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To evaluate the yearly prevalence and annual transition of multi-drug-resistant-chronic endometritis (MDR-CE) in infertile women with a history of repeated implantation failure (RIF) and to establish the third-line antibiotic treatment regimen against MDR-CE.This retrospective/prospective cohort and pilot study included 3473 RIF women between April 2010 and September 2021. The endometrial stromal plasmacyte density index (ESPDI) was calculated in 3449 CD138-immunostained endometrial sections to evaluate CE. The microbiota in the vaginal secretions and endometrial fluid was compared between 17 patients with MDR-CE and 16 patients with antibiotics-sensitive CE. In a pilot study, oral moxifloxacin (400 mg/day, 10 days, n = 24) or azithromycin (500 mg/day, 3 days, n = 24) was administered to eligible patients with MDR-CE.From April 2010 to March 2020, CE was detected in 31.4% of RIF women and MDR was detected in 7.8% of CE. While the prevalence of CE was stable for a decade, MDR in CE increased steadily (OR 8.27, 95% CI 2.58-26.43, p trend 0.001). The bacterial species/communities unique to MDR-CE were not found. The histopathologic cure rate of MDR-CE was similar between the moxifloxacin and azithromycin groups (79.2% vs 75.0%, OR 1.27, 95% CI 0.32-4.89, p value 0.73), as well as reproductive outcomes in subsequent embryo transfer cycles.In RIF women, MDR in CE increased over the decade. As a third-line treatment for MDR-CE, azithromycin may have a clinical advantage due to its shorter time administration periods.ClinicalTrials.gov Identifier: UMIN-CTR 000029449/000031909.

Supplementary Data from Orthovoltage X-Rays Exhibit Increased Efficacy Compared with γ-Rays in Preclinical Irradiation

Radionuclide irradiators (137Cs and 60Co) are commonly used in preclinical studies ranging from cancer therapy to stem cell biology. Amidst concerns of radiological terrorism, there are institutional initiatives to replace radionuclide sources with lower energy X-ray sources. As researchers transition, questions remain regarding whether the biological effects of γ-rays may be recapitulated with orthovoltage X-rays because different energies may induce divergent biological effects. We therefore sought to compare the effects of orthovoltage X-rays with 1-mm Cu or Thoraeus filtration and 137Cs γ-rays using mouse models of acute radiation syndrome. Following whole-body irradiation, 30-day overall survival was assessed, and the lethal dose to provoke 50% mortality within 30-days (LD50) was calculated by logistic regression. LD50 doses were 6.7 Gy, 7.4 Gy, and 8.1 Gy with 1-mm Cu-filtered X-rays, Thoraeus-filtered X-rays, and 137Cs γ-rays, respectively. Comparison of bone marrow, spleen, and intestinal tissue from mice irradiated with equivalent doses indicated that injury was most severe with 1-mm Cu-filtered X-rays, which resulted in the greatest reduction in bone marrow cellularity, hematopoietic stem and progenitor populations, intestinal crypts, and OLFM4+ intestinal stem cells. Thoraeus-filtered X-rays provoked an intermediate phenotype, with 137Cs showing the least damage. This study reveals a dichotomy between physical dose and biological effect as researchers transition to orthovoltage X-rays. With decreasing energy, there is increasing hematopoietic and intestinal injury, necessitating dose reduction to achieve comparable biological effects.Significance:Understanding the significance of physical dose delivered using energetically different methods of radiation treatment will aid the transition from radionuclide γ-irradiators to orthovoltage X-irradiators.

The role of Lactobacillus-dominant microbiota in the endometrium in reproductive function is unclear. We therefore aimed to explore the impact of the balance of Lactobacillus and pathological bacteria in the endometrial and vaginal microbiomes on the pregnancy outcomes of women treated with assisted reproductive technology (ART).This study included 35 women with infertility submitted to good-quality embryo transfers. The cutoff values for abundance of Lactobacillus species (spp.) and pathological bacteria in the endometrium and vagina were calculated. Women with Lactobacillus spp. and pathological bacteria abundance above the cutoff values were categorized in the high-abundance group, whereas those with abundance below cutoff values were categorized in the low abundance group. We divided the patients into four groups based on the combination of high/low abundance of Lactobacillus spp. and pathological bacteria.The 35 cases of good-quality embryo transfer resulted in 21 pregnancies. Pregnant women were present in significantly higher proportions in the high Lactobacillus spp. abundance and low pathological bacteria abundance group, whereas the opposite combination (i.e., low Lactobacillus spp. abundance and high pathological bacteria abundance) saw a significantly higher proportion of nonpregnant women (p=0.022).The balance between Lactobacillus and pathological bacterial abundance in the endometrial and vaginal microbiomes is associated with pregnancy from ART.

Pelvic venous disease (PeVD) in women encompasses a wide variety of entities all resulting in pelvic pain and varices. Successful treatment with percutaneous interventions is dependent on identifying underlying factors contributing to the disease and addressing them with either embolization of incompetent veins or stenting for venous stenoses. There are a multitude of embolization methods with marked practice heterogeneity. Moreover, with the ongoing development of dedicated venous stents in the treatment of chronic venous disease, there are more opportunities to consider this modality for the treatment of PeVD, as many patients present with combined vein reflux and central venous stenosis. The necessity to address both and the order of interventions in these patients is still to be elucidated. Here, we describe when to choose stenting or embolization for PeVD, their limitations, and our practice and identify further areas of research in this field.

