The humoral and cellular immune responses following booster vaccination with SARS-CoV-2 mRNA in people living with human immunodeficiency virus.

INTRODUCTION: People living with human immunodeficiency virus (PLWH) have higher mortality rates from COVID-19 than those without HIV. Additionally, the seroconversion rate of antibodies following a second dose of SARS-CoV-2 vaccine is lower in PLWH than non-infected individuals, indicating the need for booster vaccination. Here, we evaluated the humoral and cellular immune responses to booster SARS-CoV-2 vaccination in PLWH. METHODS: The dynamics of anti-spike IgG titers and antigen-specific interferon (IFN)-γ levels to SARS-CoV-2 vaccination were assessed over a 6-month period following a third vaccination of 34 PLWH. RESULTS: Antibody titers for humoral immunity were 50 % lower at 24 weeks post-vaccination than those at 12 weeks. However, those at 24 weeks after the booster vaccination were approximately eight times higher than before. Regarding cellular immunity, IFN-γ levels at 24 weeks after the third vaccination were lower than those at 12 weeks, but nearly 90 % of participants maintained a cut-off value of ≥0.15 IU/mL. A comparison between two groups with CD4+ T lymphocytes counts of <500/µL or ≥500/µL exhibited no statistically significant differences in antibody or IFN-γ levels. However, in the group with CD4+ T lymphocyte counts of <500/µL, the rate of IFN-γ above the cut-off value at 24 weeks after the booster vaccination was lower than that of ≥500/µL. CONCLUSION: An immune response is expected in PLWH given successful antiretroviral therapy with booster SARS-CoV-2 vaccination. However, caution should be exercised for cases with low CD4+ T-lymphocyte counts. (240/250 words).

A case of mediastinal abscess and infected aortic aneurysm caused by dissemination of Mycobacterium abscessus subsp. massiliense pulmonary disease.

An 81-year-old man was admitted to our hospital because of fever and malaise that had persisted for 3 months. The patient had undergone two aortic valve replacements, 10 and 5 years previously, because of aortic valve regurgitation and infectious endocarditis. He also had had asymptomatic Mycobacterium abscessus complex (MABC) pulmonary disease for the two previous years. Contrast-enhanced computed tomography showed a mediastinal abscess and an ascending aortic aneurysm. Mycobacterium abscessus subsp. massiliense was cultured from his blood, suggesting the aortic aneurysm was secondary to infection of an implanted device. After enlargement over only a few days, a leakage of contrast medium to the mediastinal abscess was found on computed tomography. The patient was diagnosed with rupture of an infectious aortic aneurysm, and emergency aortic replacement and drainage of the mediastinal abscess were successful. The patient was treated with several antibiotics, including meropenem, amikacin, and clarithromycin, and his general condition improved. Cultures from both the mediastinal abscess and a pericardial patch that was placed at the time of surgery 5 years previously revealed MABC. In our case, the infected aortic aneurysm most likely resulted from MABC pulmonary disease rather than from previous intraoperative contamination. This route of infection is rare. Physicians should be aware of the possibility of dissemination and subsequent infection of implants related to MABC pulmonary disease.

A case of severe COVID-19 with pulmonary thromboembolism related to heparin-induced thrombocytopenia during prophylactic anticoagulation therapy.

A 53-year-old male Japanese patient with COVID-19 was admitted to our hospital after his respiratory condition worsened on day 9 of the disease. With the diagnosis of severe COVID-19, treatment with remdesivir, dexamethasone, and unfractionated heparin was started for the prevention of thrombosis. Although the patient's respiratory status data improved after treatment, severe respiratory failure persisted. Thrombocytopenia and D-dimer elevation were observed on day 8 after heparin therapy initiation. Heparin-induced thrombocytopenia (HIT) antibody measured by immunological assay was positive, and contrast computed tomography showed pulmonary artery thrombus. The patient was diagnosed with HIT because the pre-test probability score (4Ts score) for HIT was 7 points. Heparin was changed to apixaban, a direct oral anticoagulant, which resulted in a reduction of the pulmonary thrombus and improvement of the respiratory failure. In patients with COVID-19, anticoagulant therapy with heparin requires careful monitoring of thrombocytopenia and elevated D-dimer as possible complications related to HIT. (151/250 words).

