Japanese Labeling Research Articles

Hikikomori and Sōshokukei-danshi: A semantic analysis of Japan’s social deviants

This study is a semantic analysis that examines the meanings of two contemporary Japanese labels, hikikomori and soushokukei-danshi. This duo has often been linked to the late marriage age, declining marriage rate, shoushika (low birth rate), and koureika (the aging society). The goal of this thesis is to define these individuals according to the perceptions of native Japanese speakers and to convey the definitions by using the reductive paraphrase methodology. Accordingly, cultural values reflected in the labels will be revealed. The Natural Semantic Metalanguage (NSM) approach and corpus analysis are the chosen methodology. NSM is a universal mini metalanguage, while corpus analysis is a tool that can analyse data from online sources. Combined, these methods support the goal of delivering explications that reflect the labels from a Japanese perspective. Results from the study show that the values of Japanese society and the duos are at odds with one another, subsequently, fuelling the negative stigma directed towards both cohorts: Hikikomori are individuals who are emotionally withdrawn and bound to the house for the most part. Furthermore, their condition is something they feel they cannot change so easily; and Soushokukei-danshi are young men who are uninterested in romance or attaining stereotypical male positions in the workforce. Moreover, they would rather invest time in their hobbies. Through this study, a better comprehension of what these words mean is acquired.

Goal Attainment Scaling for Depression: Validation of the Japanese GAS-D Tool in Patients with Major Depressive Disorder.

Goal attainment scaling (GAS) has been proposed as a person-centric, semi-quantitative measure that assimilates achievement of individually set goals into a single standardized "goal attainment score" that can be compared at the population level. We aimed to examine the reliability and validity of the Japanese version of the GAS for depression (GAS-D) tool in assessing goal attainment in people living with major depressive disorder (MDD). This was a prespecified analysis of a prospective, 24-week, multicenter, observational cohort study of employed Japanese outpatients with MDD initiating treatment with vortioxetine according to the Japanese label (JRCT1031210200). Participants were assessed using the Japanese version of the GAS-D and other clinical rating scales at baseline and Weeks 8, 12 and 24. Goal attainment was significantly associated with symptom severity as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS) scale, confirming convergent validity. In particular, GAS-D scores were significantly related to MADRS total score at Weeks 12 and 24, indicating that improvements in overall symptom severity with vortioxetine treatment were likely to be reflected in the achievement of individualized treatment goals. With an intraclass correlation coefficient of 0.67 (95% CI 0.45-0.82), the GAS-D also showed moderate test-retest reliability between Weeks 8 and 12 while proving independent of demographic characteristics. The results of this open-label study support the use of the GAS-D as a valid and sensitive outcome measure in the assessment of treatment response in MDD.

Initial real-world experience of clazosentan for subarachnoid hemorrhage in Japan

BACKGROUNDCerebral vasospasm (CVS) is one of the most critical factors associated with clinical outcomes of patients with subarachnoid hemorrhage (SAH). Clazosentan has been investigated worldwide as a prophylactic agent to prevent CVS. We evaluated a new CVS management protocol which included clazosentan. METHODSConsecutive 138 patients with SAH, hospitalized in our institution between January 2017 and December 2022, were included in this study. Baseline characteristics, clinical findings, and operative records were analyzed retrospectively. From May 2022, 10 mg/h clazosentan was co-administered with fasudil to all patients according to the indication in the Japanese label. Patients admitted before this date received the conventional combined protocol using the fasudil hydrochloride, nicardipine, and ozagrel. RESULTSEighteen (13.0%) patients received the new protocol during the CVS period (defined as day 1 up to day 14 after SAH onset). There were 54 (39.1%) elderly patients aged 75 years or older. Seventy-two (52.2%) patients underwent neurosurgical clipping, whereas 55 (39.9%) patients received endovascular coiling. Among the patients with new protocol, only one patient (5.6%) had symptomatic CVS, compared with 18 patients (15.0%) in those with conventional protocol. More patients who received the new protocol had fluid retention compared with control group (38.9% [7/18] vs. 8.3% [10/120]). Other results did not differ between the two groups. CONCLUSIONSClinical outcomes of the new protocol were comparable to those of conventional protocol. Clazosentan may simplify anti-vasospasm treatment. Fluid retention was a specific side-effect of clazosentan, which requires attention especially in the first half of the CVS period.

Assessing Reliability and Validity of the Oxford Depression Questionnaire (ODQ) in a Japanese Clinical Population.