Transarterial radioembolization (TARE) with yttrium-90 microspheres has emerged as an effective therapy for the treatment of both primary and metastatic hepatic lesions. It has been studied most extensively in hepatocellular carcinoma (HCC) and metastatic colorectal lesions (mCRC). The clinical success of TARE in HCC and mCRC has led to further investigation of expanding treatment to other malignancies involving the liver such as neuroendocrine carcinoma, uveal melanoma, and breast carcinoma, among others. Furthermore, interest in applications of TARE outside of the liver is emerging and small initial studies have been performed primarily in animal models to assess the effects of TARE on other organs such as the brain, stomach, spleen, kidney, and lungs. This review summarizes existing literature on the use of TARE outside of the liver.

Radionuclide irradiators (137Cs and 60Co) are commonly used in preclinical studies ranging from cancer therapy to stem cell biology. Amidst concerns of radiological terrorism, there are institutional initiatives to replace radionuclide sources with lower energy X-ray sources. As researchers transition, questions remain regarding whether the biological effects of γ-rays may be recapitulated with orthovoltage X-rays because different energies may induce divergent biological effects. We therefore sought to compare the effects of orthovoltage X-rays with 1-mm Cu or Thoraeus filtration and 137Cs γ-rays using mouse models of acute radiation syndrome. Following whole-body irradiation, 30-day overall survival was assessed, and the lethal dose to provoke 50% mortality within 30-days (LD50) was calculated by logistic regression. LD50 doses were 6.7 Gy, 7.4 Gy, and 8.1 Gy with 1-mm Cu-filtered X-rays, Thoraeus-filtered X-rays, and 137Cs γ-rays, respectively. Comparison of bone marrow, spleen, and intestinal tissue from mice irradiated with equivalent doses indicated that injury was most severe with 1-mm Cu-filtered X-rays, which resulted in the greatest reduction in bone marrow cellularity, hematopoietic stem and progenitor populations, intestinal crypts, and OLFM4+ intestinal stem cells. Thoraeus-filtered X-rays provoked an intermediate phenotype, with 137Cs showing the least damage. This study reveals a dichotomy between physical dose and biological effect as researchers transition to orthovoltage X-rays. With decreasing energy, there is increasing hematopoietic and intestinal injury, necessitating dose reduction to achieve comparable biological effects. Significance: Understanding the significance of physical dose delivered using energetically different methods of radiation treatment will aid the transition from radionuclide γ-irradiators to orthovoltage X-irradiators.

PurposeRadionuclide irradiators (137Cs and 60Co) are commonly used in preclinical studies ranging from cancer therapy to stem cell biology. There are institutional initiatives to replace radionuclide sources with lower-energy X-ray sources amidst concerns of radiological terrorism. As researchers transition, there are questions whether the biological effects of γ-rays may be recapitulated with orthovoltage X-rays, since different energy may cause different biological effects. We, therefore, sought to compare the effects of orthovoltage X-rays and 137Cs γ-rays using mouse models of acute radiation syndrome.Experimental Design137Cs γ-rays were compared with Orthovoltage X-rays, generated at 300 kVp, 10 mA with 1 mm Cu or Thoraeus filtration. We assessed 30-day overall survival following whole-body irradiation and calculated LD50 by logistic regression. Comparing equivalent doses delivered with different average energies (Ē), we assessed bone marrow, spleen, and intestinal histology and flow cytometry.ResultsThe LD50 doses are 6.7 Gy, 7.4 Gy and 8.1 Gy with 1 mm Cu filtered (Ē=120 keV), and Thoraeus filtered X-rays (Ē=160 keV), and 137Cs (E=662 keV), respectively. At constant dose, hematopoietic injury was most severe with 1 mm Cu filtered X-rays with the greatest reduction in bone marrow cellularity, stem and progenitor populations, and intestinal crypts and OLFM4+ intestinal stem cells. Thoraeus filtered X-rays provoked an intermediate phenotype, with 137Cs showing the least damage.ConclusionsOur study reveals a dichotomy between physical dose and biological effect relevant as researchers transition to orthovoltage X-rays. With decreasing energy, there is increasing hematopoietic and intestinal injury, necessitating dose-reduction to achieve comparable biological effects.Statement of Translational RelevanceRadiation is used in translational studies in fields ranging from hematopoiesis and stem cell biology to cancer radiotherapy, with 137Cs and 60Co radionuclide sources serving as the most common irradiators. Due to the threat of radiological terrorism using stolen radionuclides, there are institutional initiatives to replace these sources with orthovoltage X-ray irradiators. Yet, as shown in this study, the biological effects of radiation are highly dependent on radiation energy. Lower energy orthovoltage X-rays are absorbed differently than higher energy radionuclide γ-rays, provoking more severe hematopoietic, immunologic, and gastrointestinal radiation injury. Thus, an identical physical dose delivered with beams of differing energy does not produce the same biologic effect. As researchers transition between these sources, it is critical that we appreciate that radiation doses are not interchangeable between them. Understanding the significance of physical dose delivered using different methods will allow us to contextualize past results with future studies.

