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AimsDespite general awareness that screening for atrial fibrillation (AF) could reduce health hazards, large-scale implementation is lagging behind technological developments. As the successful implementation of a screening programme remains challenging, this study aims to identify facilitating and inhibiting factors from healthcare providers’ perspectives.Methods and resultsA mixed-methods approach was used to gather data among practice nurses in primary care in the southern region of the Netherlands to evaluate the implementation of an ongoing single-lead electrocardiogram (ECG)-based AF screening programme. Potential facilitating and inhibiting factors were evaluated using online questionnaires (N = 74/75%) and 14 (of 24) semi-structured in-depth interviews (58.3%). All analyses were performed using SPSS 26.0. In total, 16 682 screenings were performed on an eligible population of 64 000, and 100 new AF cases were detected. Facilitating factors included ‘receiving clear instructions’ (mean ± SD; 4.12 ± 1.05), ‘easy use of the ECG-based device’ (4.58 ± 0.68), and ‘patient satisfaction’ (4.22 ± 0.65). Inhibiting factors were ‘time availability’ (3.20 ± 1.10), ‘insufficient feedback to the practice nurse’ (2.15 ± 0.89), ‘absence of coordination’ (54%), and the ‘lack of fitting policy’ (32%).ConclusionLarge-scale regional implementation of an AF screening programme in primary care resulted in a low participation of all eligible patients. Based on the perceived barriers by healthcare providers, future AF screening programmes should create preconditions to fit the intervention into daily routines, appointing an overall project lead and a General Practitioner (GP) as a coordinator within every GP practice.

Background The unpredictability of response to biological therapy in ulcerative colitis (UC) patients, including vedolizumab (VDZ), an anti-α4β7 integrin antibody, poses a serious challenge for medical care. This study aims to identify the relevant cellular and molecular signatures that mark response to VDZ by combining single-cell transcriptomics (scRNAseq) and high-dimensional flow cytometry (Cytek). Methods Gut biopsies and peripheral blood mononuclear cells (PBMCs) from patients with active UC were collected 2 weeks prior and 14 weeks after starting VDZ therapy. Response was evaluated at week 14 based on endoscopy and Physician Global Assessment. Transcriptome profiles of 159.188 and 95.057 high-quality single cells were generated from biopsies and PBMCs, respectively. Additional 797.670 CD45+ mucosal cells and 900.000 PBMCs were processed for validating scRNAseq results by Cytek. Results From a total of 25 UC patients (mean age 41±12.7 years, 52% female, 36% anti-TNFα naive), 15 patients (60%) reached response at week 14. Patients with no prior use of anti-TNFα were more likely to achieve remission with VDZ compared to anti-TNFα exposed patients (89% vs 44% response rate, respectively). Analysis of cell abundances revealed a partial recovery of the epithelial and stromal cell mucosal compartments in responders at week 14. Both scRNAseq and Cytek show that in responders VDZ prevented T cells (CD8+IL17+ and CD4+PD1+ subsets) and innate immune cells (NKs, DCs and inflammatory monocytes) from entering mucosa, resulting in their enrichment in PBMCs. In contrast, non-response to VDZ was marked by an expansion of inflammatory fibroblasts and activated endothelial cells, and depletion of most epithelial subsets. VDZ retained CD4 T cells in PBMCs in non-responders, but failed to halt active mucosal inflammation at week 14. Strikingly, involvement of the innate immune cells in UC inflammation prior to VDZ treatment was much more prominent in non-responders who showed higher baseline abundance of NKs, ILCs, γδ-T cells, DCs and inflammatory monocytes in their peripheral blood and mucosa compared to responders. While VDZ inhibited integrin β7 expression on circulating T cells in all patients, only in responders it coincided with the lower mucosal abundance of lymphocytes, suggesting that T cells in non-responders might employ alternative, β7-independent trafficking routes. Conclusion This is the largest prospective scRNAseq study addressing the response to biological therapy in UC. We showed that active, innate immune cell-mediated inflammation marks the primary non-response to VDZ that persists prior to and throughout the treatment, accompanied by β7-independent lymphocyte migration.