Originally developed in English, the Oxford Depression Questionnaire (ODQ) is a patient-reported scale specifically developed for assessing emotional blunting in people with major depressive disorder (MDD). We aimed to examine the reliability and validity of the Japanese version of the ODQ. This was a prespecified analysis of a prospective, 24-week, multicenter, observational cohort study of employed Japanese outpatients with MDD initiating treatment with vortioxetine according to the Japanese label (JRCT1031210200). Participants were assessed using the Japanese version of the ODQ and other clinical rating scales at baseline and Weeks 8, 12 and 24. One hundred and sixteen patients initiated vortioxetine and had ≥1 post-baseline visit. Directionally, the associations between ODQ scores and other clinical measures were as expected and demonstrated good concurrent validity. Factor analysis shows that the scale has a good fit for three factors. The Cronbach's α coefficient was 0.912, and the scale also showed good test-retest reliability with intraclass correlation coefficients for the ODQ total score and domains ranging between 0.69 and 0.82. ODQ scores had strong positive correlations with symptom severity assessed using the Montgomery and Åsberg Depression Rating Scale and were moderately correlated with work productivity, overall functioning, and quality of life scales. Data from this prospective analysis confirm that the Japanese version of the ODQ retains the good validity and reliability of the original English scale and is suitable for use in prospective studies wanting to capture treatment effects on emotional blunting in MDD.

Safety and tolerability of agalsidase beta infusions shorter than 90 min in patients with Fabry disease: post-hoc analysis of a Japanese post-marketing study

BackgroundAgalsidase beta, an enzyme replacement therapy for Fabry disease, is dosed biweekly at 1 mg/kg body weight, with increasing infusion rates based on tolerability. The US label specifies ≥ 90-min infusions for all patients; the US and EU labels require ≤ 15 mg/hr infusions in patients < 30 kg. The Japanese label allows infusions up to 30 mg/hr, allowing < 90-min dosing for some patients weighing < 45 kg. Japanese post-marketing data were analyzed for rate of infusion-associated reactions (IARs), adverse events (AEs), and serious AEs (SAEs) based on infusion rate and patient attributes (weight, antibody status).ResultsData were available for 436 reduced-duration infusions (< 90 min) and 2242 standard infusions (≥ 90 min). SAEs were rare (0.6%), and the frequency of all safety events decreased over the treatment course. Little impact of infusion duration on safety outcomes was observed: IARs and AEs were numerically more common when infusion duration was ≥ 90 min compared to < 90 min (IARs: 2.0% vs 0.9%; AEs: 2.9% vs 1.4%), while the rate of SAEs was similar (0.4% vs 0.5%). IAR, AE, and SAE frequencies decreased significantly with increasing infusion rates, and this trend was consistent in patients < 30 kg. Safety events tended to be less frequent in patients < 30 kg vs those ≥ 30 kg (IARs: 1.8% vs 2.1%; AEs: 2.3% vs 3.6%; SAEs: 0.0% vs 0.6%), although the differences were not statistically significant. IARs occurred in < 1% of all infusions in the < 30 kg group, 84% of which were < 90 min. More anti-agalsidase beta antibody-positive patients experienced IARs (41.9% vs 30.7%; P = 0.0445) and AEs (61.1% vs 49.3%; P = 0.0497) vs antibody-negative patients; however, there was no significant difference in the frequency of SAEs. In patients with available data, no changes in antibody status were observed after infusion durations were reduced to < 90 min.ConclusionsThe results of this post-hoc analysis demonstrated no significant impact of infusion duration on safety outcomes, and no significant difference in outcomes between patients of different weights. These findings suggest that infusion times in patients who are tolerating treatment can, with careful monitoring, be gradually decreased.

The Use of Subgroup Disproportionality Analyses to Explore the Sensitivity of a Global Database of Individual Case Safety Reports to Known Pharmacogenomic Risk Variants Common in Japan.