Purpose: To investigate the relationship between the microbiome of the female genital tract and endometriosis. Methods: This prospective cohort study included 36 women who underwent laparoscopic surgery for ovarian tumor from July 2019 to April 2020. Of them, 18 had endometriosis, and 18 did not have endometriosis. Vaginal secretions, endometrial fluid, peritoneal fluid, and ovarian cystic fluid were collected during surgery. Next-generation sequencing of bacterial 16S rRNA was performed to characterize the microbiome. Results: Specific microbiomes were not detected in either peritoneal fluid or ovarian cystic fluid regardless of the presence or absence of endometriosis and the type of cyst. When the cutoff value of infectious bacterial abundance in the vagina was set as 64.3%, there were many cases more than a cutoff value in the endometriosis group significantly (p = 0.01). When the cutoff value of infectious bacterial abundance in the endometrium was set as 18.6%, there were many cases more than a cutoff level in the endometriosis cases significantly (p = 0.02). Conclusion: Peritoneal fluid and ovarian cystic fluid are almost sterile, although dysbiosis may occur in the vaginal and endometrial microbiome in women with endometriosis.

BackgroundJuvenile Arthritis Disease Activity Score (JADAS) has been developed as a composite disease activity score specific to Juvenile idiopathic arthritis (JIA). Evaluation of disease activity with a composite measure associated with subsequent changes in structural damage of joints and physical function is necessary for the proper management of Rheumatoid Arthritis (RA) with treat-to-target strategy, and this concept should be considered for patients with JIA in transition and adulthood as well. However, the usefulness of JADAS-27 and other composite measures for RA in these patients has been scarecely investigated. Additionally, JADAS-27 is unfamiliar to non-pediatric rheumatologists.ObjectivesWe aimed to investigate an optimal composite score for disease activity in adult JIA from the viewpoint of the subsequent changes in physical function.MethodsPatients diagnosed with JIA with the following conditions were enrolled: 1) disease onset at age < 18 years; 2) registered in the IORRA database for the first time between 2000 and 2020; and 3) ≥18 years old at the time of IORRA registration. The baseline of each patient was their initial entry into the IORRA database. The Simplified Disease Activity Index (SDAI), Disease Activity Score using 28 joints (DAS28), and JADAS-27 were compared. The patients were stratified into four disease activity categories: remission/inactive disease, low disease activity, moderate disease activity, and high disease activity according to mean disease activity scores in each index during the first year from baseline, and mean changes in J-HAQ (mean ΔJ-HAQ) during 2 years from baseline in each disease activity group were estimated using the linear mixed effect model to account for correlations of repeated measures without filling in the missing data after adjusting for sex, age, and disease duration.ResultsWe included 294 eligible individuals (median age at onset, 14.0 years; rheumatoid factor positive in 64.7%). The median age at baseline and disease duration was 33.8 (24.1–47.7) years and 21.0 (11.0–34.0) years, respectively. The J-HAQ was completed in all 294 patients, and 171 (58.1%) had a score of less than 0.5 at baseline, which is defined as functional remission. During the 2-year observation period, the median J-HAQ of all patients remained unchanged. There was a trend toward improvement in disease activity over time in all three composite scores. Some differeces were obsered across the three indeces: a higher proportion of patients with high disease activity and a lower proportion of patients in remission/inactive disease were observed with JADAS-27 versus SDAI and DAS28. A significant increasing trend of the estimated mean ΔJ-HAQ at 2 years after baseline was observed along with an increase in the mean disease activity during the first year measured using DAS28 (p = 0.01) and SDAI (p = 0.018), but not using JADAS-27 as shown in Table 1.Table 1.Association of the mean disease activity categories during the first year after baseline and mean changes in J-HAQ during the two years after baseline(n = 294)SDAIDAS28JADAS-27Remission/inactive disease0.019 [−0.190, 0.228]0.053 [0.024, 0.130]0.081 [−0.072, 0.234]LDA0.091 [−0.150, 0.332]0.102 [−0.013, 0.217]0.054 [−0.102, 0.210]MDA or HDA0.155 [−0.286, 0.596]0.136 [0.030, 0.242]0.087 [0.022, 0.152]p-value for trend0.0190.0100.115(Data are expressed as J-HAQ [95% confidence interval]. P-value less than 0.05 indicate a significant trend of the mean ΔJ-HAQ during the two years after baseline. LDA low disease activity; MDA moderate disease activity; HDA high disease activity)ConclusionDisease activity measured using SDAI and DAS28, but not using JADAS27, was significantly associated with subsequent changes in physical function in transitional and adult patients with JIA. This study support the use of SDAI and DAS28, but not JADAS27, in assessing disease activity in these patients to adjust treatments for preventing future deterioration of physical function.Disclosure of InterestsTakako Miyamae: None declared, Eisuke Inoue Speakers bureau: EI has received lecture fees or consulting fees from Bristol Myers Squibb Co., Ltd., Pfizer Japan Inc., and Nippontect systems Co. Ltd., Eiichi Tanaka Speakers bureau: ET has received lecture fees or consulting fees from AbbVie Japan GK, Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Celltrion Healthcare Japan CO, LTD., Chugai Pharmaceutical Co., Ltd., Daiichi-Sankyo, Inc., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kyowa Pharma Chemical CO., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Co., Mochida Pharmaceutical CO., Ltd., Nippon Kayaku Co., Ltd., Pfizer Japan Inc., Takeda Pharmaceutical Co., Ltd., Teijin Pharma Ltd, and UCB Japan Co. Ltd., Tomohiro Kawabe: None declared, Katsunori Ikari: None declared, Masayoshi Harigai Speakers bureau: MH has received speaker’s fee from AbbVie Japan GK, Astra Zeneca K. K., Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Gilead Sciences Inc., Janssen Pharmaceutical K.K., Kissei Pharmaceutical Co., Ltd., Nippon Kayaku Co., Ltd., Nippon Shinyaku Co., Ltd., Novartis Japan, Pfizer Japan Inc., CIMIC Holdings Co., Ltd., Mitsubishi Tanabe Pharma Co., Teijin Pharma Ltd and UCB Japan., Consultant of: MH is a consultant for AbbVie, Boehringer Ingelheim, Bristol Myers Squibb Co., Kissei Pharmaceutical Co., Ltd., and Teijin Pharma., Grant/research support from: MH has received research grants from AbbVie Japan GK, Asahi Kasei Corp., Astellas Pharma Inc., Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Daiichi-Sankyo, Inc., Eisai Co., Ltd., Kaken Pharmaceutical Co., Ltd., Kissei Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., Sekisui Medical, Taisho Pharmaceutical Co., Ltd., and Teijin Pharma Ltd.

