled DNA synthesis and positively associated with age in this population. It is concluded that, with increasing age, a decrease in lymphocytic excision repair capacity may be responsible for increased lymphocytic DNA damage in smokers.

Background Keeping track of progress and meeting deadlines can be difficult for organisations that simultaneously develop multiple guidelines involving multiple systematic review teams. Objectives To improve planning, organising and managing of guideline development projects by creating a standardised workflow checklist. Methods In a one-day meeting, the five guideline development methodologists, the chairman and the editorial assistant identified the main steps involved in the guideline development process. For each step, we identified specific tasks and ordered them chronologically. All decisions were made based on group consensus. The identified steps and tasks formed the basic elements of the workflow checklist. Results We identified the need for two separate checklists per guideline development project; one for overall workflow and one for each clinical question covered by the guideline. The overall guideline development workflow checklist comprised 42 tasks organised in 11 sequential steps, including items such as topic selection, composition of the guideline development group, and framing the questions. For each clinical question we identified 27 tasks organised in 8 sequential steps, excluding steps already covered by the overall workflow. Discussion This workflow checklist represents a first step in developing a standardised project management strategy to improve efficient management of the guideline development process. Further development of this tool involves selecting appropriate software for practical implementation applicable not only for our own means but also for those of other groups. Implications for Guideline Developers/Users We believe developing a standardised workflow checklist will improve efficient management of guideline development and allows transparent and up-to-date communication of its progress.

Background The GuideLine Implementability Appraisal (GLIA) instrument has been suggested for identifying potentially remediable implementability issues during the guideline development process. Objective To explore to what extent using GLIA during the development process would result in guideline revision before publication. Methods The development process of the European hyponatremia guideline -coordinated by European Renal Best Practice - was our study context. Using the GLIA web-tool, eleven clinicians and methodologists from eight countries individually appraised 27 guideline statements. In a face-to-face consensus meeting, four GLIA panelists and one guideline development group (GDG) representative summarised potential implementability issues. The GDG discussed these issues, and revised the guideline if deemed necessary. Results We identified 33 issues; the GDG accepted 26 as potentially hampering implementability. This resulted in statement reformulation with (n=5) and without (n=10) influencing clinical content, adding or (re)moving entire statements (n=8), and adding information to tables or rationales (n=3). The majority of issues declined by the GDG (n=7) addressed clinical situations that were covered elsewhere in the guideline or were considered to be uncommon. Discussion Using GLIA during the development process resulted in a revised guideline. We felt that GDG representation in the consensus meeting optimize our appraisal process. Implications for Guideline Developers/Users Guideline organizations may want to consider incorporating GLIA into their development process. This may raise GDGs’ awareness of potential implementability issues, and allow revision of the guideline accordingly prior to publication. Future research should explore the effect of GLIA-based revisions on implementability as assessed by guideline users.

Background Standardised duplicate data extraction and tabulation can be challenging for organisations that develop multiple guidelines involving multiple and remote systematic review teams simultaneously. Objectives To develop a web-based tool for facilitating duplicate data extraction and efficient discrepancy resolution. Methods Based on previous experiences with word-processing and spreadsheet tools, European Renal Best Practice listed their system requirements and collaborated with a consultancy company to identify appropriate customisable software. Results We wanted the system to: be web-based, guide reviewers through a standardised data extraction form, be easy-to-use and manage, allow enough flexibility to accommodate different guideline topics, be free-of-charge and easily accessible from different locations without the need for downloading software. We identified a customer relationship management service, Salesforce, that allowed us to build a data extraction module using their backbone structure. It incorporates centralised management of multiple systematic reviews simultaneously, batch allocation of studies to individual reviewers, guided customised point-and-click data extraction, generation of tables to assist discrepancy resolution with easy export to a cvs-file extension format. Discussion This project represents a continuous effort to facilitate efficient and high-quality systematic reviewing with participation of our guideline development groups throughout the systematic reviewing process. A first version of the system is currently being evaluated. Implications for Guideline Developers/Users Customising existing software for guideline development purposes might be an attractive and inexpensive alternative to developing new tools for data extraction when full participation of the guideline development group in the systematic review process is desired.