Chemical abundances are an essential tool in untangling the Milky Way's enrichment history. However, the evolution of the interstellar medium abundance gradient with cosmic time is lost as a result of radial mixing processes. For the first time, we quantify the evolution of many observational abundances across the Galactic disk as a function of lookback time and birth radius, $R_\text{birth}$. Using an empirical approach, we derive $R_\text{birth}$ estimates for 145,447 APOGEE DR17 red giant disk stars, based solely on their ages and [Fe/H]. We explore the detailed evolution of 6 abundances (Mg, Ca ($\alpha$), Mn (iron-peak), Al, C (light), Ce (s-process)) across the Milky Way disk using 87,426 APOGEE DR17 red giant stars. We discover that the interstellar medium had three fluctuations in the metallicity gradient $\sim 9$, $\sim 6$, and $\sim4$ Gyr ago. The first coincides with the end of high-$\alpha$ sequence formation around the time of the Gaia-Sausage-Enceladus disruption, while the others are likely related to passages of the Sagittarius dwarf galaxy. A clear distinction is found between present-day observed radial gradients with age and the evolution with lookback time for both [X/Fe] and [X/H], resulting from the significant flattening and inversion in old populations due to radial migration. We find the [Fe/H]--[$\alpha$/Fe] bimodality is also seen as a separation in the $R_\text{birth}$--[X/Fe] plane for the light and $\alpha$-elements. Our results recover the chemical enrichment of the Galactic disk over the past 12 Gyr, providing tight constraints on Galactic disk chemical evolution models., Comment: accepted for publication in MNRAS

Compositional traits in potato [Solanum tuberosum L.] are economically important but genetically complex, often controlled by many loci of small effect; new methods need to be developed to accelerate analysis and improvement of such traits, like chip quality. In this study, we used network analysis to organize hundreds of metabolic features detected by mass spectrometry into groups, as a precursor to genetic analysis. 981 features were condensed into 44 modules; module eigenvalues were used for genetic mapping and correlation analysis with phenotype data collected by the Solanaceae Coordinated Agricultural Project. Half of the modules were associated with at least one SNP according to GWAS; 11 of those modules were also significantly correlated with chip color. Within those modules features associated with chipping provide potential targets for selection in addition to selection for reduced glucose. Loci associated with module eigenvalues were not evenly distributed throughout the genome but were instead clustered on chromosomes 3, 7, and 8. Comparison of GWAS on single features and modules of clustered features often identified the same SNPs. However, features with related chemistries (for example, glycoalkaloids with precursor/product relationships) were not found to be near neighbors in the network analysis and did not share common SNPs from GWAS. Instead, the features within modules were often structurally disparate, suggesting that linkage disequilibrium complicates network analyses in potato. This result is consistent with recent genomic studies of potato showing that chromosomal rearrangements that create barriers to recombination are common in cultivated germplasm.

The study of outer halo globular cluster (GC) populations can give insight into galaxy merging, GC accretion, and the origin of GCs. We use archival Subaru Hyper Suprime-Cam (HSC) data in concert with space-based GALEX, IRAC, and Gaia EDR3 data to select candidate GCs in the outer halo of the M81 group for confirmation and future study. We use a small sample of previously discovered GCs to tune our selection criteria, finding that bright already-known GCs in the M81 group have sizes that are typically slightly larger than the Subaru PSF in our fields. In the optical bands, GCs appear to have colours that are only slightly different from stars. The inclusion of archival IRAC data yields dramatic improvements in colour separation, as the long wavelength baseline aids somewhat in the separation from stars and clearly separates GCs from many compact background galaxies. We show that some previously spectroscopically identified GCs in the M81 group are instead foreground stars or background galaxies. GCs close to M82 have radial velocities, suggesting that they fell into the M81 group along with M82. The overall M81 GC luminosity function is similar to the Milky Way and M31. M81’s outer halo GCs are similar to the Milky Way in their metallicities and numbers, and much less numerous than M31’s more metal-rich outer halo GC population. These properties reflect differences in the three galaxies’ merger histories, highlighting the possibility of using outer halo GCs to trace merger history in larger samples of galaxies.

Cultivated potato is a clonally propagated autotetraploid species with a highly heterogeneous genome. Phased assemblies of six cultivars including two chromosome-scale phased genome assemblies revealed extensive allelic diversity, including altered coding and transcript sequences, preferential allele expression, and structural variation that collectively result in a highly complex transcriptome and predicted proteome, which are distributed across the homologous chromosomes. Wild species contribute to the extensive allelic diversity in tetraploid cultivars, demonstrating ancestral introgressions predating modern breeding efforts. As a clonally propagated autotetraploid that undergoes limited meiosis, dysfunctional and deleterious alleles are not purged in tetraploid potato. Nearly a quarter of the loci bore mutations are predicted to have a high negative impact on protein function, complicating breeder's efforts to reduce genetic load. The StCDF1 locus controls maturity, and analysis of six tetraploid genomes revealed that 12 allelic variants of StCDF1 are correlated with maturity in a dosage-dependent manner. Knowledge of the complexity of the tetraploid potato genome with its rampant structural variation and embedded deleterious and dysfunctional alleles will be key not only to implementing precision breeding of tetraploid cultivars but also to the construction of homozygous, diploid potato germplasm containing favorable alleles to capitalize on heterosis in F1 hybrids.