Many gallbladder adenocarcinomas (ACs) are detected incidentally in routine cholecystectomy specimens, yet sampling practices vary when intestinal metaplasia (IM) or dysplasia are found via routine sampling. Our practice has been to submit 5 additional sections when IM is found, but cases with dysplasia are entirely submitted. We sought to determine an appropriate sampling protocol when encountering these findings. We retrospectively identified cholecystectomy specimens with these features over a 26-month period, yielding 48 of 4059 (1%) cases. Four pathologists independently classified the (2 longitudinal and 1 cystic duct margin) original sections into 1 of 3 categories (IM, low-grade dysplasia [LGD] or high-grade dysplasia [HGD]); initial findings were correlated with final diagnoses. Sixteen (33%) cases had additional findings upon further sampling, including LGD (n=10) or HGD (n=4) and AC (n=2). HGD always accompanied malignancy. We prospectively analyzed 39 of 3133 (1%) additional cholecystectomy specimens, initially submitting the same routine sections. We submitted 5 random sections from cases with IM. Cases with LGD were first examined with 1 additional section per centimeter. All remaining tissue was submitted in all of these cases and separately reviewed. Cases with HGD were entirely submitted as both test cases with HGD in initial sections ultimately showed carcinoma. This protocol detected all cases of HGD and AC. Patients with clear cystic duct margins did not experience neoplastic progression, even if dysplasia was present elsewhere. We conclude gallbladders with HGD should be entirely submitted, LGD may be representatively sampled, and routine sampling is adequate for IM.

Background One mechanism underlying the development of alcoholic liver disease is overactivation of the innate immune response. Recent investigations indicate that the lysosomal pathway of autophagy down-regulates the inflammatory state of hepatic macrophages, suggesting that macrophage autophagy may regulate innate immunity in alcoholic liver disease. The function of macrophage autophagy in the development of alcoholic liver disease was examined in studies employing mice with a myeloid-specific decrease in autophagy. Methods Littermate control and Atg5Δmye mice lacking Atg5-dependent myeloid autophagy were administered a Lieber-DeCarli control (CD) or ethanol diet (ED) alone or together with lipopolysaccharide (LPS) and examined for the degree of liver injury and inflammation. Results Knockout mice with decreased macrophage autophagy had equivalent steatosis but increased mortality and liver injury from ED alone. Increased liver injury and hepatocyte death also occurred in Atg5Δmye mice administered ED and LPS in association with systemic inflammation as indicated by elevated serum levels of proinflammatory cytokines. Hepatic macrophage and neutrophil infiltration were unaffected by decreased autophagy, but levels of proinflammatory cytokine gene induction were significantly increased in the livers but not adipose tissue of knockout mice treated with ED and LPS. Inflammasome activation was increased in ED/LPS-treated knockout mice resulting in elevated interleukin (IL)-1β production. Increased IL-1β promoted alcoholic liver disease as liver injury was decreased by the administration of an IL-1 receptor antagonist. Conclusions Macrophage autophagy functions to prevent liver injury from alcohol. This protection is mediated in part by down-regulation of inflammasome-dependent and inflammasome-independent hepatic inflammation. Therapies to increase autophagy may be effective in this disease through anti-inflammatory effects on macrophages.

Intrauterine infection is one of the most important causes of maternal death. In perinatal emergency, we often miss an opportunity to obtain culture specimens. In this study, we tried to examine whether we investigated whether bacteria causing infection can be detected from a formalin-fixed paraffin-embedded (FFPE) placental specimen. We examined the placenta from a maternal invasive infection that resulted in infectious abortion at 18 weeks of gestation. The case was diagnosed by acute fever and abdominal pain, and the patient was cured after 3 weeks of intensive antimicrobial treatment. Four Streptococcus pyogenes strains were isolated from vaginal fluid and blood cultures of the patient. All of the strain types were emm1/ST28. We amplified the V1–V2 region of 16S rRNA from an FFPE placental specimen and sequencing was performed using a next-generation sequencer (NGS). Taxonomic analysis was then performed for sequenced data. We succeeded in detecting causative pathogens from the FFPE placenta: 69.1% of the predominantly identified bacteria were S. pyogenes and other small populations of bacteria were detected. Our results revealed the utility of NGS for 16S rRNA analysis of an FFPE placenta. This method may reveal previous perinatal invasive infections of unknown origin retrospectively.

