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Background and Aims There are no agreed-on endoscopic signs for the diagnosis of villous atrophy (VA) in celiac disease (CD), necessitating biopsy sampling for diagnosis. Here we evaluated the role of near-focus narrow-band imaging (NF-NBI) for the assessment of villous architecture in suspected CD with the development and further validation of a novel NF-NBI classification. Methods Patients with a clinical indication for duodenal biopsy sampling were prospectively recruited. Six paired NF white-light endoscopy (NF-WLE) and NF-NBI images with matched duodenal biopsy sampling including the bulb were obtained from each patient. Histopathology grading used the Marsh-Oberhuber classification. A modified Delphi process was performed on 498 images and video recordings by 3 endoscopists to define NF-NBI classifiers, resulting in a 3-descriptor classification: villous shape, vascularity, and crypt phenotype. Thirteen blinded endoscopists (5 expert, 8 nonexpert) then undertook a short training module on the proposed classification and evaluated paired NF-WLE–NF-NBI images. Results One hundred consecutive patients were enrolled (97 completed the study; 66 women; mean age, 51.2 ± 17.3 years). Thirteen endoscopists evaluated 50 paired NF-WLE and NF-NBI images each (24 biopsy-proven VAs). Interobserver agreement among all validators for the diagnosis of villous morphology using the NF-NBI classification was substantial (κ = .71) and moderate (κ = .46) with NF-WLE. Substantial agreement was observed between all 3 NF-NBI classification descriptors and histology (weighted κ = 0.72-.75) compared with NF-WLE to histology (κ = .34). A higher degree of confidence using NF-NBI was observed when assessing the duodenal bulb. Conclusions We developed and validated a novel NF-NBI classification to reliably diagnose VA in suspected CD. There was utility for expert and nonexpert endoscopists alike, using readily available equipment and requiring minimal training. (Clinical trial registration number: NCT04349904.)

Background: Systemic mastocytosis (SM) is a disorder of neoplastic mast cells ranging from indolent to aggressive multi-system disease. We previously reported our large single centre experience managing SM. Since 2019 patients have had access to new treatments within trials. Prognostic scoring systems developed in SM to improve outcome predictions and guide treatment have been a focus of recent studies, although are yet to be validated in real-world setting. We sought to apply these scoring systems within our UK cohort, with a particular focus on the international prognostic score (IPSM) and the mutation-adjusted risk score (MARS). Methods: We performed a retrospective study of 192 adult patients diagnosed with SM between 2009 and 2021 including demographics, clinical data, as well as next generation sequencing (NGS) based myeloid gene panels carried out in advanced SM patients (AdvSM) where available. Prognosis for all patients was calculated based on IPSM (Sperr et al. [2019]) in all our SM patients and MARS scores in those with AdvSM (Jawhar et al. [2019]). Results: There was no gender bias in our cohort with 87 (46%) males and 105 (54%) females. Median age at diagnosis was 52 years (range 5-84) and majority of patients had indolent SM (ISM; 129/192 [67%]), 8/192 (4%) smouldering SM (SSM) and 55/192 (29%) advanced SM (AdvSM). In those with AdvSM, 43/55 (78%) had an associated haematological neoplasm (SM-AHN); 9/55 (17%) aggressive SM (ASM) and 3/55 (5%) mast cell leukaemia. As expected, AHN sub-types were myeloid with majority being CMML (16/55; 29%) [Table 1]. Median tryptase at diagnosis in ISM patients was 41ug/L (range 3-351ug/L), while in SSM it was 494ug/L (range 174-682ug/L) and in AdvSM it was 155ug/L (range 10-1551). Most patients were positive for the KIT D816V mutation (131/192; 68%). As expected, ISM and SSM (non-AdvSM) patients had better prognosis compared to those with AdvSM [Figure 1a], with median overall survival (OS) not reached in the former and 12 months in the latter with 11-year follow-up. We next applied the IPSM score to the AdvSM cohort, with the largest proportion categorised as AdvSM-3 (25/55; 45%) while 10/55 (18%) were AdvSM-4 [Table 1]. Survival outcome was notably higher in the AdvSM-1 group (4/55; 7%) with no deaths recorded, while 6/25 (24%) and 4/10 (40%) deaths were reported in AdvSM-3 and AdvSM-4 groups respectively [Figure 1b]. SM patients are known to carry somatic mutations in addition to