Purpose: To provide proof of principle of safety, breast tumor–specific uptake, and positive tumor margin assessment of the systemically administered near-infrared fluorescent tracer bevacizumab–IRDye800CW targeting VEGF-A in patients with breast cancer.Experimental Design: Twenty patients with primary invasive breast cancer eligible for primary surgery received 4.5 mg bevacizumab–IRDye800CW as intravenous bolus injection. Safety aspects were assessed as well as tracer uptake and tumor delineation during surgery and ex vivo in surgical specimens using an optical imaging system. Ex vivo multiplexed histopathology analyses were performed for evaluation of biodistribution of tracer uptake and coregistration of tumor tissue and healthy tissue.Results: None of the patients experienced adverse events. Tracer levels in primary tumor tissue were higher compared with those in the tumor margin (P < 0.05) and healthy tissue (P < 0.0001). VEGF-A tumor levels also correlated with tracer levels (r = 0.63, P < 0.0002). All but one tumor showed specific tracer uptake. Two of 20 surgically excised lumps contained microscopic positive margins detected ex vivo by fluorescent macro- and microscopy and confirmed at the cellular level.Conclusions: Our study shows that systemic administration of the bevacizumab–IRDye800CW tracer is safe for breast cancer guidance and confirms tumor and tumor margin uptake as evaluated by a systematic validation methodology. The findings are a step toward a phase II dose-finding study aimed at in vivo margin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in the tumor tissue. Clin Cancer Res; 23(11); 2730–41. ©2016 AACR.

Supplemental Materials and Methods; Suppl. Fig. 1. Comparison of tumor vs. skin fluorescence obtained from human breast tissue specimen; Suppl. Fig 2: Magnified comparison between fluorescence images obtained from 3mm thick paraffin slices and 4microm paraffin slices.

Near-Infrared Optical Imaging of Positive Tumor Margin.

In vivo tumor labeling with fluorescent agents may assist endoscopic and surgical guidance for cancer therapy as well as create opportunities to directly observe cancer biology in patients. However, malignant and nonmalignant tissues are usually distinguished on fluorescence images by applying empirically determined fluorescence intensity thresholds. Here, we report the development of fSTREAM, a set of analytic methods designed to streamline the analysis of surgically excised breast tissues by collecting and statistically processing hybrid multiscale fluorescence, color, and histology readouts toward precision fluorescence imaging. fSTREAM addresses core questions of how to relate fluorescence intensity to tumor tissue and how to quantitatively assign a normalized threshold that sufficiently differentiates tumor tissue from healthy tissue. Using fSTREAM we assessed human breast tumors stained in vivo with fluorescent bevacizumab at microdose levels. Showing that detection of such levels is achievable, we validated fSTREAM for high-resolution mapping of the spatial pattern of labeled antibody and its relation to the underlying cancer pathophysiology and tumor border on a per patient basis. We demonstrated a 98% sensitivity and 79% specificity when using labeled bevacizumab to outline the tumor mass. Overall, our results illustrate a quantitative approach to relate fluorescence signals to malignant tissues and improve the theranostic application of fluorescence molecular imaging. Cancer Res; 77(3); 623–31. ©2016 AACR.

Co-localization of Bevacizumab-IRDye800CW, hematoxylin / eosin (H/E), VEGF-A, Collagen and CD34 in Ductal Carcinoma In Situ (DCIS).

Co-localization of Bevacizumab-IRDye800CW, hematoxylin/eosin (H/E), VEGF-A, Collagen and CD34 in Breast Cancer and a Satellite Lesion.

Supplementary Material and Methods / Legends of Supplemental Figures

Multiplex pathology imaging of white-light microscopy, bevacizumab-IRDye800CW fluorescence imaging (green pseudocolor), VEGF-A (red pseudocolor), collagen (red pseudocolor) and CD34 (blue pseudocolor) in breast cancer, including overlay images is shown in a stepwise manner for reasons of clarity.

Intraoperative and Ex Vivo Optical Imaging of Axillary Lymph Nodes.

Microscopic Biodistribution of Bevacizumab-IRDye800CW

Co-localization of Hematoxylin / Eosin (H/E), VEGF-A, and Bevacizumab-IRDye800CW in Tumor-negative Lymph Nodes.