Noncollinear antiferromagnets have promising potential to replace ferromagnets in the field of spintronics as high-density devices with ultrafast operation. To take full advantage of noncollinear antiferromagnets in spintronics applications, it is important to achieve efficient manipulation of noncollinear antiferromagnetic spin. Here, using the anomalous Hall effect as an electrical signal of the triangular magnetic configuration, spin-orbit torque switching with no external magnetic field is demonstrated in noncollinear antiferromagnetic antiperovskite manganese nitride Mn$_3$GaN at room temperature. The pulse-width dependence and subsequent relaxation of Hall signal behavior indicate that the spin-orbit torque plays a more important role than the thermal contribution due to pulse injection. In addition, multistate memristive switching with respect to pulse current density was observed. The findings advance the effective control of noncollinear antiferromagnetic spin, facilitating the use of such materials in antiferromagnetic spintronics and neuromorphic computing applications., Comment: Accepted in Physical Review Applied

Purpose This study aimed to assess the efficacy of a virtual information session hosted by a diagnostic radiology residency program at addressing applicant concerns about the 2020-2021 interview cycle and highlighting key aspects of the residency program. Methods Participants were recruited to attend the virtual information session over a 2-week period via social media and communication with medical school radiology interest groups. Attendees were able to submit questions or topics of interest prior to the session. The virtual information session was hosted by trainees and faculty from a radiology residency. Data regarding the demographics of the attendees and the efficacy of the session were obtained through interactive live polling during the virtual session and a voluntary anonymous postsession survey. Results A total of 171 attendees participated in the virtual information session. Of the attendees, 42% learned about the session from Twitter and 72% were fourth-year medical students applying for residency. Among topics addressed during the session, attendees indicated that they were most interested in learning about “Application strategies during COVID-19” during an in-session poll. On the post-session survey, 96% of attendees reported being more knowledgeable about the residency program culture and the breadth of research and educational opportunities. Conclusion Given the virtual nature of the 2020-2021 residency application cycle, utilization of web-based platforms for recruitment will be essential. Virtual information sessions can be effective at providing insight into aspects of a residency program that are typically gained during the in-person interview experience.

BackgroundSerious infection is one of the most critical adverse events in patients with rheumatoid arthritis (RA) using biologic disease-modifying antirheumatic drugs (bDMARDs). During the first year, infections occur more frequently. Therefore, estimating the risk of developing a serious infection is important for the safe use of bDMARDs. The Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT) risk score predicted the incidence rate of serious infection during 1 year in patients with RA taking DMARDs. Moreover, it has been validated using data from various observational cohort studies and nationwide registries with favorable results, with a reported area under the receiver operating characteristic curve (AUROC) of 0.68–0.871–5. However, the RABBIT risk score has not been validated in RA patients starting a first bDMARD.ObjectivesTo investigate the discriminatory ability of the RABBIT risk score for predicting the development of serious infection during 1 year after starting first bDMARDs in Japanese patients with RA using data from the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort.MethodsThe IORRA cohort is a large observational cohort at the Institute of Rheumatology, Tokyo Women’s Medical University. Japanese patients with RA visiting our institute were registered and clinical parameters were assessed biannually. This study enrolled patients with RA who were registered in the IORRA cohort and treated with a first bDMARD. Patients who were missing data needed to calculate the RABBIT risk score were excluded. The RABBIT risk score was calculated using the patient’s age, comorbidities, Japanese-Health Assessment Questionnaire score, history of previous infections, and types of DMARDs used. Serious infections were defined as those requiring hospitalization or treatment with intravenous antibiotics. The occurrence of serious infection during 1 year after starting the first bDMARDs was identified using data from the biannual IORRA cohort and confirmed using medical records. The discriminatory ability of the RABBIT risk score was analyzed by the AUROC.ResultsA total of 1,081 patients with RA and a median age of 55.3 years, in which females were the majority (88.2%), were included. Serious infection occurred in eight patients during 1 year before starting their first bDMARDs. The number of patients starting a TNF inhibitor, IL-6 inhibitor, and abatacept were 830 (76.8%), 170 (15.7%), and 81 (7.5%), respectively. A total of 23 patients (1.7%) had serious infections during 1 year after starting the first bDMARD; the most frequent infection was pneumonia (n=16, 69.6%). The median RABBIT score was 2.3 (IQR 1.6–5.4) in patients with serious infections during the follow-up period, and 1.6 (IQR 1.2–2.5) in patients without serious infections. The discriminatory ability of the RABBIT risk score was slightly poor, with an AUROC of 0.67 (95% CI, 0.52– 0.79).ConclusionThe RABBIT risk score is highly practical; however, our present study suggested that some adjustments may be required to predict the risk of serious infection in Japanese patients with RA starting a first bDMARD.Figure 1.ROC curve of serious infection and RABBIT score with an AUROC of 0.67 (95% CI, 0.52– 0.79).Disclosure of InterestsTomoaki Higuchi: None declared, Eiichi Tanaka Speakers bureau: Abbvie, Asahi Kasei pharma co., Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo Co., Eisai Pharmaceutical, Janssen Pharmaceutical K.K., Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Taisho Toyama Pharmaceutical Co., and UCB Pharma., Paid instructor for: Abbvie, Asahi Kasei pharma co., Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo Co., Eisai Pharmaceutical, Janssen Pharmaceutical K.K., Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Taisho Toyama Pharmaceutical Co., and UCB Pharma., Eisuke Inoue Speakers bureau: Bristol-Meyers and Pfizer, Consultant of: Nippontect systems, Mai Abe: None declared, Kumiko Saka: None declared, Eri Sugano: None declared, Naohiro Sugitani: None declared, Yoko Shimizu: None declared, Moeko Ochiai: None declared, Rei Yamaguchi: None declared, Katsunori Ikari Speakers bureau: Asahi Kasei Pharma Corp., Astellas Pharma Inc., AbbVie Japan GK, Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., Janssen Pharmaceutical K.K., Kaken Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corp. Pfizer Japan Inc., Takeda Pharmaceutical Co. Ltd., Teijin Pharma Ltd and UCB Japan Co. Ltd., Yamanaka Hisashi: None declared, Masayoshi Harigai Speakers bureau: AbbVie Japan, Ayumi, Boehringer Ingelheim Japan, Bristol-Myers Squibb, Chugai, Eisai, Eli Lilly Japan, GlaxoSmithKline, Kissei, Pfizer Japan Inc, Takeda, Teijin, Consultant of: AbbVie Japan, Boehringer Ingelheim Japan, Bristol-Myers Squibb, Kissei, Teijin, Grant/research support from: AbbVie Japan, Asahi Kasei, Astellas, Ayumi, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Kissei, Mitsubishi Tanabe, Nippon Kayaku, Sekiui Medical, Shionogi, Taisho, Takeda, Teijin.

