The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016)

Background and purposeThe Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG 2016), a Japanese-specific set of clinical practice guidelines for sepsis and septic shock created jointly by the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine, was first released in February 2017 and published in the Journal of JSICM, [2017; Volume 24 (supplement 2)] https://doi.org/10.3918/jsicm.24S0001 and Journal of Japanese Association for Acute Medicine [2017; Volume 28, (supplement 1)] http://onlinelibrary.wiley.com/doi/10.1002/jja2.2017.28.issue-S1/issuetoc.This abridged English edition of the J-SSCG 2016 was produced with permission from the Japanese Association of Acute Medicine and the Japanese Society for Intensive Care Medicine.MethodsMembers of the Japanese Society of Intensive Care Medicine and the Japanese Association for Acute Medicine were selected and organized into 19 committee members and 52 working group members. The guidelines were prepared in accordance with the Medical Information Network Distribution Service (Minds) creation procedures. The Academic Guidelines Promotion Team was organized to oversee and provide academic support to the respective activities allocated to each Guideline Creation Team. To improve quality assurance and workflow transparency, a mutual peer review system was established, and discussions within each team were open to the public. Public comments were collected once after the initial formulation of a clinical question (CQ) and twice during the review of the final draft. Recommendations were determined to have been adopted after obtaining support from a two-thirds (> 66.6%) majority vote of each of the 19 committee members.ResultsA total of 87 CQs were selected among 19 clinical areas, including pediatric topics and several other important areas not covered in the first edition of the Japanese guidelines (J-SSCG 2012). The approval rate obtained through committee voting, in addition to ratings of the strengths of the recommendation, and its supporting evidence were also added to each recommendation statement. We conducted meta-analyses for 29 CQs. Thirty-seven CQs contained recommendations in the form of an expert consensus due to insufficient evidence. No recommendations were provided for five CQs.ConclusionsBased on the evidence gathered, we were able to formulate Japanese-specific clinical practice guidelines that are tailored to the Japanese context in a highly transparent manner. These guidelines can easily be used not only by specialists, but also by non-specialists, general clinicians, nurses, pharmacists, clinical engineers, and other healthcare professionals

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

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

Evaluating the 21-gene assay Recurrence Score® as a predictor of clinical response to 24 weeks of neoadjuvant exemestane in estrogen receptor-positive breast cancer.

[Background]The aim of this study was to investigate the association between the results of the Recurrence Score (RS) assay and the clinical response to neoadjuvant endocrine therapy in postmenopausal women with breast cancer. [Methods]Core biopsy samples at baseline and post-treatment surgical samples were obtained from 80 and 77 of 116 patients, respectively, enrolled in the multicenter prospective study of neoadjuvant exemestane therapy (JFMC34-0601). The 21-gene assay was performed after appropriate manual microdissection. The estrogen receptor (ER), progesterone receptor, HER2 and Ki-67 were assayed by immunohistochemistry at a central laboratory. Clinical response was assessed based on the RECIST (Response Evaluation Criteria In Solid Tumors) guideline. [Results]Sixty-four core biopsy samples and 52 resection samples met the RS quality requirements. The clinical response rate in those patients with a low RS result (low RS group; 19/32, 59.4 %) was significantly higher than that in those patients with a high RS result (high RS group; 3/15, 20.0 %) (P = 0.015) and similar to that in patients with an intermediate RS result (intermediate RS group; 10/17, 58.8 %). The rates of breast-conserving surgery (BCS) were 90.6 % (29/32) in the low RS group, 76.5 % (13/17) in the intermediate RS group and 46.7 % (7/15) in the high RS group. The odds ratio for BCS adjusted for continuous baseline Ki-67 was 0.114 [95 % confidence interval (CI) 0.014–0.721; P = 0.028] between the high and low RS groups. RS values in pre-treatment samples were highly correlated with those in post-treatment samples (Spearman correlation coefficient 0.745, 95 % CI 0.592–0.846). [Conclusion]Our results demonstrate the predictive value of the RS for clinical response to neoadjuvant exemestane therapy in postmenopausal women with ER-positive breast cancer

Neoadjuvant endocrine therapy with exemestane followed by response-guided combination therapy with low-dose cyclophosphamide in postmenopausal patients with estrogen receptor-positive breast cancer: A multicenter, open-label, phase II study