Representative Fluorescence Flatbed Scans of Paraffin Blocks of all Patients (N=20) and Macroscopic Segmentation of Fluorescence Tissue Localization and Target-to-Background Ratios (TBR).

With its origin coming from several sources (Big Bang, stars, cosmic rays) and given its strong depletion during its stellar lifetime, the lithium element is of great interest as its chemical evolution in the Milky Way is not well understood at present. To help constrain stellar and galactic chemical evolution models, numerous and precise lithium abundances are necessary for a large range of evolutionary stages, metallicities, and Galactic volume. In the age of stellar parametrization on industrial scales, spectroscopic surveys such as APOGEE, GALAH, RAVE, and LAMOST have used data-driven methods to rapidly and precisely infer stellar labels (atmospheric parameters and abundances). To prepare the ground for future spectroscopic surveys such as 4MOST and WEAVE, we aim to apply machine learning techniques to lithium measurements and analyses. We trained a convolution neural network (CNN), coupling Gaia-ESO Survey iDR6 stellar labels (Teff, log(g), [Fe/H], and A(Li)) and GIRAFFE HR15N spectra, to infer the atm parameters and lithium abundances for ~40,000 stars. We show that the CNN properly learns the physics of the stellar labels, from relevant spectral features through a broad range of evolutionary stages and stellar parameters. The Li feature at 6707.8 A is successfully singled out by our CNN, among the thousands of lines. Rare objects such as Li-rich giants are found in our sample. This level of performance is achieved thanks to a meticulously built, high-quality, and homogeneous training sample. The CNN approach is very well adapted for the next generations of spectroscopic surveys aimed at studying (among other elements) lithium, such as the 4MIDABLE-LR/HR (4MOST Milky Way disk and bulge low- and high-resolution) surveys. In this context, the caveats of ML applications should be appropriately investigated, along with the realistic label uncertainties and upper limits for abundances., Comment: A&A, accepted 05 December 2022, 23 pages, 23 figures. Codes and trained models available at https://github.com/SamirNepal/Li\_CNN\_2022

Background In this study, we aimed to identify and define the fundamental components of the working alliance in multidisciplinary (Flexible) Assertive Community Treatment teams with shared caseloads, in order to support their daily practice and further research. Methods After reviewing the literature, concept mapping with professionals and clients was used to define the working alliance in (F) ACT teams. The resulting concept maps formed the basis for the working alliance assessment instrument, which was pilot tested with professionals and clients through cognitive interviews with a think-aloud procedure. Results The study led to the development of a twenty five-item assessment instrument to evaluate working alliances in multidisciplinary teams (WAM) that was comprised of three subscales: bond, task/goal and team. Two different versions were developed for clients and professionals. Conclusions The WAM instrument was developed to determine the quality of the working alliance in (F) ACT teams. Future research will focus on testing its psychometric properties and predictive value.

Social functioning can be severely impaired in non-affective psychotic disorder (NAPD). Current models of psychosis pathogenesis do not tend to focus on social dysfunction and pharmacological treatment fails to ameliorate it. In this article, we propose that mentalization theory provides a valuable contribution to the understanding and treatment of NAPD. Impaired mentalizing may contribute to both positive and negatives symptoms as well as social dysfunction observed in NAPD. Furthermore, impaired mentalizing may help explain the relation between childhood abuse, insecure attachment and psychosis. Mentalization based treatment may contribute to the functional recovery of NAPD patients as it targets the social cognitive processes underlying social interaction. The article includes a description of the principles of MBT in general, specific characteristics of using MBT with patients with NAPD and a clinical vignette to illustrate these principles.