IntroductionGenetic variations of enzymes that affect the pharmacokinetics and hence effects of medications differ between ethnicities, resulting in variation in the risk of adverse drug reactions (ADR) between different populations. Previous work has demonstrated that risk-group considerations can be incorporated into approaches of statistical signal detection. It is unknown whether databases of individual case safety reports (ICSRs) are sensitive to pharmacogenomic differences between populations.ObjectiveThe aim of this study was to explore the sensitivity of a global database of ICSRs to known pharmacogenomic risk variants common in Japan.MethodsThe data source was VigiBase, the global database of ICSRs, including all reports entered in the version frozen on 5 January 2020. Subgroup disproportionality analysis was used to compare ICSRs of two subgroups, Japan and rest of world (RoW). Reports for UGT1A1-metabolized irinotecan and the CYP2C19-metabolized drugs voriconazole, escitalopram and clopidogrel were selected for comparison between the subgroups based upon known genetic polymorphisms with high prevalence in Japan. Contrast between the subgroups was quantified by IC delta ({mathrm{IC}}_{Delta }), a robust shrinkage observed-to-expected (OE) ratio on a log scale. Harmonic mean p values (HMP) were calculated for each drug to evaluate whether a list of pre-specified ADRs were collectively significantly over- (or under-)reported as hypothesized. Daily drug dosages were calculated for ICSRs with sufficient information, and dose distributions were compared between Japan and RoW and related to differences in regionally approved doses.ResultsThe predictions of over-reporting patterns for specific ADRs were observed and confirmed in bootstrap HMP analyses (p = 0.004 for irinotecan and p < 0.001 for each of voriconazole, escitalopram and clopidogrel) and compared with similar drugs with different metabolic pathways. The impact of proactive regulatory action, such as recommended dosing and therapeutic drug monitoring (TDM), was also observable within the global database. For irinotecan and escitalopram, there was evidence of use of lower dosages as recommended in the Japanese labels; for voriconazole, there was evidence of use of TDM with an over-reporting of terms related to drug level measurements and an under-reporting of liver toxicity.ConclusionsPharmaco-ethnic vulnerabilities caused by pharmacogenomic differences between populations may contribute to differences in ADR reporting between countries in a global database of ICSRs. Regional analyses within a global database can inform on the effectiveness of local risk minimization measures and should be leveraged to catalyse the conversion of real-world usage into safer use of drugs in ethnically tailored ways.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40264-021-01063-1.

Ethics of homeless representation in costume design

Marisol, set in 1993 New York City, depicts the end of the world from the perspective of a twenty-something Puerto Rican white collar woman who loses her guardian angel. In approaching the costume design for this play I encountered a deeply concerning question: how can I design costumes for homeless characters without appropriating the physical appearance of people who experience homelessness in real life? Homeless characters are represented in many iconic plays in English language theatre, from Angels in America to Oliver!, and costume designers are frequently asked to address the ethics of representation with their design choices. In this short article I share my process in sourcing primary reference images for homeless characters without appropriating the exclusionary violence of the people who are considered ‘out of place’ in today’s New York City. I considered the ethics of different approaches to sourcing primary research that I have used in the past but ultimately chose to give up ‘authenticity’ for ethics. For the design I used reference images sourced from Japanese label N. Hoolywood’s Fall 2017 Menswear Collection, a fashion design that directly appropriates people who experience homelessness. My choice to frame homelessness through the lens of fashion served our production of Marisol only because of its design concept but leaves open the question of how to ethically design costumes for homeless characters in other plays.

The Impact of Japanese Labels on the Perceived Relevance of Lean Production Practices in a Russian Bank

ABSTRACTWe investigate how the relevance of the Lean Production System (LPS) as perceived by employees of a Russian bank depends on whether LPS practices are labeled with transliterated original Japanese words or translated Russian words. Building on organizational translation scholarship contextualized to Russia, we formulate hypotheses about the mechanism through which labels affect the perceived relevance of practices. The results of an experimental study situated in a Russian bank show that transliterated Japanese labels have a negative impact on the perceived relevance of LPS practices by Russian employees. Further analysis reveals that this negative perception is fully mediated by the label's semantic fit, that is, the extent to which the label complies with the linguistic codes of the Russian language. Specifically, we find that, on average, the transliterated Japanese labels have a lower semantic fit than the translated Russian labels, and this difference in semantic fit explains the Japanese labels’ lower relevance as perceived by the bank's employees. By unpacking the causal effect of the labels used for management practices on the practices’ perceived relevance, this study advances our understanding of how organizations could influence employees’ acceptance of foreign management practices.