In a previous study we showed that a unique combination of high stiffness and high viscoelastic loss could be achieved by filling a polystyrene matrix with rigid inorganic spheres coated with a thin (∼200 nm) layer of a viscoelastic material. The sandwiching of this ‘lossy’ layer between the two rigid components was found to give a significant amplification of the tanδ loss peak associated with this material, without significantly compromising the sample stiffness. This was an experimental validation of the effect originally proposed by Gusev using finite element numerical studies. Following on from this, in the current study we have developed this concept further and shown that a similar amplification of viscoelastic loss can be achieved by incorporating rigid, but uncoated, particles into a phase separated matrix blend of polystyrene (PS) and a polystyrene/polyisoprene/polystyrene triblock co-polymer (SIS). The inspiration for this choice of the PS/SIS blend as the matrix came from some previous work where we studied, and modelled, the viscoelastic properties of these materials. In this work we show that in the filled PS/SIS blends, the loss amplification effect can been seen for different PS/SIS ratios, for different SIS polymers with different glass transition temperatures and also for glass fibres as well as for spherical particles. The key to seeing this effect is the fact that the SIS rubber phase was found to form a thin coating on the surface of the embedded particles during processing, effectively producing a surface coating layer on the particles (as well as phase separating within the PS matrix). As with our previous studies, it is shown that the experimentally measured effects are closely predicted by numerical micromechanical modelling based on the measured bulk properties of the three discrete components.

SummaryThe virulence ofBursaphelenchus xylophilus, the pine wood nematode, varies greatly among different populations. Two inbred strains, called P3 and P9, were recently establishedviarepeated full-sib mating. They exhibited remarkable differences in pathogenicity-related traits. Although their propagation did not differ when cultured on fungal lawns, P9 reproduced better in host seedlings and exhibited higher virulence. In the present study, we obtained fundamental information about P3 and P9 in terms of tolerance to oxidative stress and examined this tolerance and the cuticular ultrastructure. P9 survived better under hydrogen peroxide (H2O2)-stressed conditions than did P3. In addition, P9 had a thicker cuticle than P3. Although further studies are needed, these results suggest that the difference in tolerance in P3 and P9 was due not only to physiological features, such as H2O2-degrading ability, but also to physical factors (cuticle thickness).

Toxin-induced liver diseases lack effective therapies despite increased understanding of the role factors such as an overactive innate immune response play in the pathogenesis of this form of hepatic injury. Pentamidine is an effective antimicrobial agent against several human pathogens, but studies have also suggested that this drug inhibits inflammation. This potential anti-inflammatory mechanism of action, together with the development of a new oral form of pentamidine isethionate VLX103, led to investigations of the effectiveness of this drug in the prevention and treatment of hepatotoxic liver injury. Pretreatment with a single injection of VLX103 in the D-galactosamine (GalN) and lipopolysaccharide (LPS) model of acute, fulminant liver injury dramatically decreased serum alanine aminotransferase levels, histological injury, the number of terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL)-positive cells and mortality as compared to vehicle-injected controls. VLX103 decreased GalN/LPS induction of TNF but had no effect on other proinflammatory cytokines. VLX103 prevented the proinflammatory activation of cultured hepatic macrophages and partially blocked liver injury from GalN/TNF. In GalN/LPS-treated mice, VLX103 decreased activation of both the mitochondrial death pathway and downstream effector caspases 3 and 7 which resulted from reduced c-Jun N-terminal kinase activation and initiator caspase 8 cleavage. Delaying VLX103 treatment for up to 3 h after GalN/LPS administration was still remarkably effective in blocking liver injury in this model. Oral administration of VLX103 also decreased hepatotoxic injury in a second more chronic model of alcohol-induced liver injury, as demonstrated by decreased serum alanine and aspartate aminotransferase levels and numbers of TUNEL-positive cells. Conclusion: VLX103 effectively decreases toxin-induced liver injury in mice and may be an effective therapy for this and other forms of human liver disease. This article is protected by copyright. All rights reserved.