Background Skeletal muscle mass (SMM) loss is common in metastatic colorectal cancer (mCRC) patients and associated with poor clinical outcomes, including increased treatment‐related toxicities and reduced survival. Muscle loss may contribute to reduced health‐related quality of life (HRQoL), including fatigue. Our aim was to study associations between changes in SMM and concomitant changes in patient‐reported HRQoL. Methods This was a secondary analysis of mCRC patients in the CAIRO3 randomized clinical trial who were—after initial treatment—randomized between maintenance treatment with capecitabine plus bevacizumab (CAP‐B) and observation until first disease progression (PD1). Included patients had computed tomography images for SMM quantification, together with HRQoL assessments available at randomization and PD1. Changes in SMM (categorized as >2% loss, stable, and >2% gain) and HRQoL were computed between randomization and PD1. Changes in HRQoL score >10 points were considered clinically relevant. Associations between SMM and HRQoL changes were studied by multiple linear regression models. We also investigated whether associations differed by treatment arm for global health and the 13 other HRQoL subscales. Results Of 221 patients included (mean age 63.5 ± 8.4 years), 24% lost, 27% remained stable, and 49% gained SMM. At randomization, mean global health status was 73.5 ± 15.9 in the CAP‐B arm and 75.1 ± 17.5 in the observation arm (P = 0.48). A stable or gain in SMM was significantly associated with a clinically relevant improvement in global health status (9.9 and 14.7 points, respectively), compared with patients who lost SMM. From the subscales that did not show significant differences between the two treatment arms, we found significant and clinically relevant associations for stable or gain in SMM with improved role functioning (12.0 and 17.9, respectively) and with less fatigue (−10.0 and −15.0, respectively) and pain (−16.3 for SMM gain). From the subscales that did show significantly different associations with SMM between the two treatment arms, we only found significant results in the observation arm. Here, associations were found for stable or gain in SMM with clinically relevant improved physical (12.4 for SMM gain), cognitive (10.7 and 9.7, respectively), and social functioning (15.5 and 15.6, respectively) as well as reduced appetite loss (−28.5 and −30.7, respectively). Conclusions In mCRC, SMM preservation during CAP‐B and observation treatment is associated with significant and clinically relevant improvements in global health status and multiple functional and symptom scales. Studies are warranted to investigate whether interventions targeting SMM lead to improved HRQoL, fewer symptoms, and better functioning.

Gastrectomy with lymph node dissection is the cornerstone of curative treatment of gastric cancer. Extent of lymphadenectomy may differ depending on T-stage, as the rate of lymph node metastases may differ. The objective of this systematic review is to investigate and compare the prevalence of nodal metastases in the individual lymph node stations between different T-stages.Data reporting and structure of this systematic review follows the PRISMA checklist. The Medline and PubMed databases were systematically searched. The search included the following Mesh terms: "Stomach Neoplasms", "Lymphatic Metastasis" and "Lymph Node Excision". The primary outcome was the highest prevalence of nodal metastases per T-stage.The initial search resulted in 175 eligible articles. Five articles met the inclusion criteria and were accordingly analyzed. Concerning the lymph node stations 1 to 7, the lymph nodes along the lesser gastric curvature (station 3) show the highest metastases rate (T1: 5.5%, T2: 21.9%, T3: 41.9%, T4: 71.0%). Concerning the lymph node stations 8 to 20, the lymph nodes around the common hepatic artery (station 8) show the highest metastases rate (T1: 0.8%, T2: 7.9%, T3: 14.0%, T4: 28.2%).An overall low prevalence of nodal metastases in the individual lymph node stations in early, T1 gastric carcinomas and an overall high prevalence in more advanced, T3 and T4 gastric carcinomas endorse a more tailored approach based on the different gastric T-stages. In addition, a less extensive lymphadenectomy seems justified in early T1 carcinoma.This systematic review provides an overview of the prevalence of nodal metastases for the individual lymph node stations between different T-stages, showing an overall low prevalence in early, T1 gastric carcinomas and an overall high prevalence in the more advanced, T3 and T4 gastric carcinomas.

Tuber shape is one of the most important quality traits in potato appearance. Since poor or irregular shape results in higher costs for processing and influences the consumers’ willingness to purchase, breeding for shape uniformity and shallow eye depth is highly important. Previous studies showed that the major round tuber shape controlling locus, the Ro locus, is located on chromosome 10. However, fine mapping and cloning of tuber shape genes have not been reported. In this study, the analyses of tissue sectioning and transcriptome sequencing showed that the developmental differences between round and elongated tuber shapes begin as early as the hook stage of the stolon. To fine map tuber shape genes, a high-density genetic linkage map of the Ro region on chromosome 10 based on a diploid segregating population was constructed. The total length of the genetic linkage map was 25.8 cM and the average marker interval was 1.98 cM. Combined with phenotypic data collected from 2014 to 2017, one major quantitative trait locus (QTL) for tuber shape was identified, which explained 61.7–72.9% of the tuber shape variation. Through the results of genotyping and phenotypic investigation of recombinant individuals, Ro was fine mapped in a 193.43 kb interval, which contained 18 genes. Five candidate genes were preliminarily predicted based on tissue sections and transcriptome sequencing. This study provides an important basis for cloning Ro gene(s).