Abstract 5106 Multiple myeloma (MM) represents an incurable malignancy of antibody-producing clonal plasma cells. Over the past decade significant progress has been made in MM treatment using novel immunomodulating agents such as lenalidomide (LEN) and bortezomib (BORT). Daratumumab (DARA) is a human CD38 antibody with broad spectrum killing activity. DARA mediates MM cell death via ADCC (antibody dependent cellular cytotoxicity), CDC (complement dependent cytotoxicity) and apoptosis. We are currently exploring the possibility to further improve MM therapy by combining novel MM therapeutics with DARA. Our initial in vitro work already showed significantly improved MM cell killing by combining DARA with LEN and BORT treatment, especially in patient samples which showed poor responses to the LEN-BORT combination. We now investigated whether DARA can also further improve therapy of lenalidomide or bortezomib in combination with corticosteroids. In ex vivo assays, which allow us to address MM cell lysis directly in BM-MNC isolated from MM patients, DARA significantly enhanced killing of MM cells that were treated with LEN or dexamethasone (DEX). Importantly, DARA was also able to enhance lysis of MM cells that were poor responders to the LEN-DEX combination. This suggests that patients might benefit from a DARA-LEN-DEX combination therapy. Experiments showing effects of DARA on killing of BORT-DEX treated cells are currently underway. The results of this study extend our previous results with LEN-BORT-DARA, showing that MM cells lysis is enhanced by DARA, especially in in samples from patients that are refractory or poorly responding to existing and novel emerging combination therapies. These results support the hypothesis that powerful and complementary effects may be achieved when DARA is combined with LEN and cortocosteroids in clinical MM studies. Disclosures: Weers: Genmab: Employment, Equity Ownership, Patents & Royalties. Veer:Genmab: Research Funding. van Kessel:Genmab: Research Funding. Bakker:Genmab: Employment, Equity Ownership. Parren:Genmab: Employment, Equity Ownership, Patents & Royalties. Lokhorst:Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mutis:Genmab: Research Funding.

e18571 Background: Multiple myeloma (MM) represents an incurable malignancy of antibody-producing clonal plasma cells. Over the past decade significant progress has been made in MM treatment using ...

Abstract 3058 Daratumumab (DARA) is a fully human antibody against CD38, a membrane-associated antigen, which is considered to be a highly relevant target for the treatment of hematological malignancies such as multiple myeloma (MM) and chronic lymphocytic leukemia (CLL). DARA has the ability to effectively kill target cells by CDC, ADCC and by induction of apoptosis. While CD38 is frequently overexpressed on MM cells, it has a variable degree of expression on the malignant CLL cells. To gain detailed insight into the potential therapeutic power of DARA in tumors with different CD38 expression levels, we now investigated the correlation between the level of CD38 expression and DARA-induced kill by CDC and ADCC. To this end, we first used the human MM cell lines L363 and UM9, expressing low and intermediate CD38 levels, respectively. While both cell lines could be lysed via ADCC, they were not susceptible to killing via CDC. To delineate a possible correlation between CD38 expression and induction of CDC, we lentivirally transduced the CD38 gene into L363 and UM9 cells to generate cell lines ranging in CD38 expression from 50,000 to 800,000 molecules per cell. Hereby we covered the range of CD38 expression found in CLL and MM patients. The L363 and UM9 cell lines were also transduced with the luciferase-GFP marker genes to enable their in vivo quantitative monitoring by bioluminescence imaging (BLI). In CDC assays, up to 95% lysis of CD38-transduced L363 and UM9 cells was achieved and showed an excellent correlation with the level of CD38 expression (r2=0.90). In ADCC assays, however, killing already reached maximum levels at DARA concentrations as low as 1 ng/ml at the lowest CD38 expression levels tested. These in vitro assays indicated that cell killing via CDC is enhanced with increasing CD38 expression levels, while CDC resistant, low CD38-expressing tumors could be targeted by DARA via ADCC. To explore this in an in vivo setting, we used a newly developed MM model in Rag2−/−gc−/− mice and we inoculated the mice with nontransduced, CD38low, UM9 cells, which can be lysed by ADCC but not by CDC. Treatment of the mice with DARA one day after tumor inoculation completely prevented the outgrowth of these UM9 cells; treatment of established UM9 tumours at week 3 resulted in a significant delay in tumor growth. These results confirmed that the CDC resistant UM9 could be readily targeted by DARA in vivo, possibly via ADCC mediated by monocytes in this model. In vivo experiments with variants that express high levels of CD38 are in progress. Taken together, these in vitro and in vivo data underscore the potency of DARA as a novel antibody for CD38-targeted therapy in hematological malignancies, and warrant further exploration in clinical trials. Disclosures: de Weers: Genmab bv: Employment. Parren:Genmab: Employment.

