Analysis of the Complete Open Reading Frame of Genotype 2b Hepatitis C Virus in Association with the Response to Peginterferon and Ribavirin Therapy

BACKGROUND AND AIMS: Patients infected with genotype 2b hepatitis C virus (HCV) generally can achieve favorable responses to pegylated-interferon plus ribavirin therapy (PEG-IFN/RBV). However, a proportion of patients show poorer responses and the correlation between viral sequence variation and treatment outcome remains unclear. METHODS: The pretreatment complete open reading frame (ORF) sequences of genotype 2b HCV determined by direct sequencing were investigated for correlation with the final outcome in a total of 60 patients. RESULTS: In this study group, 87.5% (14/16) of non-sustained virological response (non-SVR) patients (n = 16) were relapsers. Compared to sustained virological response (SVR) patients (n = 44), non-SVR patients were older and could not achieve prompt viral clearance after the therapy induction. Comparing each viral protein between the two groups, viral sequences were more diverse in SVR patients and that diversity was found primarily in the E1, p7, and NS5A proteins. In searching for specific viral regions associated with the final outcome, several regions in E2, p7, NS2, NS5A, and NS5B were extracted. Among these regions, part of the interferon sensitivity determining region (ISDR) was included. In these regions, amino acid substitutions were associated with the final outcome in an incremental manner, depending upon the number of substitutions. CONCLUSIONS: Viral sequences are more diverse in SVR patients than non-SVR patients receiving PEG-IFN/RBV therapy for genotype-2b HCV infection. Through systematic comparison of viral sequences, several specific regions, including part of the ISDR, were extracted as having significant correlation with the final outcome

Estimating the immunogenicity of measles-rubella vaccination administered during a mass campaign in Lao People's Democratic Republic using multi-valent seroprevalence data.

Measles and rubella are important causes of morbidity and mortality globally. Despite high coverage reported for measles vaccination, outbreaks continue to occur in some countries. The reasons for these outbreaks are poorly understood. We apply Bayesian methods to multi-valent seroprevalence data for measles and rubella, collected 2 years and 3 months after a mass measles-rubella vaccination campaign in Lao PDR to estimate the immunogenicity and vaccination coverage. When the vaccination coverage was constrained to exceed 95% or 90%, consistent with officially-reported values, the immunogenicity of the measles vaccine component was unexpectedly low (75% (95% CR: 63-82%) and 79% (CR: 70-87%) respectively. The estimated immunogenicity increased after relaxing constraints on the vaccination coverage, with best-fitting values of 83% (95% CR: 73-91%) and 97% (95% CR: 90-100%) for the measles and rubella components respectively, with an estimated coverage of 83% (95% CR: 80-88%). The findings suggest that, if the vaccine coverage was as high as that reported, continuing measles outbreaks in Lao PDR, and potentially elsewhere, may be attributable to suboptimal immunogenicity attained in mass campaigns. Vaccine management in countries with high reported levels of coverage and ongoing measles outbreaks needs to be reviewed if measles elimination targets are to be achieved

Evaluation of nationwide supplementary immunization in Lao People's Democratic Republic: Population-based seroprevalence survey of anti-measles and anti-rubella IgG in children and adults, mathematical modelling and a stability testing of the vaccine.

BACKGROUND: Measles outbreaks have occurred in some countries despite supplementary immunization activities (SIA) using measles-containing vaccine with high vaccination coverage. We conducted a cross-sectional seroprevalence survey to estimate population immunity in Lao People's Democratic Republic where repeated mass immunization has failed to eliminate measles. METHODS AND FINDINGS: In this nationwide multistage cluster sampling survey conducted in 2014 based on probability proportionate to size sampling, blood samples were collected from 2,135 children and adults living in 52 randomly selected villages. Anti-measles and anti-rubella IgG were measured, and IgG prevalence was calculated. We applied mathematical modelling to estimate the number of cases of congenital rubella syndrome (CRS) in 2013 that were averted by the 2011 SIA. A stability testing was applied to the MR vaccine at 4°C, 25°C, and 35°C to examine stability differences between measles and rubella vaccine components. Measles IgG prevalence was significantly lower in the target age groups (5-21 years) of the 2011 SIA using a combination vaccine for measles and rubella vaccine (MR vaccine) than in young adults (22-39 years) (86.8% [95% CI: 83.0-90.6] vs. 99.0% [98.3-99.8]; p<0.001), whereas rubella IgG prevalence was significantly higher (88.2% [84.5-91.8] vs. 74.6% [70.7-78.5]; p<0.001). In the SIA target age groups, prevalence of measles IgG, but not rubella IgG, increased with age. CRS cases prevented in 2013 ranged from 16 [0-50] to 92 [32-180] if the force of infection had remained unchanged or had been reduced by 75%, respectively. In freeze-dried conditions, the measles vaccine component was more heat sensitive than the rubella component. CONCLUSIONS: Inconsistent IgG prevalence between measles and rubella in Lao PDR can be partly explained by different stability of the measles and rubella vaccine components under heat exposure. Suboptimal vaccine handling may cause insufficient immunogenicity for measles, which subsequently leads to an outbreak despite high SIA coverage, while direct evidence is lacking. Temperature monitoring of the vaccine should be conducted

Pharaoh Ant (Monomorium pharaonis): Newly Identified Important Inhalant Allergens in Bronchial Asthma

