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In 2005, researchers and policymakers gathered in Istanbul, Turkey for a conference, Delivery Systems for Substance Abuse Treatment, to address the internationally shared problem of substance use disorders. The conference included participants from the United States, Israel, and neighboring Middle Eastern countries and territories and was structured to create conditions that behavioral scientists have identified as key factors in facilitating successful intergroup contact. At the conclusion of the meeting, attendees reported being more likely to work with people from other countries or territories in their region as a result of the conference. Five years later, surveyed attendees reported having engaged in cooperative activities that the participants attributed at least in part to the conference. A number of concrete and verifiable examples of joint efforts between participants from the United States, Israel, and other Middle Eastern countries and territories were provided, suggesting the conference had a meaningful and lasting impact. This occurred despite a generally poor and declining environment for cooperation during this same period. These outcomes suggest that psychological principles can be successfully applied to real-world meetings, and that this may be a useful method for reaching participants who would not otherwise be reached by meetings explicitly promoted as peace-related. Limitations of this study include its descriptive nature and lack of a comparison group, which prevents conclusions regarding causality or magnitude of effect. This is a first step; in the future, controlled studies are needed to provide a stronger test of the effect of such structured meetings on outcomes. © 2014 American Psychological Association.

Kaori Kurata,1 Michi Onuki,2 Kazuki Yoshizumi,3 Eitaro Taniai,3 Akira Dobashi11Education and Research Institute of Information Science, Tokyo University of Pharmacy and Life Sciences, Hachioji, Tokyo, Japan; 2Insurance Pharmacy Division, Yakuju Co. Ltd, Minato-ku, Tokyo, Japan; 3Information Headquarters, Yakuju Co. Ltd., Yamato-shi, Kanagawa, JapanAim: Our study aimed to clarify how long outpatients with chronic diseases such as hypertension continuously fill prescriptions for the same medications as those prescribed initially and how many medications they take over the long term.Methods: Medication records from April 1, 2016 to March 31, 2017 with total days between initial and final dispensation date ≥330 days and total days of medication supplies ≥180 days were extracted from an electronic database in a Japanese community pharmacy chain. The continuity of refilling medications over 1 year (ie, medication fill adherence) was measured using the medication possession ratio (MPR).Results: A total of 34,549 outpatients received long-term medications under the above conditions (4.4% of all patients in the database). Mean age was 66.0±17.4 years; 63.1% were ≥65 years. The mean number of medications prescribed per patient was 3.2±2.3. More than one-fifth of patients (22.6%) were taking ≥5 medications. The mean MPR for patients overall was 93.6±11.2%; 87.2% of patients had an MPR ≥80% but 90% for around 3 medications. It can be reasonably assumed that these patients could receive a longer-term medication supply with the partial fills based on a physician’s instruction (“Bunkatu Chozai” in Japanese). This longer-term supply would be similar to a basic prescription refill, but would require a physician’s signature allowing for partial refills rather than a new prescription for each refill.Keywords: outpatient, partial fill, long-term medication, medication possession ratio, chronic disease, refill prescription

Objective: To investigate the efficacy and safety of robot-assisted radical hysterectomy (RARH) as a minimally invasive procedure in patients with cervical cancer that is curable by surgery., Materials and Methods: This study was a multicenter, open-label, single-arm clinical trial. The short-term outcome of open radical hysterectomy was used as the historical control. The primary endpoint was successful surgery with minimal blood loss (300 mL or less) and negative surgical margins. Secondary endpoints included surgical outcomes, recurrence-free survival (RFS), and overall survival (OS) rates., Results: Overall, 101 cases were enrolled in this study at 10 participating medical institutions and 100 underwent RARH. Among these cases, 89 met the primary endpoint, exceeding the threshold of 0.75 set by the lower limit. At 2 years postoperatively, 17 cases had recurrences, 4 were classified as International federation of Obstetrics and Gynecology Stage IB1 or lower, while 13 as IB2 or higher. There were three deaths, including one in Stage IB1 and two in Stage IIB in the second postoperative year, all of which had lymph node metastasis. The oncological outcomes for all cases showed RFS and OS rates of 82.7% and 96.9%, respectively, over a median observation period of 37 months. For cases with Stage IB1, RFS and OS were 94.1% and 98.5%, respectively., Conclusion: RARH demonstrated a significant reduction in blood loss while ensuring radicality, indicating the safety and efficacy of this procedure compared to conventional RH. Although it is conceivable that the results of this oncological analysis could change, as the data collection has not been fully completed, we plan to further evaluate the oncologic outcomes of RARH in future studies., Trial Registration: UMIN-CTR: UMIN000022278, registered on 11th May 2016., (© 2024. The Author(s).)