&lt;em&gt;Yaoi&lt;/em&gt;, YouTube, and Arabic-Speaking Fans

Yaoi, YouTube, and Arabic-Speaking Fans Ahmed Baroody (bio) Given the global popularity of manga and anime from Japan, it is unsurprising that these media, anime in particular, have countless fans in Arabic-speaking countries. While popular culture from abroad can easily clash with local conservative Islamic values, the focus on male characters and largely patriarchal gender roles depicted in long-popular shōnen anime such as Grendizer (Force Five: Grendizer), Mazinger, and Dragon Ball Z makes the storylines acceptable, even if the sexuality and violence in the uncensored versions available at underground stores and online are as problematic as they are exciting for viewers. The increasingly global genre of boys love (BL), which depicts male-male romance and intimacy, is quite another story, however. Although BL and its fandom have rapidly expanded around the world, given the strong Islamic prohibition of homosexuality, its small but possibly growing number of fans in the Middle East might seem unexpected, although the fans' lack of openness certainly is predictable. While the genre may be too sexual or taboo to be sold in local video stores, even in the underground stores selling uncensored shōnen anime, the internet has allowed it to reach Arabic-speaking Muslim fans via anime streaming websites, manga scanlation websites, and other channels. This availability has brought about the development of online Arabic-speaking fandoms in spite of local taboos, or perhaps in response to them. On various social networking platforms, fans have started to create their own groups and channels dedicated to yaoi—the Arabic pronunciation of which can be Romanized "yawi" or "yawe"—an older Japanese label for BL, which remains what most fans call the genre in Arabic. Yaoi has a strong presence on major platforms such as Twitter and Facebook, as well as more narrowly focused platforms such as Wattpad, dedicated to reading and writing fiction. Arabic-language yaoi fandom also has a strong presence on YouTube, with numerous fans uploading scenes from various anime as well as fan-produced anime music videos containing or edited to include BL scenes. Such users [End Page 176] are called ashig al yawi, meaning roughly, "I love yaoi," or, in other words, yaoi lovers. There are a large number of such users who flock to channels to view clips from BL anime, as well as mash-ups thereof, and imagery from BL manga and other media to evoke BL tropes. For instance, YouTubers Ashig Al Yawi, with over 6,000 subscribers, and Hidoeyuki Maya, with over 2,400 subscribers, have uploaded various BL-themed videos featuring Korean pop idols and as well as Arabic subtitled clips and mashups of BL anime, such as Yuri!!! on Ice and Banana Fish, and Thai BL dramas, sometimes with Arabic-language subtitles and always with Arabic comments, often accompanied by emoji expressing these fans' excitement over the videos. Each of these videos gets thousands, sometimes tens if not hundreds of thousands of views. Ashig Al Yawi's profile itself has received almost 1.4 million views as of January 2020 and the channel's videos seem to be enjoyed by fans. For instance, a pop music video with clips from various anime, "Video Voiced by Yaoi Lovers on How We View Our World," posted by Ashig Al Yawi in December 2017, has had over 8,500 views, and currently has over 200 comments and nearly 400 likes, against just 26 dislikes.1 Comments with a relatively high number of upvotes—roughly 20 to 30—include "This video is not just amazing, it's the BOMB," "Damn it I'm going to die from embarrassment, I love YAOI," and "It represents me." Such comments express fans' generally enthusiastic responses to the short clips of high school boy-on-boy romance and to the genre itself. Similarly, on Hidoeyuki Maya's YouTube channel, a since-removed video with an excerpt from the Korean BL anime Hyperventilation, received over 300 comments and 800 likes compared with just over 100 dislikes. Popular comments were a mix of general statements of fan pride and reactions to the video itself, such as, "My family always lectured me to not watch anime because it was childish, but . . . [now] I...

An Overview of the Commercial Publication of Japanese Boys Love (BL) Manga in Poland

An Overview of the Commercial Publication of Japanese Boys Love (BL) Manga in Poland Agata Włodarczyk (bio) When discussing the history of manga publishing in Poland, it is important to note that after World War II the country was governed by the communist party (PZPR)1 and until 1989 remained under the influence of the USSR; both conditions heavily affected the publishing market in general. During that time comic books were not regarded as a legitimate medium, and access to foreign comic books was highly restricted.2 The situation changed with the dramatic political shift in 1989, paving the way for manga to appear in mainstream book markets beginning in the second half of the 1990s, with the establishment of Japonica Polonica Fantastica (JPF) in 1996, soon followed by Waneko in 1999. Manga and anime culture in Poland grew not from an already established comics culture, but from a culture based around gamers as well as young teenagers watching anime on TV. It was apparent to these publishers that, rather than classic titles, these potential manga consumers would want to read currently popular works, manga usually known through anime broadcast on local TV, or those that fans accessed online. While JPF and Waneko began to respond to the perceived interest of this nascent fandom, they did not publish boys love (BL) manga, either by conscious choice or ignorance, creating a situation in which fans knew of the genre by accessing it online, often on scanlation sites or by purchasing foreign language editions, but were unable to buy a Polish language copy. As a result, for a long time CLAMP's X, first published in Poland in 2000,3 was regarded by fans as BL (or, more correctly, as "yaoi," an older Japanese label that still is a dominant umbrella term used among Polish fans). This was not because X was actually BL, but because the manga, by a collective association with works that sometimes include same-sex couples, was as close as fans could get to it in a commercially published work in Polish. Although an exact date is impossible to pinpoint, BL fandom itself started forming in Poland around 1998, when many female fans began discussing a possible romantic relationship between two of Sailor Moon's antagonists, [End Page 167] Zoisite and Kunzite—who are presented in the Polish version of the anime as brothers—during offline meetings, on online forums, Yahoo mailing lists, and on mIRC (chat client) channels. In 2001, a specifically BL-related webpage was created by a Japanese language student,4 with its author often organizing BL-themed meetings in Warsaw. In 2003 and 2004 the group organized Aicon, Poland's first yaoi-themed convention, involving around 350 participants each time. One of the more interesting aspects of BL fandom in Poland from its coalescence at the end of the 1990s is the fact that many of its members have enjoyed the reading and writing of slash fanfiction. Nowadays "slash" and "yaoi" are generally used synonymously by fans about male-male love relationships in any media and any form.5 The slowly growing visibility and activity of Polish BL fans since the late 1990s evidences a demand for this kind of work. In response, the tiny shortlived publisher Saisha was established and in 2003 published the first volume of Higuri You's BL manga Cutlass (Katorasu) as its first title, followed that same year by Rieko Yoshihara's light novel At no kusabi (The space between).6 Both gave fans hope that they would be able to see more of their favorite BL works translated into Polish. Saisha managed to publish one more manga, this time including explicit sex scenes, Takashima Kazusa's Wild Rock in 2005.7 However, the poor quality of the translation and editing of Ai no kusabi, combined with the complicated and restrictive purchase process, whereby fans were required to provide proof that they were of legal age to read a comic with sexual content when ordering either of the publisher's two manga by mail, seems to have brought about Saisha's downfall. While the existing manga publisher Studio JG revived the commercial publication of BL in Poland several...