Cluster II che genes of Pseudomonas syringae pv. tabaci 6605, orthologs of cluster I in Pseudomonas aeruginosa, are required for chemotaxis and virulence.

Pseudomonas syringae pv. tabaci 6605 (Pta6605) is a causal agent of wildfire disease in host tobacco plants and is highly motile. Pta6605 has multiple clusters of chemotaxis genes including cheA, a gene encoding a histidine kinase, cheY, a gene encoding a response regulator, mcp, a gene for a methyl-accepting chemotaxis protein, as well as flagellar and pili biogenesis genes. However, only two major chemotaxis gene clusters, cluster I and cluster II, possess cheA and cheY. Deletion mutants of cheA or cheY were constructed to evaluate their possible role in Pta6605 chemotaxis and virulence. Motility tests and a chemotaxis assay to known attractant demonstrated that cheA2 and cheY2 mutants were unable to swarm and to perform chemotaxis, whereas cheA1 and cheY1 mutants retained chemotaxis ability almost equal to that of the wild-type (WT) strain. Although WT and cheY1 mutants of Pta6605 caused severe disease symptoms on host tobacco leaves, the cheA2 and cheY2 mutants did not, and symptom development with cheA1 depended on the inoculation method. These results indicate that chemotaxis genes located in cluster II are required for optimal chemotaxis and host plant infection by Pta6605 and that cluster I may partially contribute to these phenotypes.

Epidemiological trends of imported infectious diseases in Japan: Analysis of imported 2-year infectious disease registry data.

INTRODUCTION: The epidemiology of infectious diseases in Japan remains undefined despite the increasing tourism. GeoSentinel, an epidemiological surveillance system for reporting imported infectious diseases, has only two participating facilities in Japan. Although the number of infectious diseases is reported by the National Institute of Infectious Diseases, there is no detailed clinical information about these cases. Therefore, we established J-RIDA (Japan Registry for Infectious Diseases from Abroad) to clarify the status of imported infectious diseases in Japan and provide detailed information. METHODS: J-RIDA was started as a registry of imported infectious diseases. Case registration began in October 2017. Between October 2017 and September 2019, 15 medical institutions participated in this clinical study. The registry collected information about the patient's age, sex, nationality, chief complaint, consultation date, date of onset, whether visit was made to a travel clinic before travel, blood test results (if samples were collected), travel history, and final diagnosis. RESULTS: Of the 3046 cases included in this study, 46.7% to Southeast Asia, 13.0% to Africa, 13.7% to East Asia, 11.5% to South Asia, 7.5% to Europe, 3.8% to Central and South America, 4.6% to North America, 3.9% to Oceania, and 2.8% to Central and west Asia. More than 85% of chief complaints were fever and general symptoms, gastrointestinal symptoms, respiratory symptoms, or dermatologic problems. The most common diseases were travelers' diarrhea, animal bite, upper respiratory infection, influenza, and dengue fever. CONCLUSIONS: We summarized two-year cases registered in Japan's imported infectious disease registry. These results will significantly contribute to the epidemiology in Japan.

Prevalence and characteristics of occult hepatitis B virus infection in Japanese human immunodeficiency virus-infected patients.

Occult hepatitis B virus (HBV) infection (OBI) is hepatitis B surface antigen (HBsAg) negative but with detectable HBV DNA. Although HIV infection has been reported to be a risk factor for OBI, the prevalence and clinical features of OBI in Japanese HIV infected patients have not been documented. This retrospective, single-center study was conducted to determine the prevalence and characteristic of OBI in Japanese antiretroviral therapy (ART) naïve HIV infected patients. OBI was defined as the presence of serum HBV DNA but without detectable HBsAg. Of the 147 ART naïve HIV infected patients, OBI was detected in 9 (6.1%) patients; 2 (4.3%) of 47 with both anti-HBs and anti-HBc positive, 6 (27.3%) of 22 with anti-HBc alone, and 1 (2.0%) of 50 with both anti-HBs and anti-HBc negative. The mean HBV DNA level was low at 28.7 ± 18.2 IU/mL. The proportion of OBI patients with anti-HBc alone was significantly higher than that of non-OBI patients (66.7% vs 14.5%, P = 0.001). In addition, the prevalence of AIDS (acquired immunodeficiency syndrome)-defining illnesses in the OBI group was significantly higher than in the non-OBI group (77.8% vs 35.5%, P = 0.001). No significant difference was found in the CD4 count or alanine aminotransferase levels of these two groups. This is the first study to reveal the prevalence and clinical features of OBI in Japanese HIV-infected patients. The persistence of anti-HBc alone and AIDS-defining illnesses were associated with the occurrence of OBI in these patients.