Background and Aims: Sarcopenia is associated with the prognosis of patients with liver cirrhosis and hepatocellular carcinoma (HCC). Given their diverse physiological activities, we hypothesized that plasma fatty acids might influence the progression of sarcopenia. This study aimed to clarify the association between fatty acids and sarcopenia in cirrhotic patients with HCC., Methods: In this single-center retrospective study, we registered 516 cases and analyzed 414 cases of liver cirrhosis and HCC. The skeletal muscle mass index was measured using a transverse computed tomography scan image at the third lumbar vertebra. The cutoff value for sarcopenia followed the criteria set by the Japan Society of Hepatology. Fatty acid concentrations were measured by gas chromatography., Results: Fatty acid levels, particularly omega-3 (n-3) polyunsaturated fatty acid (PUFA), were lower in patients with poor liver function (Child-Pugh grade B/C) and were negatively correlated with the albumin-bilirubin score ( p <0.0001). The prognosis of HCC patients with low PUFA levels was significantly worse. Among the different fatty acid fractions, only n-3 PUFAs significantly correlated with skeletal muscle mass index ( p= 0.0026). In the multivariate analysis, the n-3 PUFA level was an independent variable associated with sarcopenia ( p= 0.0006)., Conclusions: A low level of n-3 PUFAs was associated with sarcopenia in patients with liver cirrhosis and HCC., Competing Interests: The authors have no conflict of interest related to this publication., (© 2024 Authors.)

Objective This study assessed the impact of dietary therapy and reduced body weight on the loss of skeletal muscle in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). Methods This was a single-center retrospective observational study. We enrolled 129 patients with MASLD who had undergone dietary therapy at our facility. We assessed skeletal muscle mass using a bioelectrical impedance analysis (BIA) at the start of dietary treatment and 12 months after the first assessment. Variables related to muscle reduction were analyzed using a logistic regression model. Results One hundred and eighteen cases were analyzed, excluding those with missing data. In the muscle reduction group, there were more subjects with body weight reduction than in the control group (68% and 40%, respectively, p =0.002), and their body mass index (BMI) was decreased (-0.7 kg/m 2 and +0.3 kg/m 2 , respectively, p =0.0003). There was a significant correlation between the changes in the BMI and muscle mass (R =0.48, p <0.0001). We standardized muscle mass change by dividing it by weight change to analyze the severe decrease in muscle mass compared to weight change. A logistic regression analysis revealed that type 2 diabetes mellitus (T2DM) was an independent variable related to severe skeletal muscle loss (odds ratio, 2.69; 95% CI: 1.13-6.42, p =0.03). Conclusion Weight loss is associated with skeletal muscle loss during dietary treatment for MASLD. T2DM is a risk factor for severe skeletal muscle loss.

It is difficult to determine whether an individual therapy contributes to the elongation of survival because of the difficulty of organizing clinical research in patients who receive multiple treatments in HCC. We aimed to establish a new model of survival prediction in patients with intermediate stage HCC to establish standards in the recent and coming multi-MTA era. This analysis was prepared using a data set of 753 patients diagnosed HCC prior to 2017. Multiple regression analysis showed age, naïve or recurrence, the size of the largest tumor nodule, the number of nodules, total bilirubin, albumin and α-fetoprotein as independent predictors of survival. A Weibull model had the best fit and, based on these predictors, we established a new predicted survival model. The survival duration can be predicted the proposed model; EXP (4.02580 + (- 0.0086253) × age + (- 0.34667) × (naïve/recurrence) + (- 0.034962) × (number of nodules) + (- 0.079447) × (the size of the largest nodule) + (- 0.21696) × (total bilirubin) + 0.27912 × (albumin) + (- 0.00014741) × (α-fetoprotein)) × (- natural logarithm(0.5))^0.67250. This model is useful for the planning and evaluating the efficacy of recent sequential therapies in multi-MTA era., (© 2023. The Author(s).)

The first prophylactic vaccine against human papillomavirus (HPV) 16 and HPV18 was licensed in Japan in 2009. HPV vaccine effectiveness against high-grade cervical lesions has been demonstrated among young Japanese women, but evidence of its effects on invasive cervical cancer (ICC) is lacking. Using data from two different cancer registries, we compared recent trends of new ICC cases by age group using Poisson regression analysis. We also analyzed time trends in HPV16/18 prevalence among 1414 Japanese women aged <40 years newly diagnosed with ICC in the past decade. Based on the population-based cancer registry, the incidence of ICC among young women aged 20-29 years showed a significant decline from 3.6 to 2.8 per 100 000 women-years during 2016-2019, but no similar decline was observed for older age groups (p < 0.01). Similarly, using data from the gynecological cancer registry of the Japan Society of Obstetrics and Gynecology, the annual number of ICCs among women aged 20-29 years also decreased from 256 cases to 135 cases during 2011-2020 (p < 0.0001). Furthermore, a declining trend in HPV16/18 prevalence in ICC was observed only among women aged 20-29 years during 2017-2022 (90.5%-64.7%, p = 0.05; Cochran-Armitage trend test). This is the first report to suggest population-level effects of HPV vaccination on ICC in Japan. Although the declining trend in HPV16/18 prevalence among young women with ICC supports a causal linkage between vaccination and results from cancer registries, further studies are warranted to confirm that our findings are attributable to vaccination., (© 2023 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Human papillomavirus type 31 (HPV31) is detected less frequently in cervical cancer than two major causative types, HPV16 and HPV18. Here, we report a comprehensive analysis of HPV31 genome sequences in cervical lesions collected from Japanese women. Of 52 HPV31-positive cervical specimens analyzed by deep sequencing, 43 samples yielded complete genome sequences of around 7900 base pairs and 9 samples yielded partially deleted genome sequences. Phylogenetic analysis showed that HPV31 variant distribution was lineage A in 19 samples (36.5%), lineage B in 28 samples (53.8%), and lineage C in 5 samples (9.6%), indicating that lineage B variants are dominant among HPV31 infections in Japan. Deletions in the viral genome were found in the region from the E1 to L1 genes, but all the deleted genomes retained the E6 / E7 genes. Among intra-patient nucleotide variations relative to a consensus genome sequence in each sample, C-to-T substitutions were most frequently detected, followed by T-to-C and C-to-A substitutions. High-frequency, intra-patient mutations (>10%) in cervical cancer samples were found in the E1 , E2 , and E7 genes, and all of them were nonsynonymous substitutions. The enrichment of high-frequency nonsynonymous substitutions strongly suggests that these intra-patient mutations are positively selected during the development of cervical cancer/precancer.