KIT, in particular SRSF2, ASXL1 and RUNX1 (S/A/R) which are associated with adverse outcome. In our AdvSM cohort, 10/55 (18%) of patients were positive for one of these mutations on NGS-based myeloid gene panel and 8/55 (15%) carried ≥2. Additional clinically significant mutations are summarised in Table 1. We next examined the MARS score; most of our AdvSM patients categorised as low-risk (28/55, 51%), 21/55 (38%) were intermediate-risk and 6/55 (13%) high-risk [Table 1]. Survival outcome as expected in the low-risk group was higher compared to the intermediate- and high-risk groups, with 10-year OS of 87% versus 35% and 30% respectively [Figure 1c]. On reviewing our AdvSM cohort, 6/55 (11%) had progressive disease: 5 transforming to acute myeloid leukaemia (AML) and 1 to mast cell leukaemia (MCL). Interestingly, when reviewing cause of death, the highest proportion were due to AHN progression (6/16; 38%) while 2/16 (13%) were from transformation to AML [Table 1]. As expected within our cohort, there was a discrepancy between the IPSM and MARS scores as the latter includes the presence of S/A/R mutations. 2 patients diagnosed with MCL in 2016 and 2019 respectively, were categorised high risk based on both scores. Both are alive to date having received the KIT inhibitor avapritinib, with one continuing on this treatment. The other progressed to AML and underwent allogeneic stem cell transplant, with ongoing complete remission. Other treatments received by our AdvSM patients are summarised in Table 1. Conclusion: Application of the IPSM and MARS prognostic scores to our data reflects findings of other groups with better outcomes seen in non-AdvSM compared to AdvSM patients. Furthermore, although our AdvSM cohort is small, the presence of adverse risk factors could be overcome through recent advances in treatments and consolidation with stem cell transplant. Hence, identification of high-risk patients using these prognostic scores can direct targeted first-line therapy and improve outcomes. Figure 1 Figure 1. Disclosures Sriskandarajah: Celgene: Speakers Bureau; Novartis: Other: Education. Green: Novartis: Other: Education. Ong: Novartis: Other: Education. Harrison: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: Honoraria; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Grattan: Novartis: Speakers Bureau. Radia: Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Study steering group member, Research Funding; Cogent Biosciences Incorporated: Other: Study Steering Committee; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Education events; EXPLORER and PATHFINDER studies: Other: Member of the Response Adjudication Committee.

Summary Regulatory T cells (Tregs) play a pivotal role in maintaining immunological tolerance, but they can also play a detrimental role by preventing antitumor responses. Here, we characterized T helper (Th)-like Treg subsets to further delineate their biological function and tissue distribution, focusing on their possible contribution to disease states. RNA sequencing and functional assays revealed that Th2-like Tregs displayed higher viability and autocrine interleukin-2 (IL-2)-mediated activation than other subsets. Th2-like Tregs were preferentially found in tissues rather than circulation and exhibited the highest migratory capacity toward chemokines enriched at tumor sites. These cellular responses led us to hypothesize that this subset could play a role in maintaining a tumorigenic environment. Concurrently, Th2-like Tregs were enriched specifically in malignant tissues from patients with melanoma and colorectal cancer compared to healthy tissue. Overall, our results suggest that Th2-like Tregs may contribute to a tumorigenic environment due to their increased cell survival, higher migratory capacity, and selective T-effector suppressive ability., Graphical Abstract, Highlights • Memory Tregs can be classified as T helper-like Tregs (Th2, Th17, Th1, and Th1/17) • Human Th2-like Tregs exhibit the highest viability and IL-2-mediated activation • Th2-like Tregs are the subset with the highest chemotaxis toward CCL17/22 • Th2-like Tregs are enriched at tumor sites in melanoma and colorectal cancer, Halim et al. provide a comprehensive transcriptomic and functional analysis of circulating Th-like Tregs, revealing unique features in Th2-like Tregs and a significant enrichment of this subset in patients with melanoma and colorectal cancer. This suggests that Th2-like Tregs play a major role in maintaining a tumorigenic environment.