Tacrolimus ointment for the treatment of adult and pediatric atopic dermatitis: Review on safety and benefits.

Atopic dermatitis (AD) requires long‐term management, mainly with topical anti‐inflammatory agents. Topical corticosteroids (TCS) and tacrolimus ointment (TAC‐O) are recommended as first‐line treatments for AD. However, the long‐term use of TCS is limited by cutaneous adverse events such as skin atrophy. For TAC‐O, Japanese and US labelings were updated in 2003 and 2006, respectively, to include a boxed warning about a theoretical risk of skin cancer and lymphoma in patients treated with topical calcineurin inhibitors. However, TAC‐O has been used worldwide for longer than 15 years to treat adult and pediatric patients with AD. Available data suggest that TAC‐O is effective and well tolerated, and can improve quality of life. TAC‐O has successfully been used in the proactive management of AD consisting of long‐term intermittent use to prevent, delay or reduce the occurrence of AD flares. Systemic drug absorption after TAC‐O application is negligible and unlikely to result in systemic immunosuppression. There is currently no strong evidence of an increased rate of malignancy in treated patients, and observational data from postmarketing surveillance studies have shown no safety concerns. In the absence of robust evidence, the warning about the carcinogenic potential in the Japanese labeling for TAC‐O does not appear justified and should be reconsidered. This mitigation of description would allow adult and pediatric patients with AD to receive the effective treatment more appropriately.

Pharmacogenomic biomarkers: Interpretation of information included in United States and Japanese drug labels

Many drug labels contain information on pharmacogenomic biomarkers (PGBMs), but the information is not necessarily actionable. Pharmacogenomics Knowledgebase (PharmGKB) aims to clarify the level of action for PGBMs (PGx levels) implied in each label as issued by the US Food and Drug Administration. We wished to evaluate the association between the PGx level for US and Japanese drug labels and the insurance coverage for PGBM testing or approval for in vitro diagnostics (IVDs) in each country. We investigated the information on PGBMs in US and Japanese drug labels with PGx levels, insurance coverage of PGBM tests and IVD approval in the US and Japan. We analysed the relationship of PGx levels with insurance coverage. A total of 243 labels were listed by PharmGKB, and 215 (88%) had PGx levels for US labels and 52 (21%) for Japanese labels. Of the 215 US labels, 54 were designated as "Testing Required" in PGx levels. PGx levels in US labels were strongly associated with coverage of PGBM testing. Tests in 52 (96%) of the 54 labels with Testing Required had insurance coverage, 2 (50%) of 4 in "Testing Recommended," 38 (38%) of 100 in "Actionable PGx," 11 (19%) of 57 in "Informative PGx" and 3 (11%) of 28 in "No Level." In Japanese labels, only 14 of 52 were listed as Testing Required, and all were covered by the National Health Insurance in Japan. The PGx level given in drug labels provides information on availability of PGBM testing. Higher PGx levels, based on better evidence of usefulness of PGBM testing, provide a route to broader test coverage.

