Development of a real-time fluorescent reverse transcription loop-mediated isothermal amplification assay with quenching primers for rapid detection of rubella virus.

Rubella virus infection during early pregnancy sometimes causes severe birth defects termed congenital rubella syndrome. Although there are safe and effective live-attenuated vaccines, rubella has only been certified as eliminated in the Americas within the six World Health Organization regions. Rubella remains an endemic disease in many regions, and outbreaks occur wherever population immunity is insufficient. There are two main methods for diagnosis of rubella: detection of anti-rubella IgM antibodies by enzyme immunoassay and detection of the viral genome by real-time RT-PCR. Both of these methods require substantial time and effort. In the present study, a rapid rubella detection assay using real-time fluorescent reverse transcription loop-mediated isothermal amplification with quenching primers was developed. The time required for the new assay was one-half that required for a real-time RT-PCR assay. The assay had 93.6% positive percent agreement and 100% negative percent agreement for clinical specimens compared with the real-time RT-PCR assay. The new assay is considered useful for diagnosis of rubella in areas where rubella is endemic.

Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) Following Adenovirus Meningitis After First Delivery: Case Report and Literature Review.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a group of central nervous system (CNS) demyelinating diseases caused by autoantibodies against myelin oligosaccharide protein (MOG), a myelin sheath component protein, and present with a variety of symptoms, including optic neuritis, myelitis, acute disseminated encephalomyelitis (ADEM), brainstem encephalitis, and corticobasal encephalitis. It is currently unknown at what point in life MOGAD can develop or how it can be triggered by autoimmune mechanisms. Here, we report a case of a mature woman who suffered from adenoviral meningitis one month after childbirth and developed MOGAD but was able to return to child rearing with high-dose methylprednisolone therapy. This case suggests that the risk of developing MOGAD early after childbirth may be increased. The case also suggested that adenoviral infection may be involved in the development of MOGAD.

Perceived Future Outcomes of Unsuccessful Treatment and Their Association with Treatment Persistence Among Type-2 Diabetes Patients: A Cross-Sectional Content Analysis.

INTRODUCTION: Despite the known strong association between patients' knowledge of outcomes of type 2 diabetes mellitus (T2DM) and treatment persistence, this knowledge in this patient population requires further clarification. The aim of our study was to reveal the perception of unsuccessful treatment outcomes among patients with T2DM and its association with treatment persistence by analysing answers to open-ended questions. METHODS: In this cross-sectional study, 106 patients with T2DM who lived in Fukushima Prefecture, Japan, had a medical record in the Fukushima National Health Insurance Organisation database and had no cognitive problems were enrolled by purposive sampling. Treatment status was defined as "non-persistent" when a participant's treatment medical record was absent for a continuous period of ≥ 6 months; otherwise, it was referred to as "persistent". We asked about the possible future problems of untreated T2DM, inductively classified the open answers into 15 codes and then statistically examined the association between these codes and treatment persistence using logistic regression analysis adjusted for age and sex. RESULTS: Persistent treatment was prevalent among participants who mentioned the code "treatment", which encompasses the terms that indicated invasiveness, such as dialysis, insulin injection, and shots (odds ratio 4.339; 95% confidence interval 1.104-17.055). CONCLUSION: Persistent treatment was prevalent among patients with T2DM who mentioned the code "treatment", suggesting that these patients may anticipate a threat due to the invasiveness of diabetes and thus participate in persistent treatment to avoid this threat. Healthcare professionals should provide appropriate information and supportive conditions to achieve both a reduced feeling of threat and persistent treatment engagement.

Distribution of Human Sapovirus Strain Genotypes over the Last Four Decades in Japan: a Global Perspective.

Sapovirus (SaV) infections are a public health problem because they cause acute gastroenteritis in humans of all ages, both sporadically and as outbreaks. However, only a limited amount of SaV sequence information, especially whole-genome sequences for all the SaV genotypes, is publicly available. Therefore, in this study, we determined the full/near-full-length genomic sequences of 138 SaVs from the 2001 to 2015 seasons in 13 prefectures across Japan. The genogroup GI was predominant (67%, n = 92), followed by genogroups GII (18%, n = 25), GIV (9%, n = 12), and GV (6%, n = 9). Within the GI genogroup, four different genotypes were identified: GI.1 (n = 44), GI.2 (n = 40), GI.3 (n = 7), and GI.5 (n = 1). We then compared these Japanese SaV sequences with 3,119 publicly available human SaV sequences collected from 49 countries over the last 46 years. The results indicated that GI.1, and GI.2 have been the predominant genotypes in Japan, as well as in other countries, over at least four decades. The 138 newly determined Japanese SaV sequences together with the currently available SaV sequences, could facilitate a better understanding of the evolutionary patterns of SaV genotypes.