Effect of Progression in Malnutrition and Inflammatory Conditions on Adverse Events and Mortality in Patients on Maintenance Hemodialysis.

BACKGROUND/AIM: In maintenance hemodialysis (MHD), protein-energy malnutrition and chronic inflammation can be critical and are two of the main causes of mortality. METHOD: We compared the change in nutrition and inflammatory conditions between younger and older MHD patients during a 2-year period. Furthermore, using Kaplan-Meier analysis, we evaluated the correlations between changes in each parameter and any adverse events. RESULT: During the observational period, body mass index (BMI) and serum albumin levels decreased significantly in older patients. In Kaplan-Meier analysis, patients who showed a decline in BMI had an associated elevated risk for cerebro-cardiovascular disease and hospitalization. Moreover, patients who showed a decline in albumin also had an associated higher risk for infectious disease and hospitalization. CONCLUSION: This study revealed that the downward trend in nutritional status was prominent in elderly patients. Furthermore, changes in nutritional and inflammatory conditions during MHD were associated with adverse events in MHD patients.

Selective Ion Exchange in Supramolecular Channels in the Crystalline State.

Artificial ion channels are of increasing interest because of potential applications in biomimetics, for example, for realizing selective ion permeability through the transport and/or exchange of selected ions. However, selective ion transport and/or exchange in the crystalline state is rare, and to the best of our knowledge, such a process has not been successfully combined with changes in the physical properties of a material. Herein, by soaking single crystals of Li2 ([18]crown-6)3 [Ni(dmit)2 ]2 (H2 O)4 (1) in an aqueous solution containing K+ , we succeeded in complete ion exchange of the Li+ ions in 1 with K+ ions in the solution, while maintaining the crystalline state of the material. This ion exchange with K+ was selectively conducted even in mixed solutions containing K+ as well as Na+ /Li+ . Furthermore, remarkable changes in the physical properties of 1 resulted from the ion exchange. Our finding enables not only the realization of selective ion permeability but also the development of highly sensitive biosensors and futuristic ion exchange agents, for example.

MexEF-OprN multidrug efflux pump transporter negatively controls N-acyl-homoserine lactone accumulation in pseudomonas syringae pv. Tabaci 6605.

Our previous studies revealed that flagellar-motility-defective mutants such as ∆fliC of Pseudomonas syringae pv. tabaci 6605 (Pta6605) have remarkably reduced production of N-acyl-homoserine lactones (AHL), quorum-sensing molecules. To investigate the reason of loss of AHL production in ∆fliC mutant, we carried out transposon mutagenesis. Among approximately 14,000 transconjugants, we found 11 AHL production-recovered (APR) strains. In these APR strains, a transposon was inserted into either mexE or mexF, genes encoding for the multidrug efflux pump transporter MexEF-OprN, and mexT, a gene encoding a putative transcriptional activator for mexEF-oprN. These results suggest that MexEF-OprN is a negative regulator of AHL production. To confirm the negative effect of MexEF-OprN on AHL production, loss- and gain-of-function experiments for mexEF-oprN were carried out. The ∆fliC∆mexF and ∆fliC∆mexT double mutant strains recovered AHL production, whereas the mexT overexpressing strain abolished AHL production, although the psyI, a gene encoding AHL synthase, is transcribed as wild type. Introduction of a mexF or mexT mutation into another flagellar-motility- and AHL production-defective mutant strain, ∆motCD, also recovered the ability to produce AHL. Furthermore, introduction of the mexF mutation into other AHL production-defective mutant strains such as ∆gacA and ∆aefR also recovered AHL production but not to the ∆psyI mutant. These results indicate that MexEF-OprN is a decisive negative determinant of AHL production and accumulation.

Salicylic acid-dependent immunity contributes to resistance against Rhizoctonia solani, a necrotrophic fungal agent of sheath blight, in rice and Brachypodium distachyon.