Background: For women diagnosed with hereditary breast and ovarian cancer, the clinical guidelines recommend risk-reducing salpingo-oophorectomy at age 35-40 years or after completion of childbearing. However, there is limited information regarding the current status of risk-reducing salpingo-oophorectomy in Japan., Methods: To clarify factors influencing decision-making for risk-reducing salpingo-oophorectomy among Japanese women diagnosed with hereditary breast and ovarian cancer and their clinical outcomes, we analyzed the medical records of 157 Japanese women with germline BRCA pathogenic variants (BRCA1 n = 85, BRCA2 n = 71 and both n = 1) at our institution during 2011-21. Specimens obtained from risk-reducing salpingo-oophorectomy were histologically examined according to the sectioning and extensively examining the fimbriated end protocol., Results: The risk-reducing salpingo-oophorectomy uptake rate was 42.7% (67/157). The median age at risk-reducing salpingo-oophorectomy was 47 years. Older age, married state and parity were significantly associated with risk-reducing salpingo-oophorectomy (P < 0.001, P = 0.002 and P = 0.04, respectively). History of breast cancer or family history of ovarian cancer did not reach statistical significance (P = 0.18 and P = 0.14, respectively). Multivariate analyses revealed that older age (≥45 years) and married state may be independent factors associated with risk-reducing salpingo-oophorectomy. Interestingly, the annual number of risk-reducing salpingo-oophorectomy peaked in 2016-17 and has increased again since 2020. The rate of occult cancers at risk-reducing salpingo-oophorectomy was 4.5% (3/67): ovarian cancer (n = 2) and serous tubal intraepithelial carcinoma (n = 1)., Conclusion: Age and marital status significantly affected decision-making for risk-reducing salpingo-oophorectomy. This is the first study to suggest possible effects of Angelina Jolie's risk-reducing salpingo-oophorectomy in 2015 and the National Health Insurance introduced for risk-reducing salpingo-oophorectomy in 2020. The presence of occult cancers at risk-reducing salpingo-oophorectomy supports clinical guidelines recommending risk-reducing salpingo-oophorectomy at younger ages., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Duodenal varices are detected infrequently, and their rupture is very rare. We encountered an 87-year-old man who developed duodenal varices rupture during chemotherapy with atezolizumab and bevacizumab (ATZ/BV) for hepatocellular carcinoma. We identified massive bleeding of a ruptured varix in the horizontal portion of the duodenum with emergency esophagogastroduodenoscopy (EGD). Successful hemostasis was achieved by endoscopic injection sclerotherapy with Histoacryl. Although ATZ/BV can cause esophageal varices rupture, there have been no cases of duodenal varices rupture. We should take care to check the duodenal varices as well as esophagogastric varices before ATZ/BV treatment.

Background: Digital health technologies using mobile apps and wearable devices are a promising approach to the investigation of substance use in the real world and for the analysis of predictive factors or harms from substance use. Moreover, consecutive repeated data collection enables the development of predictive algorithms for substance use by machine learning methods., Objective: We developed a new self-monitoring mobile app to record daily substance use, triggers, and cravings. Additionally, a wearable activity tracker (Fitbit) was used to collect objective biological and behavioral data before, during, and after substance use. This study aims to describe a model using machine learning methods to determine substance use., Methods: This study is an ongoing observational study using a Fitbit and a self-monitoring app. Participants of this study were people with health risks due to alcohol or methamphetamine use. They were required to record their daily substance use and related factors on the self-monitoring app and to always wear a Fitbit for 8 weeks, which collected the following data: (1) heart rate per minute, (2) sleep duration per day, (3) sleep stages per day, (4) the number of steps per day, and (5) the amount of physical activity per day. Fitbit data will first be visualized for data analysis to confirm typical Fitbit data patterns for individual users. Next, machine learning and statistical analysis methods will be performed to create a detection model for substance use based on the combined Fitbit and self-monitoring data. The model will be tested based on 5-fold cross-validation, and further preprocessing and machine learning methods will be conducted based on the preliminary results. The usability and feasibility of this approach will also be evaluated., Results: Enrollment for the trial began in September 2020, and the data collection finished in April 2021. In total, 13 people with methamphetamine use disorder and 36 with alcohol problems participated in this study. The severity of methamphetamine or alcohol use disorder assessed by the Drug Abuse Screening Test-10 or the Alcohol Use Disorders Identification Test-10 was moderate to severe. The anticipated results of this study include understanding the physiological and behavioral data before, during, and after alcohol or methamphetamine use and identifying individual patterns of behavior., Conclusions: Real-time data on daily life among people with substance use problems were collected in this study. This new approach to data collection might be helpful because of its high confidentiality and convenience. The findings of this study will provide data to support the development of interventions to reduce alcohol and methamphetamine use and associated negative consequences., International Registered Report Identifier (irrid): DERR1-10.2196/44275., (©Ayumi Takano, Koki Ono, Kyosuke Nozawa, Makito Sato, Masaki Onuki, Jun Sese, Yosuke Yumoto, Sachio Matsushita, Toshihiko Matsumoto. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 11.04.2023.)