Isolation of SARS-CoV-2 from COVID-19 Patients and an Asymptomatic Individual.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China, in December 2019. Despite the recent introduction of vaccines against SARS-CoV-2, more effective vaccines and antiviral drugs must be developed. Here, we isolated five SARS-CoV-2 strains from four patients with coronavirus disease (COVID-19) and an asymptomatic individual using pharyngeal swabs, nasopharyngeal swabs, and sputum samples. Cytopathic effects in inoculated Vero cells were observed between days 3 and 7. SARS-CoV-2 infection was confirmed by quantitative reverse-transcription polymerase chain reaction (RT-qPCR) and next-generation sequencing. Phylogenetic analyses of the whole genome sequences showed that the virus isolates from the clinical samples belonged to the Wuhan and European lineages. These findings and the isolated viruses may contribute to the development of diagnostic tools, vaccines, and antiviral drugs for COVID-19.

Stroke during pregnancy and puerperium among Japanese women: a single-center registry.

BACKGROUND: Stroke is one of the major causes of maternal death. This study aimed to analyze the maternal and fetal outcomes of stroke occurred during pregnancy and puerperium. METHODS: We conducted a retrospective analysis of patients admitted to our perinatology center between 1982 and 2012 with a diagnosis of acute cerebral stroke during pregnancy or within 6 weeks postpartum. RESULTS: Thirty-four patients were registered and all the patients had never been diagnosed as stroke nor detected cerebrovascular abnormalities before the current pregnancies. They were divided into 8 ischemic strokes (ISs) and 26 intracranial hemorrhage group. In the hemorrhage group, there was a spontaneous abortion and two patients chose artificial abortions to avoid rehemorrhage, and there were another three intrauterine fetal deaths (IUFDs) in the acute stage of maternal stroke. More patients in hemorrhage group delivered in preterm than in IS group for the treatment of stroke, 10/23 (43%) versus 0/8 (0%), p < .05. More patients in hemorrhage group had low Glasgow Coma Scale (GCS) (3-8) than in IS group at the onset of the stroke, 12/26 (46%) versus 0/8 (0%), p < .05. There were three maternal deaths and 6/23 (26%) were neurologically dependent in hemorrhage group in the chronic stage, whereas 87% were independent in IS group, p < .05. CONCLUSIONS: Hemorrhagic stroke was more common etiology of stroke related to pregnancy than IS in this study. Intensive and multidisciplinary care was needed especially in hemorrhagic stroke related to pregnancy as in the hemorrhagic stroke the fetal survival rate was lower, and maternal conscious levels at the onset of the stroke and neurological outcomes in the chronic stage were worse than IS.

Identification of inhibitors of dengue viral replication using replicon cells expressing secretory luciferase.

Dengue virus (DENV) is the causative agent of dengue fever (DF), dengue haemorrhagic fever (DHF), and dengue shock syndrome (DSS) and continues to be a public health problem in the tropical and subtropical areas. However, there is currently no antiviral treatment for DENV infection. In this study, our aim was to develop a stable reporter replicon cell system that supports constant viral RNA replication in cultured cells. The isolated replicon cells exhibited high levels of luciferase activity in the culture supernatant concomitant with expression of virus-encoded NS1, NS3 and NS5 proteins in the cells. The NS1, NS3 proteins and dsRNA were detected in the replicon cells by immunofluorescence analysis. Furthermore, the anti-DENV inhibitors ribavirin and bromocriptine significantly reduced the luciferase activity in a dose-dependent manner. High-throughput screening with a compound library using the stably-transfected replicon cells showed a Z' factor value of 0.57. Our screening yielded several candidates including one compound that has already shown anti-DENV activity. Taken together, our results demonstrate that this DENV subgenomic replicon cell system expressing a secretory luciferase gene can be useful for the high-throughput screening of anti-DENV compounds and the analysis of the replication mechanism of the DENV RNA.