Introduction: Systemic mastocytosis (SM) is a heterogeneous disorder of neoplastic mast cells ranging from an indolent to aggressive multi-system disease. We registered our UK Mastocytosis Centre of Excellence with the European Competence Network of Mastocytosis (ECNM) in 2005. Our multidisciplinary team (MDT) includes haematologists, haematopathologists, dermatologist, immunologist and molecular diagnosticians. Over 500 patients have been reviewed in our quarterly SM-MDT. We present a large single centre experience of a rare disorder. Method: We have reviewed prospective and retrospectively collected clinical data for 125 adult patients from 2009. The data captures clinical, laboratory, diagnostic results and management. Local patients with a tryptase level of >20ug/L are offered haematology review and bone marrow investigation with KIT D816V mutation analysis using digital PCR. Patients seen for a second opinion have their diagnostic material reviewed. Since 2018, next generation sequencing (NGS) based myeloid gene panels are carried out on patients with advanced SM (AdvSM). Results: Classification of mastocytosis patients: In 125 patients no gender bias was seen: 56 (44.8%) were male and 69 (55.2%) female. Median age of patients with indolent SM (ISM) was 49 years (range 22-78); and for AdvSM: (aggressive SM, SM with an associated haematological neoplasm and mast cell leukaemia) was 64years (range 5-77). The median serum tryptase level was 48.9ug/L for ISM patients (range 4-682) and 120ug/L for AdvSM patients (range 24-854). 112/125 patients had a bone marrow biopsy. 13 patients chose not to have a biopsy. 88% (110/125) of patients had a mast cell disorder. 4% (5/125) had no marrow involvement. 84% (105/125) met WHO criteria for a diagnosis of SM - Figure 1.These were sub-classified: 71/105 (67%) ISM; 2/105 (2%) smouldering SM (SSM); 3/105 (3%) aggressive SM (ASM); 2/105 (2%) mast cell leukaemia (MCL) and 27/105 (26%) SM with an associated hematologic neoplasm (SM-AHN). The most frequent associated haematological neoplasms were MPN and CMML. Lymphomas (n=3) and plasma cell dyscrasias (n=1) were seen patients. In 10/27 (37%) cases of SM-AHN the SM was the initial diagnosis with subsequent development of an AHN. In 5/27(19%) cases the AHN component preceded the SM and in 12/27 (44%) cases the 2 components were co-diagnosed. Mutation status : 24/32 patients with AdvSM were noted to be positive for an activating KIT mutation (D816V, n=23; D816L, n=1). 15/32 AdvSM patients had NGS myeloid gene panel analysis for the SAR panel (SRSF2, ASXL1 and RUNX1) which confers poor prognosis. 4 of the15 patients harboured at least 2 out of 3 SAR mutations. JAK2 V617F mutation was detected in 7 of 8 classical MPN patients and in 1 of 4 patients with MPNu/MDS overlap. 4 patients had a TET2 mutation. 1 patient with mast cell leukaemia had a GATA2 mutation in addition to all 3 in the SAR panel. Cutaneous involvement: 70% (88/125) of patients had skin involvement: 62% (78/125) urticaria pigments, 3% (4/125) telangiectasia macularis eruptiva perstans and 5% (6/125) having non-specific involvement. Skin involvement was more common in ISM (78%) than AdvSM (54% in SM-AHN, none in the 2 patients with MCL). Management : Treatments in ISM are usually for symptom control. Antihistamines, anti-inflammatory agents, anti-leukotriene agents, mast cell stabilising agents, bisphosphonates, proton-pump inhibitors, PUVA and steroids are used. Various cytoreductive therapies have been used in AdvSM (hydroxycarbamide, pegylated interferon-α, cladrabine, cytarabine, azacitadine alone/combination with midostaurin). Patients with SM-AHN have tailored management depending on the disease component that requires treatment. Access to targeted therapies for AdvSM patients in a trial or compassionate use programme has been successful: 7/32 patients with advanced SM have been enrolled into trials (midostaurin 1; avapritinib 6). Conclusions: Our data reflects the heterogeneous nature of the SM classification spectrum clinically and diagnostically. An experienced MDT provides holistic high standard of care within a comprehensive centre for good patient outcomes (Figure 2). Development of a portfolio of novel therapeutic options in multi-centred, international collaborative trials is beneficial to patients and pivotal for research in this rare disorder. Disclosures Cross: Novartis: Consultancy, Research Funding; Incyte: Consultancy. McLornan:Jazz Pharmaceuticals: Honoraria, Speakers Bureau; Novartis: Honoraria. Radia:Blueprint Medicines: Consultancy; Novartis: Consultancy, Speakers Bureau. OffLabel Disclosure: There are very few medications available in mastocytosis and various off label medications have been used including pegylated interferon alpha.