Rhizoctonia solani is a soil-borne fungus causing sheath blight. In consistent with its necrotrophic life style, no rice cultivars fully resistant to R. solani are known, and agrochemical plant defense activators used for rice blast, which upregulate a phytohormonal salicylic acid (SA)-dependent pathway, are ineffective towards this pathogen. As a result of the unavailability of genetics, the infection process of R. solani remains unclear. We used the model monocotyledonous plants Brachypodium distachyon and rice, and evaluated the effects of phytohormone-induced resistance to R. solani by pharmacological, genetic and microscopic approaches to understand fungal pathogenicity. Pretreatment with SA, but not with plant defense activators used in agriculture, can unexpectedly induce sheath blight resistance in plants. SA treatment inhibits the advancement of R. solani to the point in the infection process in which fungal biomass shows remarkable expansion and specific infection machinery is developed. The involvement of SA in R. solani resistance is demonstrated by SA-deficient NahG transgenic rice and the sheath blight-resistant B. distachyon accessions, Bd3-1 and Gaz-4, which activate SA-dependent signaling on inoculation. Our findings suggest a hemi-biotrophic nature of R. solani, which can be targeted by SA-dependent plant immunity. Furthermore, B. distachyon provides a genetic resource that can confer disease resistance against R. solani to plants.

Potential risk of HBV reactivation in patients with resolved HBV infection undergoing direct-acting antiviral treatment for HCV.

BACKGROUND & AIMS: Despite a known risk of hepatitis B virus (HBV) reactivation during direct-acting antiviral (DAA) treatment for patients with hepatitis C virus (HCV)-HBV coinfection, it remains unclear whether patients with past HBV infection are at risk for reactivation. This study evaluated the risk of HBV reactivation during treatment with sofosbuvir (SOF)-based regimens, focusing on patients with resolved HBV infection. METHODS: This study analyzes the data of 183 consecutive patients treated with SOF-based regimens. From these patients, 63 with resolved HBV infection (negative for hepatitis B surface antigen [HBsAg] and undetectable HBV DNA but positive for hepatitis B core antibody) were eligible for this study. HBV reactivation was defined as a quantifiable HBV DNA level >20 IU/mL. RESULTS: Among the patients antibody to HBsAg (anti-HBs) positive (10-500 mIU/mL) (n = 30), the titre of anti-HBs was significantly decreased with time, as shown by the results of repeated-measures analysis of variance (P = .0029). Overall, four patients (6.3%) with resolved HBV infection came to have detectable HBV DNA during treatment, including one who had HBV reactivation at week 4 (HBV DNA 80 IU/mL). However, none developed hepatic failure. Among four patients who had detectable HBV DNA during treatment, all were negative or had very low-titre (<20 mIU/mL) anti-HBs at baseline. CONCLUSIONS: The titre of anti-HBs was significantly decreased from the early stage of DAA treatment. Chronic hepatitis C patients with resolved HBV infection and negative or very low-titre anti-HBs at baseline are at risk for having detectable HBV DNA transiently during treatment.

Oral Versus Intravenous Iron Supplementation for the Treatment of Iron Deficiency Anemia in Patients on Maintenance Hemodialysis-Effect on Fibroblast Growth Factor-23 Metabolism.

OBJECTIVE: Iron administration affects serum levels of intact (I-) fibroblast growth factor-23 (FGF23) and its cleavage product C-terminal (C-) FGF23 in iron-deficient patients on maintenance hemodialysis (MHD). The objective of this study was to compare the effect of oral or intravenous iron administration on serum levels of I-FGF23 and C-FGF23 in iron-deficient patients on MHD. DESIGN AND METHODS: A prospective randomized study. SUBJECTS: Participants on MHD with severe iron deficiency (n = 61). INTERVENTION: Participants were randomized to receive oral iron (50 mg of sodium ferrous citrate daily; oral group, n = 29) or intravenous iron (40 mg of saccharated ferric oxide weekly; IV group, n = 32). MAIN OUTCOME MEASURE: Changes in I-FGF23 and C-FGF23 after 10 weeks of treatment. RESULTS: Iron supplementation significantly increased hemoglobin, mean corpuscular volume, ferritin, and transferrin saturation rate, and decreased erythropoiesis-stimulating agent dose and erythropoiesis-stimulating agent resistance index value. Serum phosphate, calcium, and intact parathyroid hormone levels did not change significantly during the study. I-FGF23 levels increased significantly in the IV group and did not change in the oral group, whereas C-FGF23 levels were significantly reduced in both groups. Serum interleukin-6 and tumor necrosis factor-α levels were increased in both groups. Multiple regression analysis indicated the relationship between iron or erythropoiesis and FGF23 metabolism. CONCLUSION: Iron administration to patients on MHD with severe iron deficiency decreased C-FGF23 levels, whereas intravenous iron increased I-FGF23 levels though oral iron did not. If the target of chronic kidney disease-mineral and bone disorder therapy is reducing I-FGF23 levels, we suggest the use of oral iron.