Analysis of Spontaneous Postmarket Case Reports Submitted to the FDA Regarding Thromboembolic Adverse Events and JAK Inhibitors.

The Janus kinase (JAK) inhibitor baricitinib is approved in Europe and Japan for the treatment of rheumatoid arthritis. In April 2017, the US FDA expressed concern about thromboembolic events (deep venous thrombosis [DVT] and pulmonary embolism [PE]) observed in placebo-controlled clinical trials of baricitinib. The European and Japanese labels for baricitinib were recently updated to include a precaution related to potential thromboembolic events in patients at risk. Given that the FDA-approved drugs tofacitinib and ruxolitinib are in the same class, we conducted a safety review of the FDA's Adverse Event Reporting System (FAERS) to assess postmarketing reporting rates for related thromboembolic risks. Adverse event (AE) data for tofacitinib, tofacitinib extended-release (XR), and ruxolitinib were obtained from the FAERS. Reporting odds ratios (RORs) and the R package 'PhViD' to estimate the empirical Bayesian geometric mean (EBGM) were used to detect AEs with higher-than-expected reporting rates within the FAERS. We did not find evidence in the FAERS for elevated reporting rates for DVT and PE across the three JAK inhibitors we analyzed. However, multiple drug-AE combinations relating to thromboembolic events had both RORs and EBGM values above 1, indicating a trend toward higher-than-expected reporting rates. For pulmonary thrombosis, the ROR values for ruxolitinib, tofacitinib, and tofacitinib XR were 1.46 (95% confidence interval [CI] 0.76-2.80), 2.46 (1.55-3.91), and 2.48 (0.80-7.71), respectively, while the EBGM values were 1.25 (0.70), 2.46 (1.64), and 1.56 (0.57), respectively. Ruxolitinib had ROR values of 4.08 (2.25-7.38) and 1.22 (0.97-1.53) for portal vein thrombosis and thrombosis, respectively. The EBGM values for the same drug-AE combinations were 3.04 (1.79) and 1.16 (0.96). Our safety review of postmarketing FAERS reports associated with three FDA-approved JAK inhibitors did not find elevated reporting rates for DVT and PE specifically. However, the FAERS data indicated that pulmonary thrombosis may potentially be a class-wide issue for JAK inhibitors. Portal vein thrombosis may also be a potential risk for ruxolitinib. While these FAERS data add to a growing body of evidence that JAK inhibitors may be contraindicated in patients at risk of thromboembolic events, the data need to be confirmed by future AE reporting trends, analysis of electronic health records, and/or future clinical trials.

Edoxaban versus enoxaparin for the prevention of venous thromboembolism after total knee or hip arthroplasty: pooled analysis of coagulation biomarkers and primary efficacy and safety endpoints from two phase 3 trials.

BackgroundThe objective of this analysis was to assess the effects of edoxaban compared with enoxaparin on key coagulation biomarkers and present pooled primary efficacy and safety results from phase 3 STARS E-3 and STARS J-V trials for prevention of venous thromboembolism (VTE) after total knee arthroplasty (TKA) or total hip arthroplasty (THA).MethodsIn the randomized, double-blind, double-dummy, multicenter, STARS E-3 and STARS J-V trials, patients received edoxaban 30 mg or enoxaparin 2000 IU (20 mg) twice daily for 11 to 14 days. The studies were conducted in Japan and Taiwan; enoxaparin dosing was based on Japanese label recommendations. The primary efficacy endpoint was incidence of VTE; the safety endpoint was major or clinically relevant nonmajor (CRNM) bleeding. Blood samples were taken at presurgical evaluation, pretreatment (postsurgery), predose on day 7, predose on completion of treatment, and at a follow-up examination 25 to 35 days after the last dose of study drug for D-dimer, prothrombin fragment 1 + 2 (F1+2), and soluble fibrin monomer complex (SFMC) measurement.ResultsA total of 716 patients enrolled in STARS E-3 and 610 patients enrolled in STARS J-V; 1326 patients overall. This analysis included 657 patients who received edoxaban 30 mg QD and 650 patients who received enoxaparin 20 mg BID. Incidence of VTE was 5.1 and 10.7% for edoxaban and enoxaparin, respectively (P <0.001). Incidence of combined major and CRNM bleeding was 4.6 and 3.7% for edoxaban and enoxaparin, respectively (P = 0.427). On day 7, mean D-dimer (4.4 vs 5.5 μg/mL), F1+2 (363 vs 463 pmol/L), and SFMC (5.7 vs 6.8 μg/mL) were lower in edoxaban-treated patients relative to enoxaparin-treated patients, respectively (P <0.0001 for all). At end of treatment, mean D-dimer (5.4 vs 6.2 μg/mL), F1+2 (292 vs 380 pmol/L), and SFMC (6.2 vs 7.2 μg/mL) were lower in edoxaban-treated patients relative to enoxaparin-treated patients (P <0.0001 for all).ConclusionsEdoxaban was superior to enoxaparin in prevention of VTE following TKA and THA, with comparable rates of bleeding events. Relative to enoxaparin, edoxaban significantly reduced D-dimer, F1+2, and SFMC.Trial registrationClintrials.gov NCT01181102 and NCT01181167. Both registered 8/12/2010.Electronic supplementary materialThe online version of this article (doi:10.1186/s12959-016-0121-1) contains supplementary material, which is available to authorized users.