The Phase-I trigger readout electronics upgrade of the ATLAS Liquid Argon calorimeters enhances the physics reach of the experiment during the upcoming operation at increasing Large Hadron Collider luminosities. The new system, installed during the second Large Hadron Collider Long Shutdown, increases the trigger readout granularity by up to a factor of ten as well as its precision and range. Consequently, the background rejection at trigger level is improved through enhanced filtering algorithms utilizing the additional information for topological discrimination of electromagnetic and hadronic shower shapes. This paper presents the final designs of the new electronic elements, their custom electronic devices, the procedures used to validate their proper functioning, and the performance achieved during the commissioning of this system., Comment: 56 pages, 41 figures, 6 tables

Background Gastrectomy with lymph node dissection is the cornerstone of curative treatment of gastric cancer. Extent of lymphadenectomy may differ depending on T-stage, as the rate of lymph node metastases may differ. The objective of this systematic review is to investigate and compare the prevalence of nodal metastases in the individual lymph node stations between different T-stages. Methods Data reporting and structure of this systematic review follows the PRISMA checklist. The Medline and PubMed databases were systematically searched. The search included the following Mesh terms: "Stomach Neoplasms", "Lymphatic Metastasis" and "Lymph Node Excision". The primary outcome was the highest prevalence of nodal metastases per T-stage. Results The initial search resulted in 175 eligible articles. Five articles met the inclusion criteria and were accordingly analyzed. Concerning the lymph node stations 1 to 7, the lymph nodes along the lesser gastric curvature (station 3) show the highest metastases rate (T1: 5.5%, T2: 21.9%, T3: 41.9%, T4: 71.0%). Concerning the lymph node stations 8 to 20, the lymph nodes around the common hepatic artery (station 8) show the highest metastases rate (T1: 0.8%, T2: 7.9%, T3: 14.0%, T4: 28.2%). Conclusion An overall low prevalence of nodal metastases in the individual lymph node stations in early, T1 gastric carcinomas and an overall high prevalence in more advanced, T3 and T4 gastric carcinomas endorse a more tailored approach based on the different gastric T-stages. In addition, a less extensive lymphadenectomy seems justified in early T1 carcinoma. Synopsis This systematic review provides an overview of the prevalence of nodal metastases for the individual lymph node stations between different T-stages, showing an overall low prevalence in early, T1 gastric carcinomas and an overall high prevalence in the more advanced, T3 and T4 gastric carcinomas.

Tuber shape is one of the most important quality traits in potato appearance. Since poor or irregular shape results in higher costs for processing and influences the consumers' willingness to purchase, breeding for shape uniformity and shallow eye depth is highly important. Previous studies showed that the major round tuber shape controlling locus, the

Aims People with psychotic disorders receive mental healthcare services mainly for their psychiatric care needs. However, patients often experience multiple physical or social wellbeing-related care needs as well. This study aims to identify care needs, investigate their changes over time and examine their association with mental healthcare consumption and evidence-based pharmacotherapy. Methods This study combined annually obtained routine outcome monitoring (ROM) data with care consumption data of people with a long-term psychotic illness receiving treatment in four Dutch mental healthcare institutes between 2012 and 2016. Existing treatment algorithms were used to determine psychiatric, physical and social wellbeing-related care needs based on self-report questionnaires, semi-structured interviews and physical parameters. Care consumption was measured in hours of outpatient mental healthcare consumption per year. Generalised estimating equation models were used to calculate odds ratios of care needs and their associations with time, mental healthcare consumption and medication use. Results Participants (n = 2054) had on average 7.4 care needs per measurement and received 25.4 h of care per year. Physical care needs are most prevalent and persistent and people with more care needs receive more mental healthcare. Care needs for psychotic symptoms and most social wellbeing-related care needs decreased, whereas the chance of being overweight significantly increased with subsequent years of care. Several positive associations were found between care needs and mental healthcare consumption as well as positive relations between care needs and evidence-based pharmacotherapy. Conclusions This longitudinal study present a novel approach in identifying care needs and their association with mental healthcare consumption and pharmacotherapy. Identification of care needs in this way based on ROM can assist daily clinical practice. A recovery-oriented view and a well-coordinated collaboration between clinicians and general practitioners together with shared decisions about which care needs to treat, can improve treatment delivery. Special attention is required for improving physical health in psychosis care which, despite appropriate pharmacotherapy and increasing care consumption, remains troublesome.