Clinical and pathogenic features of SCCmec type II and IV methicillin-resistant Staphylococcus aureus in Japan.

Staphylococcal chromosomal cassette mec (SCCmec) type IV methicillin-resistant Staphylococcus aureus (MRSA) has rapidly disseminated in healthcare settings, and its characteristics in the United States and Europe are well known. Because Japanese SCCmec type IV MRSA clones are different and less well documented, this retrospective, single center study was done to determine and compare the characteristics of SCCmec type II and IV MRSA in Japan. For the analysis, 55 SCCmec type II and 101 type IV MRSA samples were collected from lower respiratory tract specimens or from skin or soft tissue. The patients of the SCCmec type IV group were significantly younger than those of the type II group (P < 0.001). The rate of MRSA pneumonia was significantly lower for SCCmec type IV than for type II (7.8% vs 29.0%, P = 0.026). In contrast, the rate of skin and soft tissue infection was not significantly different (66.0% vs 61.9%, P = 0.788). The distribution of MRSA pathogenic genes (sea, seb, sem, seo) was significantly different between SCCmec types II and IV (P < 0.001), which indicates that their clonal complex may be completely different. Interestingly, all SCCmec type II MRSA that caused MRSA pneumonia had seb and egc and lacked tst that belonged to sequence type (ST) 764. This is the first study to reveal and compare the characteristics of Japanese SCCmec type II and type IV MRSA. The information from this study will be helpful for the management of Japanese MRSA infection.

Expression profiling of marker genes responsive to the defence-associated phytohormones salicylic acid, jasmonic acid and ethylene in Brachypodium distachyon.

BACKGROUND: Brachypodium distachyon is a promising model plants for grasses. Infections of Brachypodium by various pathogens that severely impair crop production have been reported, and the species accordingly provides an alternative platform for investigating molecular mechanisms of pathogen virulence and plant disease resistance. To date, we have a broad picture of plant immunity only in Arabidopsis and rice; therefore, Brachypodium may constitute a counterpart that displays the commonality and uniqueness of defence systems among plant species. Phytohormones play key roles in plant biotic stress responses, and hormone-responsive genes are used to qualitatively and quantitatively evaluate disease resistance responses during pathogen infection. For these purposes, defence-related phytohormone marker genes expressed at time points suitable for defence-response monitoring are needed. Information about their expression profiles over time as well as their response specificity is also helpful. However, useful marker genes are still rare in Brachypodium. RESULTS: We selected 34 candidates for Brachypodium marker genes on the basis of protein-sequence similarity to known marker genes used in Arabidopsis and rice. Brachypodium plants were treated with the defence-related phytohormones salicylic acid, jasmonic acid and ethylene, and their transcription levels were measured 24 and 48 h after treatment. Two genes for salicylic acid, 7 for jasmonic acid and 2 for ethylene were significantly induced at either or both time points. We then focused on 11 genes encoding pathogenesis-related (PR) 1 protein and compared their expression patterns with those of Arabidopsis and rice. Phylogenetic analysis suggested that Brachypodium contains several PR1-family genes similar to rice genes. Our expression profiling revealed that regulation patterns of some PR1 genes as well as of markers identified for defence-related phytohormones are closely related to those in rice. CONCLUSION: We propose that the Brachypodium immune hormone marker genes identified in this study will be useful to plant pathologists who use Brachypodium as a model pathosystem, because the timing of their transcriptional activation matches that of the disease resistance response. Our results using Brachypodium also suggest that monocots share a characteristic immune system, defined as the common defence system, that is different from that of dicots.