Nucleos(t)ide analogues (NAs) suppress hepatitis B virus (HBV) replication, but the risk of hepatocellular carcinoma still remains. The presence of detectable HBV DNA in the serum during NA therapies for chronic hepatitis B patients has been reported to be associated with the risk of hepatocellular carcinoma. In this study, we investigated the antiviral effect of switching from entecavir (ETV) to tenofovir alafenamide fumarate (TAF) in chronic hepatitis B patients who had detectable HBV DNA in the serum at least once within a year. Among a total of 77 cases in 7 hospitals that switched NAs from ETV to TAF, 23 patients with detectable HBV DNA in a year before switching were analyzed. When the detection frequencies of HBV DNA in the 1st and 2nd years after switching to TAF were analyzed, they were significantly lower than those in the year before switching (68.8% vs. 34.1% for the 1st year and 21.3% for the 2nd year, P < 0.001 for both). The HBsAg decline tended to be larger after switching than before (-2.5% vs. -3.0% for 1st year and -3.1% for 2nd year), but the difference was not significant. One patient died of a cardiovascular event 11 months after the treatment switch, but no adverse effects due to TAF including renal function were observed. In conclusion, it was suggested that switching from ETV to TAF might be effective to suppress the HBV DNA level further in patients whose HBV DNA is detectable, even if at a very low level.

Background: Human papillomavirus (HPV) type 67 is phylogenetically classified into Alphapapillomavirus species 9 (alpha-9) together with other carcinogenic types (HPV16, 31, 33, 35, 52 and 58), but is the only alpha-9 type defined as possibly carcinogenic. This study aimed to determine whole-genome sequences of HPV67 isolated from Japanese women with cervical cancer or cervical intraepithelial neoplasia (CIN) to better understand the genetic basis of the oncogenic potential of HPV67., Methods: Total cellular DNA isolated from cervical exfoliated cells that were single positive for HPV67 (invasive cervical cancer, n = 2; CIN3, n = 6; CIN 2, n = 1; CIN1, n = 2; the normal cervix, n = 1) was subjected to PCR to amplify HPV67 DNA, followed by next generation sequencing to determine the complete viral genome sequences. Variant lineages/sublineages were assigned through viral whole-genome phylogenetic analysis. The transcriptional activity of the virus early promoter was assessed by luciferase reporter assays in cervical cancer cell lines., Results: Phylogenetic analyses of HPV67 genomes from Japan (n = 12) revealed that 11 belonged to lineage A (sublineage A1, n = 9; sublineage A2, n = 2) and one belonged to lineage B. All cancer cases contained sublineage A1 variants, and one of these contained an in-frame deletion in the E2 gene. The long control region of the HPV67 genome did not induce transcription from the virus early promoter in HeLa cells, but showed weak transcriptional activity in CaSki cells., Conclusions: The single detection of HPV67 in cervical cancer and precancer specimens strongly suggests the carcinogenic potential of this rare genotype. The phylogenetic analysis indicates a predominance of lineage A variants among HPV67 infections in Japan. Since only 23 complete genome sequences of HPV67 had been obtained until now, the newly determined genome sequences in this study are expected to contribute to further functional and evolutionary studies on the genetic diversity of HPV67., (© 2022. The Author(s).)