What's in a Name? Linguistic Labels in the Adoption of a Lean Production System in a Russian Bank

In this study we ask whether the vocabulary of Toyota’s lean production system (“LPS”) affects its adoption in a non-Japanese context. New institutionalism argues that a management system is easier to transfer when it is theorized into an abstract model of cause-effect relationships among its components. Yet, abstract categories of management are expressed using a natural language that has its own everyday meanings and connotations. To explore what happens when a large Russian retail bank introduces LPS using the original Japanese labels versus Russian ones, we developed an abstract model of LPS as a cause-effect relationship between problems and solutions, and designed a survey questionnaire to assess the acceptance of this model by the bank’s employees. Samples of the employees at two of the bank’s branches were randomly assigned to one of two versions of the questionnaire: one using the original Japanese labels transliterated with the Cyrillic alphabet or one that had all the original Japanese labels translated into the Russian language. Our analysis showed that the bank’s employees were more likely to assess the relevance of LPS consistently with our abstract model when the system’s components were labeled in Russian rather than transliterated Japanese. The Russian labels made visible the causal link from problems to solutions and reduced the resistance to accepting lean production’s problems as relevant. Indeed, the labeling language appears to affect the transferability of a management system in general, and the acceptance of the problems that the system is supposed to address in particular.

Effect of database profile variation on drug safety assessment: an analysis of spontaneous adverse event reports of Japanese cases.

BackgroundThe use of a statistical approach to analyze cumulative adverse event (AE) reports has been encouraged by regulatory authorities. However, data variations affect statistical analyses (eg, signal detection). Further, differences in regulations, social issues, and health care systems can cause variations in AE data. The present study examined similarities and differences between two publicly available databases, ie, the Japanese Adverse Drug Event Report (JADER) database and the US Food and Drug Administration Adverse Event Reporting System (FAERS), and how they affect signal detection.MethodsTwo AE data sources from 2010 were examined, ie, JADER cases (JP) and Japanese cases extracted from the FAERS (FAERS-JP). Three methods for signals of disproportionate reporting, ie, the reporting odds ratio, Bayesian confidence propagation neural network, and Gamma Poisson Shrinker (GPS), were used on drug-event combinations for three substances frequently recorded in both systems.ResultsThe two databases showed similar elements of AE reports, but no option was provided for a shareable case identifier. The average number of AEs per case was 1.6±1.3 (maximum 37) in the JP and 3.3±3.5 (maximum 62) in the FAERS-JP. Between 5% and 57% of all AEs were signaled by three quantitative methods for etanercept, infliximab, and paroxetine. Signals identified by GPS for the JP and FAERS-JP, as referenced by Japanese labeling, showed higher positive sensitivity than was expected.ConclusionThe FAERS-JP was different from the JADER. Signals derived from both datasets identified different results, but shared certain signals. Discrepancies in type of AEs, drugs reported, and average number of AEs per case were potential contributing factors. This study will help those concerned with pharmacovigilance better understand the use and pitfalls of using spontaneous AE data.

Agreement of label information of cardiovascular drugs in pregnancy among Korea, the USA, the UK, and Japan

Drug label is a common source of information; however, the content varies widely. This study aims to evaluate label information on cardiovascular drugs regarding pregnancy for their similarities in Korea, USA, UK, and Japan. Study drugs were selected as following (1) cardiovascular drugs according to the WHO ATC code (C01–C09) and (2) drugs currently marketed in all four countries were included. Evidence level was classified into five categories (‘Definite’, ‘Probable’, ‘Possible’, ‘Unlikely’, and ‘Unclassified’) and recommendation level was classified into four categories (‘Contraindicated’, ‘Cautious’, ‘Compatible’, and ‘Unclassified’). Frequency and proportion were presented. Percent agreement and kappa coefficient with 95% confidence interval (CI) were calculated using SAS ver. 9.3. Total of 50 cardiovascular drugs were included. ‘Unclassified’ was represented the most in Korea, followed by Japan and UK (58%, 54%, and 46%, p<0.05). For recommendation level, the majority of drugs in all four countries were classified as ‘contraindicated’ or ‘cautious’. Japanese labels had the largest proportion of ‘contraindicated’ level (62%), and Korea and UK followed (58%, 44%, p<0.05). Only in the USA, 10.0% of the drugs were ‘compatible’ whereas, there were none in Korea, UK, and Japan (p<0.01). Korea and Japan showed a substantial agreement in evidence and recommendation level (kappa=0.69, 0.67). Labels of cardiovascular drugs in pregnancy differed widely. Reliable safety information in pregnancy should be provided through regular updates.