Association of IL28B rs8099917 genotype and female sex with spontaneous clearance of hepatitis C virus infection: a Japanese cross-sectional study.

Hepatitis C virus (HCV) infection is a serious global health problem. Previous studies have suggested that the interleukin 28B (IL28B) rs8099917 genotype is related to spontaneous clearance of HCV in Caucasian populations. Our objective was to investigate the association of the IL28B rs8099917 genotype with spontaneous clearance of HCV by community-dwelling Japanese. A cross-sectional community-based population study of 993 Japanese residents was conducted. Based on anti-HCV antibody and HCV RNA levels, 50 subjects were assigned to the spontaneous-clearance group, 155 to the chronic-infection group, and 788 to the control group. Logistic regression analysis was done to examine the roles of the IL28B rs8099917 genotype and sex. To analyze the interactions between these factors, an "IL28B rs809991 genotype × sex" interaction term was included in the multivariate analysis. Significantly more subjects in the spontaneous-clearance group than in the chronic-infection group had the favorable IL28B rs8099917 genotype and were female. Multivariate logistic regression analysis extracted the favorable IL28B rs8099917 TT genotype (odds ratio [OR] 9.39; 95% confidence interval [CI], 2.16-40.83, P = 0.003) and female sex (OR, 2.27; 95% CI, 1.16-4.45, P = 0.017) as factors contributing to the spontaneous clearance of HCV. No significant interaction was found between the IL28B rs8099917 genotype and sex (P for interaction = 0.428). Both the favorable IL28B rs8099917 genotype and female sex were associated with the spontaneous clearance of HCV in this Japanese population.

The kinetics of the hepatitis B surface antigen level after the initiation of antiretroviral therapy for hepatitis B virus and human immunodeficiency virus coinfected patients.

BACKGROUND: Hepatic flares (HF), which reflect hepatitis B virus (HBV)-related immune reconstitution inflammatory syndrome (IRIS), frequently occur in patients with HBV and human immunodeficiency virus (HIV) coinfection after the start of antiretoroviral therapy (ART). The rate of hepatitis B envelope antigen (HBeAg) and hepatitis B surface antigen (HBsAg) loss is higher for patients with HF after the initiation of ART. METHODS: We retrospectively examined the kinetics of the HBsAg and HBeAg levels of six HBV/HIV coinfected patients after the commencement of ART that included tenofovir. All were male and HBeAg positive. RESULTS: Three patients developed HF after the initiation of ART. All subsequently lost HBeAg and one of them lost HBsAg after HF. None who did not experience HF lost HBeAg. The HBsAg and HBeAg levels remarkably decreased when HF occurred, but the decline of HBsAg was very slow in the periods before and after HF. The median decline of the HBsAg level at 48 weeks was 2.20 Log IU/mL for patients with HF, but only 1.00 Log IU/ml for patients without HF. Little decline was seen for either group in the median decline of the HBsAg level from 48 weeks to 96 weeks, 0.28 Log IU/mL in the HF group and 0.06 Log IU/mL in the non-HF group. CONCLUSION: The immune reconstitution of a HBV/HIV coinfected patient plays an important role in the clearance of HBV. If HBsAg and HBeAg levels decrease rapidly when HF occurs, the hepatic flare would be due to HBV-related IRIS.

Therapeutic drug monitoring of telaprevir in chronic hepatitis C patients receiving telaprevir-based triple therapy is useful for predicting virological response.

