Impact of Concomitant Thiopurine on the Efficacy and Safety of Filgotinib in Patients with Ulcerative Colitis: Post hoc Analysis of the Phase 2b/3 SELECTION Study

BACKGROUND AND AIMS: SELECTION is the first study to assess the impact of concomitant thiopurine and other immunomodulator [IM] use on the efficacy and safety of a Janus kinase inhibitor, filgotinib, in patients with ulcerative colitis. METHODS: Data from the phase 2b/3 SELECTION study were used for this post hoc analysis. Patients were randomized [2:2:1] to two induction studies [biologic-naive, biologic-experienced] to filgotinib 200 mg, 100 mg, or placebo. At week 10, patients receiving filgotinib were re-randomized [2:1] to continue filgotinib or switch to placebo until week 58 [maintenance]. Outcomes were compared between subgroups with and without concomitant IM use. RESULTS: At week 10, a similar proportion of patients in +IM and -IM groups treated with filgotinib 200 mg achieved Mayo Clinic Score [MCS] response [biologic-naive: 65.8% vs 66.9%; biologic-experienced: 61.3% vs 50.5%] and clinical remission [biologic-naive: 26.0% vs 26.2%; biologic-experienced: 11.3% vs 11.5%]. At week 58, a similar proportion of patients in +IM and -IM groups treated with filgotinib 200 mg achieved MCS response [biologic-naive: 74.2% vs 75.0%; biologic-experienced: 45.5% vs 61.4%] and clinical remission [biologic-naive: 51.6% vs 47.4%; biologic-experienced: 22.7% vs 24.3%]. The probability of protocol-specified disease worsening during the maintenance study in patients treated with filgotinib 200 mg did not differ between +IM and -IM groups [p = 0.6700]. No differences were observed in the incidences of adverse events between +IM and -IM groups in induction/maintenance studies. CONCLUSIONS: The efficacy and safety profiles of filgotinib treatment in SELECTION did not differ with or without concomitant IM use

Characterisation of Ppy-lineage cells clarifies the functional heterogeneity of pancreatic beta cells in mice

Aims/hypothesis Pancreatic polypeptide (PP) cells, which secrete PP (encoded by the Ppy gene), are a minor population of pancreatic endocrine cells. Although it has been reported that the loss of beta cell identity might be associated with beta-to-PP cell-fate conversion, at present, little is known regarding the characteristics of Ppy-lineage cells. Methods We used Ppy-Cre driver mice and a PP-specific monoclonal antibody to investigate the association between Ppy-lineage cells and beta cells. The molecular profiles of endocrine cells were investigated by single-cell transcriptome analysis and the glucose responsiveness of beta cells was assessed by Ca2+ imaging. Diabetic conditions were experimentally induced in mice by either streptozotocin or diphtheria toxin. Results Ppy-lineage cells were found to contribute to the four major types of endocrine cells, including beta cells. Ppy-lineage beta cells are a minor subpopulation, accounting for 12–15% of total beta cells, and are mostly (81.2%) localised at the islet periphery. Unbiased single-cell analysis with a Ppy-lineage tracer demonstrated that beta cells are composed of seven clusters, which are categorised into two groups (i.e. Ppy-lineage and non-Ppy-lineage beta cells). These subpopulations of beta cells demonstrated distinct characteristics regarding their functionality and gene expression profiles. Ppy-lineage beta cells had a reduced glucose-stimulated Ca2+ signalling response and were increased in number in experimental diabetes models. Conclusions/interpretation Our results indicate that an unexpected degree of beta cell heterogeneity is defined by Ppy gene activation, providing valuable insight into the homeostatic regulation of pancreatic islets and future therapeutic strategies against diabetes

Differences in code status practice patterns among emergency clinicians working in Japan and the United States

ObjectiveThis study aimed to examine self-reported code-status practice patterns among emergency clinicians from Japan and the U.S.MethodsA cross-sectional questionnaire was distributed to emergency clinicians from one academic medical center and four general hospitals in Japan and two academic medical centers in the U.S. The questionnaire was based on a hypothetical case involving a critically ill patient with end-stage lung cancer. The questionnaire items assessed whether respondent clinicians would be likely to pose questions to patients about their preferences for medical procedures and their values and goals.ResultsA total of 176 emergency clinicians from Japan and the U.S participated. After adjusting for participants' backgrounds, emergency clinicians in Japan were less likely to pose procedure-based questions than those in the U.S. Conversely, emergency clinicians in Japan showed a statistically higher likelihood of asking 10 out of 12 value-based questions.ConclusionSignificant differences were found between emergency clinicians in Japan and the U.S. in their reported practices on posing procedure-based and patient value-based questions.Practice implicationsSerious illness communication training based in the U.S. must be adapted to the Japanese context, considering the cultural characteristics and practical responsibilities of Japanese emergency clinicians

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

DOĞU VE GÜNEYDOĞU ANADOLU NEOJEN-KUVATERNER VOLKANİTLERİNE İLİŞKİN YENİ JEOKİMYASAL, RADYOMETRİK VE İZOTOPİK VERİLERİN YORUMU

Doğu ve Güneydoğu Anadolu'da Orta Miyosenden itibaren etkin olmaya başlayan çarpışma zonu volkanizması incelenmiş ve çeşitli yörelerdeki değişik yüzleklerinden örnekler alınarak majör, iz ve nadir toprak element (REE) kimyasal analizleri, stronsiyum izotop (87 Sr/86 Sr) ölçümleri ve K/Ar yöntemi ile radyometrik yaş belirlemeleri yapılmıştır. Volkanik kayaçların, majör element kapsamlarına, göre yapılan diyagramlarda genellikle kalkalkalin ve alkalin, kısmen de toleyitik nitelikler taşıdıkları gözlenmiş, petrografik adlamaların yanı sıra, kimyasal bileşimlerine göre de adlandırmaları yapılmıştır. Volkanitlerin iz element kapsamları genellikle üst kıtasal kabuk, kısmen alt kabuk ve ender olarak da manto ortalama değerlerine uymaktadır. Örneklerde ölçülen stronsiyum izotop oranları 0.70350—0.70640 arasında geniş bir aralıkta olup, bölgede Anadolu ve Arap plakalarının birbirleriyle çarpışmalarından önce alta dalan Arap plakasına ilişkin kabuk parçasının volkanitleri oluşturan magmaya bulaştığının işareti olarak yorumlanmıştır. K/Ar yöntemine göre yapılan radyometrik yaş belirlemelerinde, ölçülen en eski yaş, Eleşkirt Kösedağ'a ait olup, 11.4 ± 0.9 my, en genç yaşlar ise 30 000 yıl ile Nemrut dağı kalderası içindeki obsidiyenlere ve Tendürek dağının trakiandezitik lavlarına aittir. Makalede ayrıca tüm Doğu ve Güneydoğu Anadolu volkanitlerinin dağılımları ile volkanolojik, jeokimyasal, petrografik, radyometrik ve izotopik özellikleri irdelenmiştir