Evolutionary Analysis of the VP1 and RNA-Dependent RNA Polymerase Regions of Human Norovirus GII.P17-GII.17 in 2013-2017.

Human norovirus (HuNoV) GII.P17-GII.17 (Kawasaki2014 variant) reportedly emerged in 2014 and caused gastroenteritis outbreaks worldwide. To clarify the evolution of both VP1 and RNA-dependent RNA polymerase (RdRp) regions of GII.P17-GII.17, we analyzed both global and novel Japanese strains detected during 2013-2017. Time-scaled phylogenetic trees revealed that the ancestral GII.17 VP1 region diverged around 1949, while the ancestral GII.P17 RdRp region diverged around 2010. The evolutionary rates of the VP1 and RdRp regions were estimated at ~2.7 × 10-3 and ~2.3 × 10-3 substitutions/site/year, respectively. The phylogenetic distances of the VP1 region exhibited no overlaps between intra-cluster and inter-cluster peaks in the GII.17 strains, whereas those of the RdRp region exhibited a unimodal distribution in the GII.P17 strains. Conformational epitope positions in the VP1 protein of the GII.P17-GII.17 strains were similar, although some substitutions, insertions and deletions had occurred. Strains belonging to the same cluster also harbored substitutions around the binding sites for the histo-blood group antigens of the VP1 protein. Moreover, some amino acid substitutions were estimated to be near the interface between monomers and the active site of the RdRp protein. These results suggest that the GII.P17-GII.17 virus has produced variants with the potential to alter viral antigenicity, host-binding capability, and replication property over the past 10 years.

The detection of house dust mite Dermatophagoides farinae, Der f 2 and Zen-1 allergen-specific immunoglobulin E antibodies in dogs with atopic Dermatitis in Malaysia.

Canine atopic dermatitis (AD) is a chronic, inflammatory and pruritic allergic skin disease in dogs. House dust mites such as Dermatophagoides farinae are one of the known causative agents for the induction of canine AD worldwide. D. farinae protein Der f 2 is known as an important allergen involved in canine AD and recently, Zen-1 has also been identified as an allergenic protein. There is limited information on the prevalence and role of allergen sensitization to crude D. farinae extract (CDF), Der f 2 and Zen-1 among dogs diagnosed with AD in Malaysia. The aim of this study was to determine the proportion of CDF-, Der f 2- and Zen-1-specific reactive sera among dogs diagnosed with AD in Malaysia using an enzyme-linked immunosorbent assay (ELISA). Serum samples were collected from dogs diagnosed with AD from several veterinary clinics in Malaysia. The canine case records were retrieved and information on signalment, dermatological and non-dermatological histories, clinical presentation, food allergies, and exclusion of ectoparasitic, microbial and fungal skin infections were obtained through a survey form. All serum samples were evaluated to quantify the CDF-, Der f 2- and Zen-1-specific immunoglobulin E (IgE) levels. A total of 24.6%, 48.4% and 29.8% of dogs diagnosed with AD were positive for CDF-, Der f 2- and Zen-1-specific IgE, respectively. These results suggest that CDF-, Der f 2- and Zen-1 are important allergens that can contribute to AD in dogs in Malaysia, and serological testing can be performed to provide additional treatment options involving specific immunotherapies.

Baseline Carotid Intima-Media Thickness and Stroke Recurrence During Secondary Prevention With Pravastatin.

Background and Purpose- As a prespecified post hoc analysis of the J-STARS (Japan Statin Treatment Against Recurrent Stroke) Echo Study, the 5-year stroke recurrence rate according to the baseline mean carotid intima-media thickness (IMT) with and without pravastatin treatment was investigated. Methods- Patients were randomly assigned to receive pravastatin 10 mg/day (pravastatin group) or control group (nonstatin treatment; 1:1) for 5 years. Baseline mean IMT of the common carotid artery was measured by ultrasonography. Cox proportional hazards models were used to investigate whether the stroke (any ischemic stroke, atherothrombotic brain infarction, or lacunar infarction) recurrence rate was different according to tertiles of baseline mean IMT. Results- A total of 793 patients, including 388 in the pravastatin group and 405 in the control group, were investigated. In the control group, Cox proportional hazards models showed that participants in the highest tertile IMT group (≥0.931 mm) had a higher rate of atherothrombotic brain infarction than those in the lowest tertile IMT group (<0.812 mm; [hazard ratio, 9.08; 95% CI, 1.15-71.43]). Patients in the pravastatin group had a lower risk of atherothrombotic brain infarction than those in the control group only in the highest tertile IMT group by the log-rank test ( P value=0.045). Conclusions- Long-term pravastatin administration may prevent the occurrence of atherothrombotic brain infarction in noncardioembolic infarction patients with the highest tertile IMT. Clinical Trial Registration- URL: https://www.clinicaltrials.gov . Unique identifier: NCT00361530.