Although geographical differences in the distribution of human papillomavirus genotypes have been observed worldwide, no studies have reported on national differences in the prevalence of human papillomavirus types in Japan. Here, we report a cross-sectional study to explore regional differences in the prevalence of human papillomavirus types among Japanese women with cervical intraepithelial neoplasia or invasive cervical cancer. Using human papillomavirus genotyping data from the nationwide prospective study on human papillomavirus vaccine effectiveness, we compared the frequency of detection of 15 high-risk and two low-risk human papillomavirus types in each disease category between the women who visited hospitals located in eastern Japan and those who visited hospitals located in western Japan. The risk of cervical intraepithelial neoplasia progression was assessed by calculating a prevalence ratio of each human papillomavirus type for cervical intraepithelial neoplasia grade 2/3 versus grade 1. Among the human papillomavirus types studied, human papillomavirus 52 was detected significantly more frequently in western hospitals than in eastern hospitals in cervical intraepithelial neoplasia grade 1 patients, but was less frequent in cervical intraepithelial neoplasia grade 2/3. The prevalence of particular human papillomavirus types was not significantly different between patients in hospitals in eastern Japan and those in hospitals in western Japan for invasive cervical cancer. In both eastern and western hospitals, a higher risk of cervical intraepithelial neoplasia progression was observed in patients infected with human papillomavirus 16, 31 or 58. In contrast, there was a significantly higher prevalence of human papillomavirus 52 infection in women with cervical intraepithelial neoplasia grade 2/3 than in those with cervical intraepithelial neoplasia grade 1 in eastern hospitals (prevalence ratio, 1.93; 95% confidence interval, 1.48-2.58), but not in western hospitals (prevalence ratio, 1.03; 95% confidence interval, 0.83-1.30). Regional differences of human papillomavirus 52 prevalence in cervical intraepithelial neoplasia lesions may exist and emphasize the importance of continuous monitoring of human papillomavirus type prevalence throughout the country in order to accurately assess the efficacy of human papillomavirus vaccines., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Backgrounds: Entecavir (ETV) and tenofovir alafenamide fumarate (TAF) have been used widely to treat patients with chronic hepatitis B virus (HBV) infection, but it is still unclear how best to use these drugs. Although some studies compared the efficacies of treatment switch from ETV to TAF, there has been no randomized study., Methods: We performed a prospective multicenter randomized controlled study in which subjects were enrolled from April 2018 to June 2019 and observed for 2 years until March 2021 to clarify the efficacy and safety of switching from ETV to TAF., Results: Thirty-three patients were enrolled and randomized into 2 groups, and a total of 30 patients were evaluated; a TAF-switching group (n = 16) and an ETV-continuing group (n = 14). The mean age of the 30 patients was 61 years old and 18 patients (60%) were male. The serum HBV DNA in all patients were below detection limit. The mean change in hepatitis B surface antigen (HBsAg) levels after 2 years was not significantly different between the TAF and ETV groups (-0.08 vs -0.20 log IU/mL, P = .07). Comparing the group with a HBsAg decline (≤ -0.1 log IU/mL) and a group without a HBsAg decline in an overall analysis, the prior ETV duration was significantly shorter in the HBsAg-declined group (49 vs 92 months, P = .03). Although the eGFR levels tended to decrease in the TAF group compared to ETV (-6.15 vs -2.26 mL/min/1.73 m2, P = .09), no significant differences were observed in patients with baseline eGFR < 60 (-2.49 vs 0.40 mL/min/1.73 m2, P = .25)., Conclusion: The efficacy and safety were comparable in the TAF-switching group and the ETV-continuing group. Because the present study was conducted in limited patients, a larger study will be required., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Patients with a chronic hepatitis B virus (HBV) infection who are treated with nucleos(t)ide analogues (NAs) are still at risk for hepatocellular carcinoma (HCC), and it has been clinically questioned whether patients with a high risk of HCC can be identified efficiently. We aimed to clarify the risk factors associated with the development of HCC during NA therapies. A total of 611 chronically HBV-infected patients without a history of HCC, who were treated with NAs for more than 6 months (median 72 months), from 2000 to 2021, were included from 16 hospitals in the Tohoku district in Japan. Incidences of HCC occurrence were analyzed with clinical factors, including on-treatment responses. Alanine aminotransferase (ALT) normalization, based on the criteria of three guidelines, was analyzed with other parameters, including the age−male−ALBI−platelets (aMAP) risk score. During the observation period, 48 patients developed HCC, and the cumulative HCC incidence was 10.6% at 10 years. Non-achievement of ALT normalization at 1 year of therapy was mostly associated with HCC development when ALT ≤ 30 U/L was used as the cut-off (cumulative incidence, 19.9% vs. 5.3% at 10 years, p < 0.001). The effectiveness of the aMAP risk score at the start of treatment was validated in this cohort. A combination of an aMAP risk score ≥ 50 and non-achievement of ALT normalization could stratify the risk of HCC significantly, and notably, there was no HCC development in 103 patients without these 2 factors. In conclusion, non-achievement of ALT normalization (≤30 U/L) at 1 year might be useful in predicting HCC during NA therapies and, in combination with the aMAP risk score, could stratify the risk more precisely.