This paper is concerned with the prediction of the viscoelastic properties of rubber filled polymer blends. The question asked was as follows. Can the temperature dependent viscoelastic properties of phase separated polymer blends be adequately predicted using only a rational two phase micromechanics based analytical model with no empirical fitting parameters? In particular can this be achieved using only a knowledge of the individual bulk phase properties and the blend microstructure, but without any further detailed polymer physics knowledge such as the presence of an interphase region or any additional nanoscale structures within the separated rubber phase with the properties different from those of the two bulk phases? Blends of a polystyrene matrix containing phase separated rubber inclusions (a polystyrene-polyisoprene-polystyrene triblock polymer (SIS)) were manufactured in a range of blend fractions (up to 20 vol % of the triblock co-polymer). Experimental measurements, for the storage modulus G′ and the loss tangent tanδ, of both the individual phases and the blends, were made using dynamic mechanical tests over a range of temperatures from −50 to +70 °C. Numerical predictions, of the same properties, were first obtained using the generalised self-consistent Christensen and Lo model which uses a simple representative volume element (RVE) of an isolated sphere of the minority rubber component in a surrounding sheath of polystyrene matrix embedded in a homogeneous effective medium. The agreement between the Christensen and Lo model and the experimental measurements, for G′ and tanδ, was found to be excellent for rubber contents up to 10%. For a 20% rubber content, an improved prediction was obtained by altering the RVE to include the observed effect of having a polystyrene central core in a number of the dispersed rubber zones at this rubber fraction, using the Herve and Zaoui generalization of the Christensen and Lo model. Although conjoined (and therefore non-spherical) zones became more prevalent at the highest rubber content, use of the Tandon and Weng model showed that this shape anisotropy would not be expected to affect the viscoelastic properties.

Aims We explored the factors promoting long-term mental health among adolescent survivors of the 2008 Wenchuan earthquake in China. We examined the associations of their long-term mental health with disaster-related storytelling and school-based psychoeducation, and of school-based psychoeducation with disaster-related storytelling. Methods A secondary school-based cross-sectional survey was conducted 6 years after the disaster. Participants with traumatic experiences such as injury, loss, witnessing someone's death/injury and home destruction (N = 1028, mean age 15, standard deviation 1.38, male 51%) were eligible. Mental health/disaster education (MHE/DE) was defined as taking one or more lessons in MHE and/or DE at school since the earthquake. Experiences of storytelling about the disaster involved expressing distressing memories and feelings regarding the earthquake since the disaster happened, according to four groups: never expressed distressing memories and feelings, expressed them through writing/drawing, expressed them through talking to lay supporters and expressed them through talking to health professionals. Analysis of covariance was used to compare mean scores on five selected subscales of the Symptom Checklist-90 (SCL-90), the Athens Insomnia Scale (AIS) and the Psychotic-Like Experiences (PLEs) scale among the four storytelling groups. Linear regression analysis was used to identify the relationships between MHE/DE and current mental health as measured by the SCL-90, AIS and PLEs. The relationship between education and storytelling was probed by χ2 test. Results The talked-to-lay-supporters group showed better mental health on the SCL-90 (p ⩽ 0.001), AIS (p < 0.001) and PLEs (p = 0.004), while the consulted-health-professionals group showed worse mental health on the three dimensions of the SCL-90: depression (p = 0.05), anxiety (p = 0.02) and fear (p = 0.04), and on PLEs (p = 0.02) compared with the never-expressed group. MHE and DE were inversely associated with SCL-90, AIS and PLE scores. Participants who received these forms of education talked about their disaster experiences to lay supporters more than those who did not. Conclusions MHE and DE at school may promote adolescents’ mental health after a disaster. Experience of storytelling about the disaster to lay supporters may be helpful for long-term psychological recovery, and may be a potential mediating factor for school-based education and better mental health. Because of the cross-sectional nature of this study, causality cannot be inferred; therefore, further prospective intervention studies are needed to elucidate the effect of these factors on adolescent survivors’ mental health.

The pine wood nematode Bursaphelenchus xylophilus is the causal agent of pine wilt disease, one of the most devastating forest diseases in East Asian and West European countries. The lifecycle of B. xylophilus includes four propagative larval stages and gonochoristic adults which are involved in the pathogenicity, and two stages of dispersal larvae involved in the spread of the disease. To elucidate the ecological roles of each developmental stage in the pathogenic life cycle, we performed a comprehensive transcriptome analysis using RNA-seq generated from all developmental stages of B. xylophilus and compared transcriptomes between stages. We found more than 9000 genes are differentially expressed in at least one stage of the life cycle including genes involved in general nematode biology such as reproduction and moulting but also effector genes likely to be involved in parasitism. The dispersal-stage transcriptome revealed its analogy to C. elegans dauer and the distinct roles of the two larval stages from each other regarding survival and transmission. This study provides important insights and resources to understand B. xylophilus parasitic biology.

During sepsis, bacterial products, particularly LPS, trigger injury in organs such as the liver. This common condition remains largely untreatable, in part due to a lack of understanding of how high concentrations of LPS cause cellular injury. In the liver, the lysosomal degradative pathway of autophagy performs essential hepatoprotective functions and is induced by LPS. We, therefore, examined whether hepatocyte autophagy protects against liver injury from septic levels of LPS. Mice with an inducible hepatocyte-specific knockout of the critical autophagy gene Atg7 were examined for their sensitivity to high-dose LPS. Increased liver injury occurred in knockout mice, as determined by significantly increased serum alanine aminotransferase levels, histological evidence of liver injury, terminal deoxynucleotide transferase-mediated deoxyuridine triphosphate nick end-labeling, and effector caspase-3 and -7 activation. Hepatic inflammation and proinflammatory cytokine induction were unaffected by the decrease in hepatocyte autophagy. Although knockout mice had normal NF-κB signaling, hepatic levels of Akt1 and Akt2 phosphorylation in response to LPS were decreased. Cultured hepatocytes from knockout mice displayed a generalized defect in Akt signaling in response to multiple stimuli, including LPS, TNF, and IL-1β. Akt activation mediates hepatocyte resistance to TNF cytotoxicity, and anti-TNF antibodies significantly decreased LPS-induced liver injury in knockout mice, indicating that the loss of autophagy sensitized to TNF-dependent liver damage. Hepatocyte autophagy, therefore, protects against LPS-induced liver injury. Conditions such as aging and steatosis that impair hepatic autophagy may predispose to poor outcomes from sepsis through this mechanism.