Stearoyl-CoA desaturase-1 is required for flavivirus RNA replication.

Dengue virus (DENV) is the most prevalent human arthropod-borne virus and causes severe problems worldwide, mainly in tropical and sub-tropical regions. However, there is no specific antiviral drug against DENV infection. We and others recently reported that stearoyl-CoA desaturase-1 (SCD1) inhibitor showed potent suppression of hepatitis C virus replication. In this study, we examined the impact of SCD1 on DENV replication. We found that SCD1 inhibitors (MK8245 and #1716) dramatically suppressed DENV replication in a dose-dependent manner without cytotoxicity. This anti-DENV efficacy was observed against all four DENV serotypes and other flaviviruses, including Zika virus and Japanese encephalitis virus. A subgenomic replicon system of DENV was used to confirm that SCD1 inhibitor suppressed viral RNA replication. Interestingly, exogenous supplementation of unsaturated fatty acids resulted in recovery of the DENV titer even in the presence of SCD1 inhibitor, suggesting that fatty acid biosynthesis contributes to DENV genome replication. These findings indicate that SCD1 is a novel host factor required for DENV replication, and SCD1 inhibitor is a potential candidate for treating dengue fever.

Subcutaneous Heparin Therapy for Patients with Cancer-Associated Stroke.

BACKGROUND: Anticoagulation therapy, particularly subcutaneous heparin therapy, is recommended for cancer-associated thrombosis. However, not starting or discontinuing anticoagulation was not rare. The aim of the present study was to examine the practical issues related to anticoagulation therapy and effects of subcutaneous heparin therapy for cancer-associated stroke. METHODS: Patients with cancer-associated stroke in our stroke center between October 2014 and August 2017 who were diagnosed as having acute ischemic stroke based on diffusion-weighted imaging were retrospectively enrolled. Baseline clinical characteristics, heparin injection, reasons for no subcutaneous heparin therapy, and clinical outcomes were collected. RESULTS: A total of 59 patients with cancer-associated stroke (75 ± 10 years old, male 42%) were enrolled. Lung cancer was the most frequently observed cancer (n = 17, 29%), followed by gastric cancer (n = 8, 14%) and pancreatic cancer (n = 8, 14%). Of the 19 patients (32%) who underwent subcutaneous heparin therapy, it was discontinued in 9 (47%), mainly because of patients' medical conditions (deterioration of cancer or hemorrhagic complication). Ten patients with long-term subcutaneous heparin therapy did not have stroke recurrence. In contrast, among nine patients who discontinued subcutaneous heparin therapy, three (33%) had recurrence of ischemic stroke. Of the 40 patients without subcutaneous heparin therapy, the main reasons for no subcutaneous heparin therapy were the patients' medical conditions (n = 22, 55%). CONCLUSIONS: Although subcutaneous heparin therapy was given to only one third of cancer-associated stroke patients, long-term subcutaneous heparin therapy might prevent recurrence of cancer-associated stroke.

Evaluation of Brain Activity Using Near-infrared Spectroscopy in Inflammatory Bowel Disease Patients.

Depression is implicated as a risk factor for the recurrence of inflammatory bowel disease (IBD). Near-infrared spectroscopy (NIRS) and brain-derived neurotrophic factor (BDNF) are useful tools for evaluation of brain activity and a depressive state, respectively. The aim of this study was to clarify the association between brain activity or depressive symptoms and IBD using NIRS and BDNF. This study included 36 ulcerative colitis (UC) patients, 32 Crohn's disease (CD) patients, and 17 healthy controls (HC). Center for Epidemiologic Studies Depression Scale (CES-D) scores were determined, NIRS was performed, and serum BDNF levels were measured in all subjects. NIRS showed that the mean oxygenated hemoglobin concentration was significantly lower in the frontal lobe in the UC group than in the HC group (HC 167 ± 106 vs. UC 83.1 ± 85.3, p < 0.05). No significant difference was seen between the HC and CD groups. There were also no significant differences in CED-D scores and BDNF levels among the groups. Changes in the NIRS values of the UC group may indicate decreased brain activity and a fundamental difference between UC and CD, which are often lumped together as two types of IBD.