In Japan, the National Immunization Program against human papillomavirus (HPV) targets girls aged 12-16 years, and catch-up vaccination is recommended for young women up to age 26 years. Because HPV infection rates increase soon after sexual debut, we evaluated HPV vaccine effectiveness by age at first vaccination. Along with vaccination history, HPV genotyping results from 5795 women younger than 40 years diagnosed with cervical intraepithelial neoplasia grade 2-3 (CIN2-3), adenocarcinoma in situ (AIS), or invasive cervical cancer were analyzed. The attribution of vaccine-targeted types HPV16 or HPV18 to CIN2-3/AIS was 47.0% for unvaccinated women (n = 4297), but 0.0%, 13.0%, 35.7%, and 39.6% for women vaccinated at ages 12-15 years (n = 36), 16-18 years (n = 23), 19-22 years (n = 14), and older than 22 years (n = 91), respectively, indicating the greater effectiveness of HPV vaccination among those initiating vaccination at age 18 years or younger (P < .001). This finding was supported by age at first sexual intercourse; among women with CIN2-3/AIS, only 9.2% were sexually active by age 14 years, but the percentage quickly increased to 47.2% by age 16 and 77.1% by age 18. Additionally, the HPV16/18 prevalence in CIN2-3/AIS was 0.0%, 12.5%, and 40.0% for women vaccinated before (n = 16), within 3 years (n = 8), and more than 3 years after (n = 15) first intercourse, respectively (P = .004). In conclusion, our data appear to support routine HPV vaccination for girls aged 12-14 years and catch-up vaccination for adolescents aged 18 years and younger in Japan., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Human papillomavirus (HPV) is a sexually transmitted virus with an approximately 8-kilo base DNA genome, which establishes long-term persistent infection in anogenital tissues. High levels of genetic variations, including viral genotypes and intra-type variants, have been described for HPV genomes, together with geographical differences in the distribution of genotypes and variants. Here, by employing a maximum likelihood method, we performed phylogenetic analyses of the complete genome sequences of HPV16, HPV18 and HPV58 available from GenBank ( n = 627, 146 and 157, respectively). We found several characteristic clusters that exclusively contain HPV genomes from Japan: two for HPV16 (sublineages A4 and A5), one for HPV18 (sublineage A1) and two for HPV58 (sublineages A1 and A2). Bayesian phylogenetic analyses of concatenated viral gene sequences showed that divergence of the most recent common ancestor of these Japan-specific clades was estimated to have occurred ~98,000 years before present (YBP) for HPV16 A4, ~39,000 YBP for HPV16 A5, ~38,000 YBP for HPV18 A1, ~26,000 for HPV58 A1 and ~25,000 YBP for HPV58 A2. This estimated timeframe for the divergence of the Japan-specific clades suggests that the introduction of these HPV variants into the Japanese archipelago dates back to at least ~25,000 YBP and provides a scenario of virus co-migration with ancestral Japanese populations from continental Asia during the Upper Paleolithic period.

Since the human papillomavirus (HPV) vaccination program for Japanese girls aged 12-16 years began in 2010, vaccination uptake has been low in women born before 1993 but high (approximately 70%) in those born during 1994-1999. We previously compared the prevalence of vaccine types HPV16 and HPV18 in cervical intraepithelial neoplasia grade 1-3 (CIN1-3) or adenocarcinoma in situ (AIS) between vaccinated and unvaccinated cohorts and found direct protection effects among vaccinated women in Japan. In this study, we focused on changes in HPV16/18 prevalence among "unvaccinated" cohorts with CIN/AIS. We analyzed HPV16/18 prevalence among 5051 unvaccinated women aged <40 years, newly diagnosed with CIN/AIS during 2012-2021 for time trends. Declining trends in HPV16/18 prevalence over 9 years were observed in CIN1 (36.0-10.0%, P trend = 0.03) and CIN2-3/AIS (62.5-36.4%, P trend = 0.07) among women aged <25 years. HPV16/18 prevalence in CIN1 and CIN2-3/AIS diagnosed at age 20-24 years was lower in 1994-1999 birth cohorts compared with 1988-1993 birth cohorts (4.5% vs. 25.7% for CIN1 and 40.0% vs. 58.1% for CIN2-3/AIS, both p = 0.04). Significant reduction in HPV16/18 prevalence among young unvaccinated women with CIN1 and CIN2-3/AIS suggests herd effects of HPV vaccination in Japan.

Enterohaemorrhagic Escherichia coli (EHEC) produces Shiga toxin 1 (Stx1) and Shiga toxin 2 (Stx2). Although stx1 and stx2 were found within the late operons of the Stx-encoding phages (Stx-phages), stx1 could mainly be transcribed from the stx1 promoter ( P Stx1 ), which represents the functional operator-binding site (Fur box) for the transcriptional regulator Fur (ferric uptake regulator), upstream of stx1 . In this study, we found that the production of Stx1 by EHEC was affected by oxygen concentration. Increased Stx1 production in the presence of oxygen is dependent on Fur, which is an Fe 2+ -responsive transcription factor. The intracellular Fe 2+ pool was lower under microaerobic conditions than under anaerobic conditions, suggesting that lower Fe 2+ availability drove the formation of less Fe 2+ -Fur, less DNA binding to the P Stx1 region, and an increase in Stx1 production.

Background: Non-alcoholic liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and it can progress to non-alcoholic steatohepatitis (NASH). Alterations in the gut microbiome have been implicated in the development of NAFLD/NASH, although the underlying mechanisms remain unclear., Results: We found that the consumption of the prebiotic inulin markedly ameliorated the phenotype of NAFLD/NASH, including hepatic steatosis and fibrosis, in mice. Inulin consumption resulted in global changes in the gut microbiome, including concomitant enrichment of the genera Bacteroides and Blautia, and increased concentrations of short-chain fatty acids, particularly acetate, in the gut lumen and portal blood. The consumption of acetate-releasing resistant starch protected against NAFLD development. Colonisation by Bacteroides acidifaciens and Blautia producta in germ-free mice resulted in synergetic effects on acetate production from inulin. Furthermore, the absence of free fatty acid receptor 2 (FFAR2), an acetate receptor, abolished the protective effect of inulin, as indicated by the more severe liver hypertrophy, hypercholesterolaemia and inflammation. These effects can be attributed to an exacerbation of insulin resistance in the liver, but not in muscle or adipose tissue., Conclusion: These findings demonstrated that the commensal microbiome-acetate-FFAR2 molecular circuit improves insulin sensitivity in the liver and prevents the development of NAFLD/NASH. Video abstract., (© 2021. The Author(s).)