OBJECTIVES: This prospective, pharmacokinetic study was done to investigate the impact of telaprevir plasma trough concentration (Ctrough) in the early stage of treatment on the response to telaprevir-based triple therapy for chronic hepatitis C patients. METHODS: Participants were 70 chronic hepatitis C patients infected with genotype 1. All patients received 12 week triple therapy that included telaprevir (2250 mg/day), pegylated interferon-α2b (pegylated-IFNα2b) (60-150 µg/week) and ribavirin (600-1000 mg/day) followed by a 12 week dual therapy that included pegylated-IFNα2b and ribavirin. Plasma telaprevir Ctrough was determined by a validated assay using HPLC at days 3, 7 and 14. The study was registered as a clinical trial on the University Hospital Medical Information Network (ID 000009656). RESULTS: The rates of undetectable hepatitis C virus RNA at week 4 [rapid virological response (RVR)] and at 24 weeks after therapy [sustained virological response (SVR)] were 71.4% and 82.9%, respectively. Of the patients with RVR, 90% achieved SVR. The mean telaprevir Ctrough levels at days 3, 7 and 14 of SVR patients (2.748, 2.733 and 2.999 µg/mL, respectively) were significantly higher than those of non-SVR patients (1.616, 1.788 and 2.314 µg/mL, respectively) (all P < 0.05). Multiple logistic regression analysis of possible predictors of SVR extracted higher telaprevir Ctrough at day 3 (OR 1.012 by 0.001 µg/mL, P < 0.0001) and interleukin 28B (rs8099917) TT allele (OR 6.16 versus non-TT alleles, P < 0.0001). CONCLUSIONS: Therapeutic drug monitoring of telaprevir in the early stage of treatment is useful in clinical practice for predicting the virological response of patients receiving telaprevir-based triple therapy.

Nocturnal difference in the ultra low frequency band of heart rate variability in patients stratified by Kampo medicine prescription.

BACKGROUND: The Yo/Yin concept is fundamental to making a Kampo (sho) diagnosis and may be deeply related to the autonomic nervous system. There is, however, little objective data to confirm the validity of these concepts. METHODS AND RESULTS: After diagnosis using standardized Kampo techniques, 20 men and 67 women (mean age, 52.4 years) for whom the prescribed Kampo medication was effective were judged to be correctly classified as Yo- (n=49) or Yin-sho (n=38) and enrolled. Autonomic nervous function was assessed at first visit using HRV obtained from 24-h Holter ECG. Nocturnal ultra low frequency-1 (ULF-1, 0.0001-0.0003 Hz) and ULF-2 (0.0003-0.003 Hz) were significantly higher in the Yin-sho than in the Yo-sho group (P=0.030, P=0.016), suggesting a higher variation of autonomic nervous activity according to sleep stage. On multivariate analysis BMI (≥ 23.0 kg/m(2)) and ULF-1 (≥ 1,150 ms(2)) were identified as independent factors associated with a differential diagnosis of Yo- or Yin-sho (odds ratio [OR], 11.63, P=0.002; OR, 0.30, P=0.038, respectively). When the sleep period was divided into 3 phases, the ULF-1 of the Yin-sho group was significantly higher than that of the Yo-sho group in the late phase of sleep (P=0.023). CONCLUSIONS: On heart rate variability analysis there was a sleep stage-related difference in the autonomic nervous activity of patients treated with standard Yo- and Yin-sho Kampo medicines.

A case of successful treatment with telaprevir-based triple therapy for hepatitis C infection after treatment failure with vaniprevir-based triple therapy.

Recently direct-acting antiviral agents, such as hepatitis C virus (HCV) non-structural 3/4A (NS3/4A) protease inhibitors (PI), have been introduced, and triple therapy regimens that include PI with conventional pegylated interferon α and ribavirin have significantly improved the sustained virological response (SVR) rate, up to 80% for both treatment-naïve and treatment-experienced patients with HCV genotype 1. We here report for the first time a case of the successful treatment of HCV genotype 1 infection with a first generation PI drug (telaprevir) based triple therapy after treatment failure with a second generation PI drug (vaniprevir) based triple therapy. A 67-year-old treatment-naïve Japanese man with HCV genotype 1b infection took part in a phase III clinical trial of vaniprevir-based triple therapy. His serum HCV RNA had become undetectable at week 2 and SVR was highly expected, but HCV RNA reappeared at week 4 after vaniprevir treatment. Polymerase chain reaction direct sequence of the HCV NS3/4A gene at week 8 after vaniprevir treatment showed the emergence of a vaniprevir-resistance mutation (D168V), the probable reason for the treatment failure. Six months later, retreatment with telaprevir-based triple therapy was started. Although the dosages of telaprevir and ribavirin had to be reduced due to severe anemia, the patient achieved an SVR. This case shows the value of repeating PI-based triple therapy with a different drug, a process that would reduce the chance of drug resistant mutation.