Patients with estrogen receptor (ER)‐positive breast cancer are less likely to achieve a pathological complete response (pCR) with neoadjuvant chemotherapy. Neoadjuvant endocrine therapy may be more appropriate than neoadjuvant chemotherapy in these hormone‐sensitive patients. Most patients with ER‐positive breast cancer are postmenopausal, and therefore, generally older and less able to tolerate chemotherapy. We aimed to investigate the efficacy and safety of tailored neoadjuvant endocrine and chemoendocrine therapy for postmenopausal breast cancer patients. Untreated patients with primary invasive ER‐positive, HER2‐negative, stage I‐IIIA breast cancer, and Ki67 index ≤30% were enrolled. Patients received exemestane 25 mg/d for 12 weeks. Based on clinical response and change in Ki67 index, assessed at 8‐12 weeks, patients with complete response (CR), partial response (PR) with Ki67 index ≤5% after treatment, or stable disease (SD) with Ki67 index ≤5% before and after treatment were defined as responders. For the subsequent 24 weeks, responders continued exemestane monotherapy (group A), and nonresponders received exemestane 25 mg/d plus cyclophosphamide 50 mg/d (group B). The primary endpoint was clinical response at weeks 24 and 36. A total of 59 patients (median age, 69 years) started initial exemestane monotherapy. After exclusion of three patients who discontinued during this period, 56 remained enrolled to receive subsequent treatment. Clinical response rates (CR and PR) and 95% CI at weeks 24 and 36 were 85% (12/14; 57.2%‐98.2%) and 71% (10/14; 41.9%‐91.6%), respectively, in group A; and 54% (23/42; 38.7%‐70.2%) and 71% (30/42; 55.4%‐84.3%), respectively, in group B. At week 36, no significant difference was found in median Ki67 index between the groups (3.5% and 4.0%). There were no treatment‐related deaths. We found that clinical response comparable to that of responders was achieved in nonresponders after addition of cyclophosphamide to the initial endocrine therapy

Restriction of right of ownership for environmental protection reasons - a comparative study of legal systems

of the doctoral thesis entitled: "Restriction of right of ownership for environmental protection reasons - a comparative study of legal systems" The right of ownership and the exercising of the right of use resulting from this rank among the fundamental human rights and are to be universally observed. However, due to its very nature, the individual's right of ownership has to be restricted. On the one hand, in order to ensure the exercising of the right of ownership and other basic rights by other legal entities. On the other hand, in order to ensure the enforcement of matters of public interest. One of the most important matters of public interest, which requires the restriction of the right of ownership, is the protection of the environment. The subject of this thesis is the restriction of the right of ownership for environmental protection reasons and is based on a comparison of the legal systems of both Switzerland and the Czech Republic. This thesis, written in the Czech language by the jurist who graduated in law at the Law Faculty of the University of Zurich, is intended in particular for jurists and other interested parties from the Czech Republic. This is why the author pays special attention to the formulation and representation of the legal framework governing the restriction of the..

Concept design of new compact electron cyclotron resonance ion source with permanent magnets for multi-ion radiotherapy.

The multi-ion radiotherapy with dose distribution and Liner Energy Transfer optimization is being studied at QST. Helium, carbon, oxygen and neon ions are considered as ion species for multi-ion therapy. A basic experiment using these ion beams has been carried out at the HIMAC. For heavy-ion radiotherapy facility, it is desirable to operate with only one ECR ion source. We considered the operating method with only one ion source for multi-ion radiotherapy. Ionization gases were helium, methane, oxygen, and neon to produce He2+, C4+, O6+ and Ne7+ ions. Requirement values of beam current were 940 µA correspond to He2+, 290 µA to C4+, 330 µA to O6+, and 245 µA to Ne7+, respectively. This value was obtained from the number of particles required for the cancer treatment and the transmission efficiency of the accelerator in the HIMAC. We performed some beam tests for design of a new compact ion source with the existing 18 GHz ECR ion source (NIRS-HEC). From the results of the beam tests, we estimate the mirror magnetic field ofNIRS-HEC by using POISSON/SUPERFISH code. Then, the structure of the permanent magnets for new ECR ion source is determined so that they reproduce the values of the upstream mirror peak (Binj), B minimum (Bmin) and the downstream mirror peak (Bext) at the NIRS-HEC. The magnetic field of Binj, Bmin and Bext at NIRS-HEC were 1.14 T, 0.475 T and 0.9 T, respectively.We will describe about the beam tests with the NIRS-HEC and design of the new compact ECR ion source