Intestinal microbiota-derived metabolites have biological importance for the host. Polyamines, such as putrescine and spermidine, are produced by the intestinal microbiota and regulate multiple biological processes. Increased colonic luminal polyamines promote longevity in mice. However, no direct evidence has shown that microbial polyamines are incorporated into host cells to regulate cellular responses. Here, we show that microbial polyamines reinforce colonic epithelial proliferation and regulate macrophage differentiation. Colonisation by wild-type, but not polyamine biosynthesis-deficient, Escherichia coli in germ-free mice raises intracellular polyamine levels in colonocytes, accelerating epithelial renewal. Commensal bacterium-derived putrescine increases the abundance of anti-inflammatory macrophages in the colon. The bacterial polyamines ameliorate symptoms of dextran sulfate sodium-induced colitis in mice. These effects mainly result from enhanced hypusination of eukaryotic initiation translation factor. We conclude that bacterial putrescine functions as a substrate for symbiotic metabolism and is further absorbed and metabolised by the host, thus helping maintain mucosal homoeostasis in the intestine.

Human papillomavirus type 16 (HPV16) is the most common HPV genotype found in invasive cervical cancer (ICC). Recent comprehensive genomics studies of HPV16 have revealed that a large number of minor nucleotide variations in the viral genome are present in each infected woman; however, it remains unclear whether such within-host variations of HPV16 are linked to cervical carcinogenesis. Here, by employing next-generation sequencing approaches, we explored the mutational profiles of the HPV16 genome within individual clinical specimens from ICC ( n = 31) and normal cervix ( n = 21) in greater detail. A total of 367 minor nucleotide variations (167 from ICC and 200 from the normal cervix) were detected throughout the viral genome in both groups, while nucleotide variations at high frequencies (>10% abundance in relative read counts in a single sample) were more prevalent in ICC (10 in ICC versus 1 in normal). Among the high-level variations found in ICC, six were located in the E1/E2 genes, and all of them were non-synonymous substitutions (Q142K, M207I, and L262V for E1; D153Y, R302T, and T357A for E2). In vitro functional analyses of these E1/E2 variants revealed that E1/M207I, E2/D153Y, and E2/R302T had reduced abilities to support viral replication, and that E2/D153Y and E2/R302T failed to suppress the viral early promoter. These results imply that some within-host variations of E1/E2 present at high levels in ICC may be positively selected for and contribute to cervical cancer development through dysfunction or de-stabilization of viral replication/transcription proteins., (Copyright © 2020 Hirose, Yamaguchi-Naka, Onuki, Tenjimbayashi, Tasaka, Satoh, Tanaka, Iwata, Sekizawa, Matsumoto and Kukimoto.)

In Japan, a bivalent human papillomavirus (HPV) vaccine against carcinogenic HPV16/18 was licensed in 2009, and a quadrivalent vaccines against HPV16/18 and non-carcinogenic HPV6/11 was licensed in 2011. Recently, the next-generation 9-valent vaccine targeting HPV6/11/16/18/31/33/45/52/58 has been approved. Accurate HPV genotyping is essential for HPV vaccine research and surveillance. The Roche Linear Array (LA) has long been a standard assay for HPV genotyping, but its recent product discontinuation notice has urged us to introduce an alternative assay with comparable performance. In the present study, an in-house HPV genotyping assay that employs PCR with PGMY09/11 primers and reverse blotting hybridization (PGMY-CHUV) was compared with LA to assess genotype-specific agreement. A total of 100 cervical precancer specimens were subjected to both PGMY-CHUV and LA. For detection of genotypes included in the 9-valent vaccine, PGMY-CHUV completely agreed with LA for detection of HPV6, HPV11, HPV16, HPV18, HPV33 and HPV45, and showed near-complete agreement for HPV31 and HPV58 (98% and 99%, respectively). Moreover, PGMY-CHUV detected a significantly higher prevalence of HPV52 than LA (22% vs. 14%, P = 0.008 by McNemar's exact test), with 92.0% overall agreement, 63.6% positive agreement and a kappa value of 0.73. Most (87.5%) of HPV52 discordant cases involved mixed infections with HPV35 or HPV58. In conclusion, while the two assays present equivalent data for assessing the effectiveness of the bivalent and quadrivalent vaccines, PGMY-CHUV is more suitable for evaluating the impact of the current 9-valent vaccine because of its superior detection of HPV52 in co-infection cases.