The explosive Zika virus epidemic in the Americas is amplifying spread of this emerging pathogen into previously unaffected regions of the world, including Europe (Gulland, 2016), where local populations are immunologically naïve. As summertime approaches in the northern hemisphere, Aedes mosquitoes in Europe may find suitable climatic conditions to acquire and subsequently transmit Zika virus from viremic travellers to local populations. While Aedes albopictus has proven to be a vector for the transmission of dengue and chikungunya viruses in Europe (Delisle, E., et al., 2015, ECDC,, n.d) there is growing experimental and ecological evidence to suggest that it may also be competent for Zika virus(Chouin-Carneiro et al., 2016; Grard et al., 2014; Li et al., 2012; Wong et al., 2013). Here we analyze and overlay the monthly flows of airline travellers arriving into European cities from Zika affected areas across the Americas, the predicted monthly estimates of the basic reproduction number of Zika virus in areas where Aedes mosquito populations reside in Europe (Aedes aegypti in Madeira, Portugal and Ae. albopictus in continental Europe), and human populations living within areas where mosquito-borne transmission of Zika virus may be possible. We highlight specific geographic areas and timing of risk for Zika virus introduction and possible spread within Europe to inform the efficient use of human disease surveillance, vector surveillance and control, and public education resources., Highlights • A validated climate model suggests mosquito-borne Zika transmission risk peaks in July and August in parts of Southern Europe • This analysis assumes European and Latin American Aedes vectors have similar competence to transmit Zika virus • Air travel peak from regions of the Americas aligns with peak predicted capacity of European Aedes vectors to transmit Zika • Findings could help health officials identify where and when risk for Zika importation and local transmission is heightened The imminent arrival of summer in the northern hemisphere brings an elevated risk of Zika virus epidemics outside of the Americas. In Europe, established populations of Aedes aegypti and Aedes albopictus mosquitoes might be capable of transmitting Zika virus locally, if travellers introduce the virus from other areas of the world. Here we calibrate a model of vectorial capacity for Zika virus transmission in Europe, which we overlay with arriving air travellers into Europe from Zika affected areas in the Americas. We highlight specific geographic areas and timing of risk for Zika virus introduction and potential autochthonous transmission to inform European disease surveillance and control activities.

This study investigated the effect of goal assignment on the goal commitment, self-efficacy, and performance of individuals who differed on the power distance cultural value dimension. Data were collected from 143 university students in Australia. They were randomly assigned to either a participative or assigned goal setting condition to complete class schedules. Instructional method (i.e., “tell and sell”) and research administrator supportiveness were held constant across the two conditions. Consistent with previous findings, it was hypothesized that self-efficacy and goal commitment would mediate the relation of goal assignment and performance. Extending previous research, it was hypothesized that power distance would moderate the relation of goal assignment and each of goal commitment, self-efficacy, and performance. Hierarchical regression analyses fully supported the mediating and partially supported the moderating hypotheses. Moreover, multigroup structural equation modeling (MSEM) indicated that for low power distance individuals only, self-efficacy mediated the effect of goal assignment on performance.