Frontal activity measured by near-infrared spectroscopy in patients taking different atypical antipsychotic drugs: A cross-sectional study.

Using near-infrared spectroscopy, we examined changes in the concentration of oxygenated hemoglobin ([oxy-Hb]) in the frontal lobe during a verbal fluency task in 20 patients with schizophrenia (10 patients each receiving olanzapine [OLZ] and risperidone [RIS]) and 10 healthy controls. We found that [oxy-Hb] levels in the prefrontal region were higher in the patients receiving OLZ than in those receiving RIS. These results suggest that antipsychotic drugs have different effects on cerebral hemodynamic patterns, which may reflect frontal lobe function. Further studies with a larger sample size are needed to verify our preliminary findings.

Long-Term Effect of Pravastatin on Carotid Intima-Media Complex Thickness: The J-STARS Echo Study (Japan Statin Treatment Against Recurrent Stroke).

BACKGROUND AND PURPOSE: The effect of statins on progression of carotid intima-media complex thickness (IMT) has been shown exclusively in nonstroke Western patients. This study aimed to determine the effect of low-dose pravastatin on carotid IMT in Japanese patients with noncardioembolic ischemic stroke. METHODS: This is a substudy of the J-STARS trial (Japan Statin Treatment Against Recurrent Stroke), a multicenter, randomized, open-label, parallel-group trial to examine whether pravastatin reduces stroke recurrence. Patients were randomized to receive pravastatin (10 mg daily, usual dose in Japan; pravastatin group) or not to receive any statins (control group). The primary outcome was IMT change of the common carotid artery for a 5-year observation period. IMT change was compared using mixed-effects models for repeated measures. RESULTS: Of 864 patients registered in this substudy, 71 without baseline ultrasonography were excluded, and 388 were randomly assigned to the pravastatin group and 405 to the control group. Baseline characteristics were not significantly different, except National Institutes of Health Stroke Scale scores (median, 0 [interquartile range, 0-2] versus 1 [interquartile range, 0-2]; P=0.019) between the 2 groups. Baseline IMT (mean±SD) was 0.887±0.155 mm in the pravastatin group and 0.887±0.152 mm in the control group (P=0.99). The annual change in the IMT at 5-year visit was significantly reduced in the pravastatin group as compared with that in the control group (0.021±0.116 versus 0.040±0.118 mm; P=0.010). CONCLUSIONS: The usual Japanese dose of pravastatin significantly reduced the progression of carotid IMT at 5 years in patients with noncardioembolic stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00361530.

Factors Associated with Intima-Media Complex Thickness of the Common Carotid Artery in Japanese Noncardioembolic Stroke Patients with Hyperlipidemia: The J-STARS Echo Study.

AIMS: There may be ethnic differences in carotid atherosclerosis and its contributing factors between Asian and other populations. The purpose of this study was to examine intima-media complex thickness (IMT) of the carotid artery and associated clinical factors in Japanese stroke patients with hyperlipidemia from a cohort of the Japan Statin Treatment Against Recurrent Stroke Echo Study. METHODS: Patients with hyperlipidemia, not on statins, who developed noncardioembolic ischemic stroke were included in this study. Mean IMT and maximum IMT of the distal wall of the common carotid artery were centrally measured using carotid ultrasonography. Significant factors related to mean IMT and maximum IMT were examined using multivariable analysis. RESULTS: In 793 studied patients, mean IMT was 0.89±0.15 mm and maximum IMT was 1.19±0.32 mm.Age (per 10 years, parameter estimate=0.044, p＜0.001), smoking (0.022, p=0.004), category of blood pressure (0.022, p=0.006), HDL cholesterol (per 10 mg/dl, －0.009, p=0.008), and diabetes mellitus (0.033, p=0.010) were independently associated with mean IMT. Age (per 10 years, 0.076, p＜0.001), smoking (0.053, p=0.001), HDL cholesterol (－0.016, p=0.036), and diabetes mellitus (0.084, p=0.002) were independently associated with maximum IMT. CONCLUSION: Baseline mean and maximum values of carotid IMT in Japanese noncardioembolic stroke patients with hyperlipidemia were 0.89±0.15 mm and 1.19±0.32 mm, respectively, which were similar to those previously reported from Western countries. Age, smoking, hypertension, HDL cholesterol, and diabetes mellitus were associated with mean IMT, and those, except for hypertension, were associated with maximum IMT.