This study was supported in part by the Bilateral Open Partnership Joint Research Projects ‘Study on assessing the risk of establishment and control of Sirex noctilio, a significant exotic pest of Pinus plantations’ from the Japan Society for the Promotion of Science (JSPS), and the National Research Foundation in South Africa, and Grants-in-Aid for Scientific Research Nos. 70435585 and 17H03831 from JSPS.

Background:Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) requires a long-term maintenance therapy (MT), often accompanied by hospitalization due to relapse and/or comorbidities such as infection1. However, data about direct medical costs of hospitalization during MT in patients with AAV is limited to date despite of an increasing concern about the economic burden of patients with AAV2-3.Objectives:To describe frequency of hospitalization and its direct medical costs during MT after the remission-induction therapy (RT) in patients with AAV using Japanese health insurance database.Methods:This retrospective longitudinal population-based study was conducted using claims data in Japan provided by Medical Data Vision Co., Ltd. We defined individuals as AAV cases receiving RT if they met all of the following: 1) having at least one ICD10 code (M300, M301, M313, or M318); 2) having at least one prescription of oral corticosteroids with prednisolone-equivalent dosage ≥30 mg/day, methylprednisolone pulse therapy, immunosuppressive drugs (cyclophosphamide [IVCY], methotrexate, or mycophenolate mofetil), or rituximab (RTX) during hospitalization between April 2008 and April 2017; and 3) having at least 7 days of hospitalization. The observation started from the next day of discharge from the first hospitalization for RT and ended at 24 months later, the month of loss of follow-up, or April 2017. We described the frequency of hospitalization and calculated direct medical costs (per month) during the observation. We analyzed medical costs from a societal perspective. We classified reasons of hospitalization into 3 categories; intensification of treatments for AAV, AAV MT including IVCY or RTX treatments, and comorbidities (infection, cardiovascular disease [CVD], malignancy, and others) using ICD10 codes plus treatments or interventions during the hospitalization.Results:In this study, 1,703 patients with AAV were included. The median [IQR] age was 72 [63, 79] years and 55.7% were female. The total number of hospitalization was 1,897 in 863 patients (50.7%). Among the hospitalizations, 296 hospitalization in 235 patients were categorized as intensification of treatments for AAV, 627 hospitalization in 297 patients were AAV MT, and 974 hospitalization in 572 patients were categorized as comorbidities. In the last category, infections were most frequent (220), followed by malignancy (54) and CVD (15). The mean direct medical costs per month was 20,945 EUR (1 EUR=125 JPY) in patients with hospitalization and 599 EUR in those without. Patients with hospitalization due to intensification of treatments for AAV had the highest direct medical costs (3,000 EUR), followed by those with hospitalization due to comorbidities (2,001 EUR), and those with hospitalization due to AAV MT (1,649 EUR).Conclusion:More than half of the patients had hospitalization during MT, and hospitalization due to comorbidities were most frequent. The mean direct medical costs in patients with at least one hospitalization was approximately 3.5 times as high as that in those without hospitalization.References:[1]Presse Med. 2015; 44:e251-e257[2]J. Rheumatol. 2015; 42:2383-91[3]Clin Exp Rheumatol.2019:137-43Acknowledgments:This work was supported by AMED under Grant Number JP17ek0109121.Disclosure of Interests:Ryoko Sakai Grant/research support from: Tokyo Women’s Medical University (TWMU) has received unrestricted research grants forDivision of Epidemiology and Pharmacoepidemiology of Rheumatic Diseases from Ayumi Pharmaceutical Co. Ltd., Bristol Meyers Squib, Chugai Pharmaceutical Co. Ltd., Nippon Kayaku Co. Ltd., Taisho Toyama Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Corp., and with which TWMU paid the salary of R.S., Eiichi Tanaka Consultant of: ET has received lecture fees or consulting fees from Abbvie, Asahi Kasei pharma co., Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo Co., Eisai Pharmaceutical, Janssen Pharmaceutical K.K., Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Taisho Toyama Pharmaceutical Co., and UCB Pharma., Speakers bureau: ET has received lecture fees or consulting fees from Abbvie, Asahi Kasei pharma co., Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo Co., Eisai Pharmaceutical, Janssen Pharmaceutical K.K., Nippon Kayaku, Pfizer, Takeda Pharmaceutical, Taisho Toyama Pharmaceutical Co., and UCB Pharma., masayoshi harigai Grant/research support from: AbbVie Japan GK, Ayumi Pharmaceutical Co., Bristol Myers Squibb Co., Ltd., Eisai Co., Ltd., Mitsubishi Tanabe Pharma Co., Nippon Kayaku Co., Ltd., and Teijin Pharma Ltd. MH has received speaker’s fee from AbbVie Japan GK, Ayumi Pharmaceutical Co., Boehringer Ingelheim Japan, Inc., Bristol Myers Squibb Co., Ltd., Chugai Pharmaceutical Co., Ltd., Eisai Co., Ltd., Eli Lilly Japan K.K., GlaxoSmithKline K.K., Kissei Pharmaceutical Co., Ltd., Oxford Immuotec, Pfizer Japan Inc., and Teijin Pharma Ltd. MH is a consultant for AbbVie, Boehringer-ingelheim, Kissei Pharmaceutical Co., Ltd. and Teijin Pharma.