Abstract 3030 Although multiple myeloma (MM) is considered an incurable malignancy of antibody-producing clonal plasma cells, over the past decade significant progress has been made in MM treatment by the availability of novel immunomodulating agents such as lenalidomide (LEN) and bortezomib (BORT). We are currently exploring the possibility to further improve MM therapy by combining LEN and BORT with novel agents, such as daratumumab (DARA), a human antibody directed against CD38 which mediates MM cell lysis via ADCC (antibody dependent cellular cytotoxicity), CDC (complement dependent cytotoxicity) and apoptosis. Our initial in vitro work show significantly improved MM cell killing by combined DARA with LEN treatment. We now investigated whether further improvement of this combination therapy is possible by addition of BORT. In ex vivo assays, which allow us to address killing directly in BM-MNC isolated from MM patients, we demonstrate that the DARA+LEN+BORT combination significantly exceeds the effectiveness of LEN+BORT treatment (P Disclosures: Veer: GenMab, Utrecht, NL: Research Funding. Weers:Genmab: Employment. Bakker:GenMab, Utrecht, Netherlands: Employment. Parren:Genmab: Employment. Lokhorst:GenMab, Utrecht,NL: Research Funding. Mutis:GenMab, Utrecht, NL: Research Funding.

Abstract 3059 Since its approval by the FDA, lenalidomide (LEN) demonstrates impressive results in patients with newly-diagnosed and relapsed multiple myeloma (MM). Despite these improvements, MM remains incurable, and new innovative treatments need to be developed in efforts to improve long term outcomes. Recently we have developed a new human CD38 antibody, daratumumab (DARA) which mediates MM cell killing via complement dependent cytotoxicity (CDC), antibody dependent cellular cytotoxicity (ADCC) and apoptosis. In the current study we evaluated the potential benefits of combining lenalidomide (LEN) with daratumumab (DARA). We demonstrate that DARA-dependent ADCC of purified primary MM cells, as well as of CD38+ UM 9 MM cells was significantly augmented by pre-treatment of PBMC effector cells with LEN. Importantly, a synergism between LEN and DARA was observed in ex-vivo assays, which allowed us to investigate ADCC directly in whole BM-MNC, thus without isolating MM cells from their natural environment. Interestingly, DARA-induced ADCC was significantly upregulated in PBMC derived from three MM patients who were undergoing LEN treatment. In conclusion, these results support the hypothesis that powerful and complementary effects may be achieved by combining LEN and DARA in clinical MM management. Disclosures: Veer: GenMab, Utrecht: Research Funding. Weers:Genmab: Employment. Bakker:GenMab, Utrecht, Netherlands: Employment. Parren:Genmab: Employment. Lokhorst:GenMab: Research Funding. Mutis:GenMab: Research Funding.

A simple, selective and quantitative estimation of tranylcypromine using liquid chromatography and electrochemical detection with apomorphine as internal standard in human plasma is described. Sample preparation is done by liquid-liquid extraction. The absolute mean recovery of apomorphine is 95%, the recovery of tranylcypromine is 81%. This method gives a simple estimation method to assay plasma concentrations of tranylcypromine in the therapeutic range (5–200 ng/ml) with good reproducibility and linearity.

The restricted use of cellular phones in patient areas in hospitals seems hard to enforce considering the growth in use and the decrease in size of these devices. The electromagnetic incompatibility of the first-generation mobile phones (i.e. GSM) with medical equipment has been described. Information on the safety of new mobile communication technology (second-generation GPRS and third-generation UMTS) is scarce. A recent paper showed minor interference with GRPS and UMTS suggesting improved safety with new networks [1].

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