Dynamic changes in near-infrared spectroscopy (NIRS) findings in first-episode schizophrenia: a case report.

The clinical course of schizophrenia is characterized by recurrence and chronicity and has a large burden on society.　Nevertheless, diagnosis of schizophrenia is based only on distinctive symptoms and the disease course.　Near-infrared spectroscopy (NIRS) is a useful method for measuring changes in the hemoglobin concentration in the cortical surface area and reflects brain function.　We measured NIRS four times during the clinical course in a patient with first-episode schizophrenia.A 17-year-old woman admitted to our hospital because of hallucinations, delusions and appetite loss. After treatment with low-dose antipsychotics, NIRS findings showed a prompt increase in the cerebral blood volume in the frontal region.　On the basis of the clinical course of this patient, we introduce a new point of view, namely, that NIRS findings may be useful as a state marker that indicates the severity of schizophrenia in some cases.

Analysis of Factors Associated with Progression and Long-Term Outcomes of Penetrating Artery Territory Infarction: A Retrospective Study.

BACKGROUND: Patients with penetrating artery territory infarction occasionally show progressive motor deficits during the acute stage with poor prognosis. Predictive indices or medical therapies for suppressing the symptomatic progression (SP) of penetrating artery infarction have not been established. In this study, we investigated SP-related clinical factors and functional outcomes, specifically improvement 3 months post ictus in patients with penetrating artery infarction. METHODS: We retrospectively examined acute stroke patients with penetrating artery infarction admitted at 7 collaborative hospitals. SP was defined as an increase by 1 point or higher in the National Institutes of Health Stroke Scale score. Functional improvement was assessed based on the modified Rankin Scale at 3 months. The influence of factors, such as patient characteristics, clinical data, medical treatment during the acute stage and on SP, and functional improvement was statistically analyzed. RESULTS: Four hundred eighty-eight patients (310 men; mean age, 70 years) were examined. Sixty-eight patients (14%) exhibited SP. Multivariate logistic regression analysis revealed that higher hemoglobin A1c (odds ratio [OR], 1.30; 95% confidence interval [CI], 1.10-1.55), body mass index (BMI; OR, .85; 95% CI, .77-.94), and systolic blood pressure on admission (OR, 1.63; 95% CI, 1.19-2.25) were independent predictors of SP in penetrating artery infarction. Dual antiplatelet therapy (DAPT; OR, 3.48; 95% CI, 1.52-8.38) independently influenced functional improvement. CONCLUSIONS: Initial high blood pressure, diabetes, and low BMI on admission were associated with early progression of penetrating artery infarction. DAPT during the acute stage may contribute to functional improvement.

Development of Interstitial Lung Disease after Initiation of Apixaban Anticoagulation Therapy.

BACKGROUND: Nonvitamin K antagonist oral anticoagulants may cause interstitial lung disease (ILD) similar to that seen for other cardiovascular drugs. The aim of this study was to determine trends and medical conditions associated with ILD in patients taking apixaban. METHODS: A single-center observational survey conducted between February 2013 and May 2015 examined patients who developed ILD after initiation of apixaban administration. RESULTS: Chest computed tomography showed that 4 (~.45%) out of approximately 870 apixaban users developed ILD. All patients were elderly Japanese men with decreased creatinine clearance who had nonvalvular atrial fibrillation. Three of the four were confirmed smokers, whereas three had a history of lung disease. Dyspnea occurred during the initial week after starting apixaban administration in 3 patients and at 90 days in 1 patient. All patients underwent methylprednisolone pulse therapy, with three requiring mechanical ventilation. Although 2 patients recovered, the other two died of respiratory failure. CONCLUSIONS: Development of ILD during anticoagulation with apixaban is not rare. When apixaban is administered in elderly high-risk patients, subjects need to be carefully monitored for respiratory symptoms. As drug-induced ILD is often reported in Japan, further studies that clarify if these types of cases are common in countries other than Japan will also need to be undertaken.