BackgroundPatients with moderately active psoriatic arthritis (PsA) and limited joint involvement have considerable disease burden1,2. Recent data shows these patients have a high likelihood of achieving treatment goals if treated with apremilast3. This is the first report of outcomes in patients with PsA who received apremilast for 12 months in Dutch clinical practice.ObjectivesWe report disease outcomes, including the PsA Impact of Disease (PsAID) 12-item questionnaire, swollen joint count (SJC), tender joint count (TJC), dactylitis and enthesitis, among patients in the prospective, multicenter, observational REWARD study who completed 12 months of apremilast treatment.MethodsThe ongoing REWARD study enrolled patients who had initiated apremilast for the treatment of PsA in the Netherlands between 13 April 2017 and 24 March 2021, and includes up to 12 months follow-up1,4. We report interim data from patients with data available as of 16 September 2021. Baseline data are summarized separately for patients who discontinued apremilast before their month 12 study visit (stoppers) and patients still receiving apremilast at their month 12 visit (completers). Post baseline data are summarized for completers. Continuous data are summarized using mean and SD, categorical data are summarized using n and percent.Results98 patients were included in this interim analysis; 32 had completed 12 months of apremilast treatment (completers), 54 had discontinued apremilast before month 12 (stoppers), 12 were ongoing in the study. Compared with stoppers, completers were more likely to be biologic naïve and have dactylitis, and had lower BSA. All other baseline characteristics were similar (Table 1). Among completers, all PsAID domains improved after 3 months of apremilast treatment and these improvements were maintained through month 12 (Figure 1). Mean SJC and TJC decreased between baseline and month 12 (SJC, 4.2 and 1.0 at baseline and month 12, respectively; TJC, 7.1 and 3.3, respectively). The proportion of completers with SJC, TJC, enthesitis and dactylitis scores of 0 increased from baseline to month 12 (Figure 1B). The proportion of completers reporting at least one adverse event (AE) was comparable to the overall study population (14/32 [44%] and 48/98 [49%], respectively); the reported adverse events were similar to the known safety profile of apremilast.Table 1.Baseline characteristicsAll=all patients included in this interim analysis; Completers= patients that received apremilast for 12 months; Stoppers= patients that stopped apremilast treatment prior to 12 months.BMI=Body Mass Index, PsO=Psoriasis, BSA PsO= Body Surface Area Psoriasis, SJC=Swollen Joint Count, TJC=Tender Joint Count, PsAID=Psoriatic Arthritis Impact of Disease, VAS=Visual Analog Scale, CRP= C-reactive protein, cDAPSA=Clinical Disease Activity in Psoriatic Arthritis, Rem=Remission, Mod=Moderate, PsA= Psoriatic ArthritisFigure 1.(A) PSAID scores in completers and (B) percentage of completers with no swollen joints, no tender joints, no dactylitis and no enthesitis at baseline (BSL), month 3, 6 and 12 (M3, M6, M12).ConclusionIn this interim analysis of the REWARD study, patients completing 12 months of apremilast treatment were more likely to be biologic naïve than patients who discontinued apremilast within 12 months of initiation, and had significant decreases in TJC, SJC, dactylitis and enthesis during apremilast treatment. Completed patients also reported decreased PsAID scores during apremilast treatment, indicating improvements in their quality of life.References[1]Jansen TL, et al. Ann Rheum Dis. 2019; 78:913 [abstract FRI0442][2]Wervers et al. J Rheumatol. 2018;45:1526.[3]Mease PJ, et al. Arthritis Care Res. 2020; 72, 6, 814–821[4]Bos R, et al. Ann Rheum Dis. 2021; 80:805 [POS1053]AcknowledgementsSylvia de Jong and Claire Desborough, Amgen employees, provided medical writing and editorial assistance.Disclosure of InterestsReinhard Bos Consultant of: AbbVie BV, Genzyme Europe, Grant/research support from: Galapagos, Tim Jansen Speakers bureau: Grunenthal, Sobi, Consultant of: AbbVie, Celgene Corporation, Grant/research support from: ReumaNederland, Olatec, Grunenthal, Ian Bridges Shareholder of: Amgen, Employee of: Amgen, Sylvia de Jong Shareholder of: Amgen, Employee of: Amgen, Novartis, Marijn Vis Consultant of: AbbVie, Celgene Corporation, Eli Lilly, Novartis, Pfizer, Grant/research support from: Novartis, Pfizer

Background Patient-derived bulk expression profiles of cancers can provide insight into the transcriptional changes that underlie reprogrammed metabolism in cancer. These profiles represent the average expression pattern of all heterogeneous tumor and non-tumor cells present in biopsies of tumor lesions. Hence, subtle transcriptional footprints of metabolic processes can be concealed by other biological processes and experimental artifacts. However, consensus independent component analyses (c-ICA) can capture statistically independent transcriptional footprints of both subtle and more pronounced metabolic processes. Methods We performed c-ICA with 34,494 bulk expression profiles of patient-derived tumor biopsies, non-cancer tissues, and cell lines. Gene set enrichment analysis with 608 gene sets that describe metabolic processes was performed to identify the transcriptional components enriched for metabolic processes (mTCs). The activity of these mTCs was determined in all samples to create a metabolic transcriptional landscape. Results A set of 555 mTCs was identified of which many were robust across different datasets, platforms, and patient-derived tissues and cell lines. We demonstrate how the metabolic transcriptional landscape defined by the activity of these mTCs in samples can be used to explore the associations between the metabolic transcriptome and drug sensitivities, patient outcomes, and the composition of the immune tumor microenvironment. Conclusions To facilitate the use of our transcriptional metabolic landscape, we have provided access to all data via a web portal (www.themetaboliclandscapeofcancer.com). We believe this resource will contribute to the formulation of new hypotheses on how to metabolically engage the tumor or its (immune) microenvironment.