The Language of Lean Production and the Organized Anarchy of Its Foreign Adoption

A vast literature on the adoption of management systems ignores the role of the language in which a system is introduced to the target audience. We show that a foreign adoption of lean production, as it is described in the extant literature, satisfies the conditions of organized anarchy, a classical behavioral perspective on organizations developed by Cohen, March, and Olsen (1972). Accordingly, employees’ decisions to accept lean production follow the “garbage can” model which predicts that employees pick and choose components of lean production as they see fit, often accepting solutions but rejecting the problems that those solutions are supposed to address. We argue that the use of a foreign language exacerbates this shift in focus. To test our arguments, we study the impact of the terminology, transliterated Japanese versus invented Russian, on the acceptance of the lean production system in a large Russian retail bank and its Belorussian subsidiary. Samples of the employees in two branches, one from each bank, were randomly assigned to one of the two types of survey questionnaires, a “transliterated” Japanese or Russian one. The questions assessed the relevance of the lean system’s key components to a respondent’s job. Our results are consistent with the garbage can model of decision-making: the employees are more likely to identify the solutions as useful and reject the problems as irrelevant if they are offered Japanese labels than Russian ones. Also, employees find solutions more relevant than problems at an early stage of adoption in the Belorussian bank than at a later stage in the Russian one. This suggests that some order can emerge from organized anarchy as lean production takes hold in the organization.

SAT0138 The effectiveness of adalimumab concomitant with disease-modifying antirheumatic drugs other than methotrexate in rheumatoid arthritis

BackgroundIt has been defined that ADA monotherapy has only limited effectiveness compared to combination therapy with Methotrexate (MTX). On the other hand, MTX cannot be administered in some patients because...

Anticoagulant Therapy with the Oral Direct Factor Xa Inhibitors Rivaroxaban, Apixaban and Edoxaban and the Thrombin Inhibitor Dabigatran Etexilate in Patients with Hepatic Impairment

The direct factor Xa (FXa) inhibitors rivaroxaban, apixaban and edoxaban, and the thrombin inhibitor dabigatran etexilate (dabigatran) have gained approval for use in several indications, most notably for the prevention and treatment of venous thromboembolism (VTE) and for the prevention of stroke in patients with atrial fibrillation. Hepatic impairment can affect the disposition of these anticoagulants considerably not only because of the hepatic metabolism of the direct FXa inhibitors but also because moderate to severely impaired hepatic function will affect coagulation. This review describes the key pharmacological properties of novel oral anticoagulants with special attention to patients with impaired hepatic function. In subjects with moderately impaired liver function (i.e. Child-Pugh classification B), the area under the plasma concentration-time curve (AUC) of rivaroxaban (10 mg single dose) is increased by 2.27-fold, which is paralleled by an increase in FXa inhibition. The AUC of apixaban (5 mg single dose) is increased by 1.09-fold, whereas the AUC of edoxaban (15 mg single dose) is decreased by 4.8 % and the AUC of dabigatran (150 mg single dose) is decreased by 5.6 %. Specific labelling restrictions for rivaroxaban, apixaban and dabigatran regarding impaired hepatic function are based on both the Child-Pugh classification and liver-related exclusion criteria applied in pivotal clinical trials. Rivaroxaban is contraindicated in patients with hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients classified as Child-Pugh B and C. Apixaban can be used with caution in patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment or in patients with alanine aminotransferase and aspartate aminotransferase levels >2× upper limit of normal (ULN). Apixaban is not recommended in patients with severe hepatic impairment and is contraindicated in those with hepatic disease associated with coagulopathy and clinically relevant bleeding risk. Dabigatran is not recommended in patients with elevated liver enzymes (>2× ULN). Dabigatran is contraindicated in patients with hepatic impairment or liver disease expected to have any impact on survival. Currently, edoxaban is not available in the US or European markets. However, the Japanese label did not restrict use in hepatic dysfunction but advises care in patients with severe hepatic impairment.