The nonstinging house ant, Monomorium pharaonis (pharaoh ant), was recently identified as a cause of respiratory allergy. This study was performed to evaluate the extent of sensitization to pharaoh ant, and its clinical significance in asthmatic patients. We carried out skin prick tests in 318 patients with asthma. Specific IgE (sIgE) to pharaoh ant was measured by ELISA, and cross-reactivity was evaluated by ELISA inhibition tests. Bronchial provocation testing was performed using pharaoh ant extracts. Fifty-eight (18.2%) of 318 patients showed positive skin responses to pharaoh ant, and 25 (7.9%) had an isolated response to pharaoh ant. Positive skin responses to pharaoh ant were significantly higher among patients with non-atopic asthma than among those with atopic asthma (26.0% vs. 14.9%, p<0.05). There was significant correlation between sIgE level and skin responses to pharaoh ant (rho=0.552, p<0.001). The ELISA inhibition tests indicated that pharaoh ant allergens had various pattern of cross-reactivity to house dust mites and cockroaches. Bronchial provocation tests to pharaoh ant were conducted for 9 patients, and eight showed typical asthmatic reactions. In conclusion, pharaoh ant is an important source of aeroallergens, and it should be included in the skin test battery for screening the causative allergens in patients with asthma

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Effects of a Newly Developed Gratitude Intervention Program on Work Engagement Among Japanese Workers:A Pre- and Posttest Study

OBJECTIVE: This study aimed to develop a 3-week gratitude intervention program that included gratitude lists and behavioral gratitude expression and to examine the effect of the program on work engagement, gratitude, self-efficacy, psychological distress, and job performance in a pretest-posttest study design. METHODS: Eight hundred thirty-five employees were recruited for the study. The outcomes were measured at baseline, postintervention, and at 6-week follow-up. Estimated means at the three points were compared in a mixed model for repeated measures. RESULTS: One hundred forty-five workers were included and analyzed. Work engagement showed no significant improvement after the intervention. However, gratitude, self-efficacy, psychological distress, and job performance improved significantly. CONCLUSIONS: The program might be effective for improving gratitude, self-efficacy, psychological distress, and job performance, but further modification of the program is needed to improve the effect on work engagement

A case of anaphylactoid reaction due to Matsutake mushroom (Tricoloma matsutake) ingestion

The case history of a 27-year-old man with Matsutake mushroom-dependent anaphylactoid reaction is reported. The patient suffered from general cutaneous erythema, with itching, urticaria angiedema to his face and body, and with inspiratory dyspnea, soon after consuming a meal of Matsutake mushrooms. A challenge test with about 100 g grilled Matsutake mushrooms resulted in irritation of the throat, inspiratory dyspnea and lowering of peak flow rate, all of which were observed after about 30 min. These symptoms disappeared spontaneously 4 h later, without treatment. About 5 h after the challenge, the patient suffered from dyspnea and general cutaneous erythema, with urticaria of his face and body. Hydrocortisone was given and next morning he had no more symptoms. Laboratory data showed elevation of neutrophils and myeloperoxidase after the challenge, but no elevation of serum histamine. This is the second case of anaphylaxis or anaphylactoid reaction to Matsutake mushrooms for which IgE antibody to Matsutake may not be the cause

Ease-of-use preference for the ELLIPTA&reg; dry powder inhaler over a commonly used single-dose capsule dry powder inhaler by inhalation device-na&iuml;ve Japanese volunteers aged 40 years or older

Yuko Komase,1 Akimoto Asako,2 Akihiro Kobayashi,3 Raj Sharma4 1Department of Respiratory Internal Medicine, St Marianna University School of Medicine, Yokohama City Seibu Hospital, Yokohama, Kanagawa, Japan; 2MA Respiratory Department, Development and Medical Affairs Unit, GlaxoSmithKline KK, Tokyo, Japan; 3Biomedical Data Sciences Department, GlaxoSmithKline KK, Tokyo, Japan; 4Global Respiratory Franchise Medical Department, GSK, Stockley Park, UK Background: In patients receiving inhaled medication, dissatisfaction with and difficulty in using the inhaler can affect treatment adherence. The incidence of handling errors is typically higher in the elderly than in younger people. The aim of the study was to assess inhaler preference for and handling errors with the ELLIPTA&reg; dry powder inhaler (DPI), (GSK), compared with the established BREEZHALER&trade;, a single-dose capsule DPI (Novartis), in inhalation device-na&iuml;ve Japanese volunteers aged &ge;40 years. Methods: In this open-label, nondrug interventional, crossover DPI preference study comparing the ELLIPTA DPI and BREEZHALER, 150 subjects were randomized to handle the ELLIPTA or BREEZHALER DPIs until the point of inhalation, without receiving verbal or demonstrative instruction (first attempt). Subjects then crossed over to the other inhaler. Preference was assessed using a self-completed questionnaire. Inhaler handling was assessed by a trained assessor using a checklist. Subjects did not inhale any medication in the study, so efficacy and safety were not measured. Results: The ELLIPTA DPI was preferred to the BREEZHALER by 89% of subjects (odds ratio [OR] 70.14, 95% confidence interval [CI] 33.69&ndash;146.01; P-value not applicable for this inhaler) for ease of use, by 63% of subjects (OR 2.98, CI 1.87&ndash;4.77; P&lt;0.0001) for ease of determining the number of doses remaining in the inhaler, by 91% for number of steps required, and by 93% for time needed for handling the inhaler. The BREEZHALER was preferred to the ELLIPTA DPI for comfort of the mouthpiece by 64% of subjects (OR 3.16, CI 1.97&ndash;5.06; P&lt;0.0001). The incidence of handling errors (first attempt) was 11% with ELLIPTA and 68% with BREEZHALER; differences in incidence were generally similar when analyzed by age (&lt; or &ge;65 years) or sex. Conclusion: These data, obtained in an inhalation device-na&iuml;ve population, suggest that the ELLIPTA DPI is preferred to an established alternative based on its ease-of-use features and is associated with fewer handling errors. Keywords: chronic obstructive pulmonary disease, dry powder inhaler, ELLIPTA&reg;, BREEZHALER&trade