Background: Patient-derived bulk expression profiles of cancers can provide insight into transcriptional changes that underlie reprogrammed metabolism in cancer. These profiles represent the average expression pattern of all heterogeneous tumor and non-tumor cells present in biopsies of tumor lesions. Hence, subtle transcriptional footprints of metabolic processes can be concealed by other biological processes and experimental artifacts. However, consensus Independent Component Analyses (c-ICA) can capture statistically independent transcriptional footprints, of both subtle and more pronounced metabolic processes. Methods: We performed c-ICA with 34,494 bulk expression profiles of patient-derived tumor biopsies, non-cancer tissues, and cell lines. Gene set enrichment analysis with 608 gene sets that describe metabolic processes was performed to identify transcriptional components enriched for metabolic processes (mTCs). The activity of these mTCs were determined in all samples to create a metabolic transcriptional landscape. Results: A set of 555 mTCs were identified of which many were robust across different datasets, platforms, and patient-derived tissues and cell lines. We demonstrate how the metabolic transcriptional landscape defined by the activity of these mTCs in samples can be used to explore associations between the metabolic transcriptome and drug sensitivities, patient outcomes, and the composition of the immune tumor microenvironment. Conclusions: To facilitate the use of our transcriptional metabolic landscape, we have provided access to all data via a web portal ( www.themetaboliclandscapeofcancer.com ). We believe this resource will contribute to the formulation of new hypotheses on how to metabolically engage the tumor or its (immune) microenvironment.

Background Vedolizumab (VDZ), a monoclonal antibody that targets α4β7 integrin, was approved to treat moderate-to-severe ulcerative colitis (UC) based on the presumption that it blocks T cell recruitment to the inflamed intestinal mucosa. The clinical evidence suggests that up to 50% of UC patients do not achieve disease remission under VDZ treatment. This study aims to identify changes in cell abundances and molecular pathways associated with VDZ response in UC. To this end, we included anti-tumor necrosis factor (anti-TNF)-naïve and anti-TNF-exposed patients with active UC, and utilized single-cell RNA sequencing (scRNAseq) and high-dimensional flow cytometry (Cytek) to assess the peripheral blood and the gut mucosal compartments. Methods Gut mucosal biopsies from inflamed and non-inflamed regions, and peripheral blood mononuclear cells (PBMCs) were obtained from UC patients 2 wks before (t0) and 14 wks after (t4) the start of VDZ administration. Response to treatment was prospectively evaluated based on endoscopic assessment (defined as a decrease in total Mayo score between t0 and t4) and physician global assessment (PGA) that incorporates disease activity score and biochemical measurements. Results A total of 25 UC patients (pts) were included: 44% anti-TNF-naïve. Endoscopic response to VDZ was observed in 32% of UC pts, while 56% of pts showed response based on PGA. The VDZ response rate (by PGA) was higher in anti-TNF-naïve pts vs anti-TNF-exposed pts (82% vs 36% responders, respectively). A preliminary analysis was performed on samples from 8 (out of 25) UC pts, profiling >70,000 gut mucosal cells and >25,000 PBMCs. Within the mucosal compartment, at t0 we identified immune cells (50% of all captured cells), stromal cells (10%), and epithelial cells (40%). Upon inflammation, the proportion of immune cells increased to 70%, stromal cells to 20%, while epithelial cells depleted to 10%. Notably, all main identified immune cell lineages – T cells, B cells and myeloid cells – contributed to the expansion of the immune cell compartment in inflamed mucosa. In line with scRNAseq data, we identified all major immune cell populations and detected expression of both the classic gut-directed and the redundant trafficking integrins by Cytek. Conclusion The preliminary results substantiate our current understanding of VDZ biology in UC. We confirm that anti-TNF-naïve pts have a higher response rate to VDZ vs anti-TNF-exposed pts. With this unique cohort, our study has the power to further explore molecular mechanisms and pathways that underlie VDZ response at the single-cell level.