To obtain baseline data for cervical cancer prevention in Japan, we analyzed human papillomavirus (HPV) data from 5045 Japanese women aged less than 40 years and diagnosed with cervical abnormalities at 21 hospitals during 2012-2017. These included cervical intraepithelial neoplasia grade 1 (CIN1, n = 573), CIN2-3 (n = 3219), adenocarcinoma in situ (AIS, n = 123), and invasive cervical cancer (ICC, n = 1130). The Roche Linear Array was used for HPV genotyping. The HPV type-specific relative contributions (RCs) were estimated by adding multiple infections to single types in accordance with proportional weighting attributions. Based on the comparison of type-specific RCs between CIN1 and CIN2-3/AIS/ICC (CIN2+), RC ratios were calculated to estimate type-specific risks for progression to CIN2+. Human papillomavirus DNA was detected in 85.5% of CIN1, 95.7% of CIN2-3/AIS, and 91.2% of ICC. Multiple infections decreased with disease severity: 42.9% in CIN1, 40.4% in CIN2-3/AIS, and 23.7% in ICC (P < .0001). The relative risk for progression to CIN2+ was highest for HPV16 (RC ratio 3.78, 95% confidence interval [CI] 3.01-4.98), followed by HPV31 (2.51, 1.54-5.24), HPV18 (2.43, 1.59-4.32), HPV35 (1.56, 0.43-8.36), HPV33 (1.01, 0.49-3.31), HPV52 (0.99, 0.76-1.33), and HPV58 (0.97, 0.75-1.32). The relative risk of disease progression was 1.87 (95% CI, 1.71-2.05) for HPV16/18/31/33/35/45/52/58, but only 0.17 (95% CI, 0.14-0.22) for HPV39/51/56/59/66/68. Human papillomavirus 16/18/31/33/45/52/58/6/11 included in a 9-valent vaccine contributed to 89.7% (95% CI, 88.7-90.7) of CIN2-3/AIS and 93.8% (95% CI, 92.4-95.3) of ICC. In conclusion, our data support the Japanese guidelines that recommend discriminating HPV16/18/31/33/35/45/52/58 genotypes for CIN management. The 9-valent vaccine is estimated to provide over 90% protection against ICC in young Japanese women., (© 2020 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

The medial circumflex femoral artery (MCFA) typically presents as a major branch of the profunda femoris artery or it can also directly originate from the common femoral artery. Many anatomical variations of the MCFA have been described due to their clinical significance. We herein report a case of an unusual anatomical variation of the MCFA crossing anterior to the femoral vein that led to iatrogenic arteriovenous fistula formation after cardiac catheterization. The identification of such rare vascular anatomical variations is of great importance when attempting femoral arterial or venous puncture in order to minimize unnecessary complications., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2020, Yamamoto et al.)

Recent large-scale genomics studies of human papillomaviruses (HPVs) have shown a high level of genomic variability of HPV16, the most prevalent genotype in HPV-associated malignancies, and provided new insights into the biological and clinical relevance of its genetic variations in cervical cancer development. Here, we performed deep sequencing analyses of the viral genome to explore genetic variations of HPV16 that are prevalent in Japan. A total of 100 complete genome sequences of HPV16 were determined from cervical specimens collected from Japanese women with cervical intraepithelial neoplasia and invasive cervical cancer, or without cervical malignancies. Phylogenetic analyses revealed the variant distribution in the Japanese HPV16 isolates; overall, lineage A was the most prevalent (94.0%), in which sublineage A4 was dominant (52.0%), followed by sublineage A1 (21.0%). The relative risk of sublineage A4 for cervical cancer development was significantly higher compared to sublineages A1/A2/A3 (odds ratio = 6.72, 95% confidence interval = 1.78-28.9). Interestingly, a novel cluster of variants that branched from A1/A2/A3 was observed for the Japanese HPV16 isolates, indicating that unique HPV16 variants are prevalent among Japanese women.

Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn's disease, is an intractable disease of the gastrointestinal tract. Multiple environmental factors, including food ingredients, have been implicated in the development of these diseases. For example, animal fat-rich diets are predisposing factors for ulcerative colitis, whereas n-3 unsaturated fatty acids such as docosahexaenoic acid (DHA) show protective effects in experimental colitis and are negatively correlated with the incidence of ulcerative colitis and Crohn's disease. Given that DHA exhibits agonistic activity on retinoid X receptor (RXR), activation of RXR could be a therapeutic strategy for IBD. However, conventional full RXR agonists are known to show considerable adverse effects. We therefore took advantage of a partial RXR agonist, CBt-PMN, to minimize the adverse effects, and evaluated its efficacy in dextran sodium sulfate-induced colitis. Administration of CBt-PMN efficiently ameliorated the symptoms of colitis. This effect was attributed to the down-regulation of pro-inflammatory cytokines such as Tnf and Il6 in colon-infiltrating monocytes. Down-regulation of pro-inflammatory cytokines by CBt-PMN was also evident in lipopolysaccharide-stimulated bone marrow-derived macrophages (BMDMs). Among many RXR-associated nuclear receptors, activation of peroxisome proliferator-activated receptor δ (PPARδ) and nuclear hormone receptor 77 (Nur77) suppressed cytokine production by BMDMs. These observations suggest that the activation of PPARδ/RXR and Nur77/RXR heterodimers by CBt-PMN through the permissive mechanism is responsible for diminishing the monocyte-mediated inflammatory response in the gut. Our data highlight the importance of RXR activation in the regulation of colitis., (© The Japanese Society for Immunology. 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The prognostic impact of human papillomavirus (HPV) type on invasive cervical cancer (ICC) was analyzed for 137 women treated for ICC at a single institution between 1999 and 2007. The study subjects were divided into three groups according to HPV genotype: HPV16-positive (n = 59), HPV18-positive (n = 33), and HPV16/18-negative ICC (non-HPV16/18, n = 45). The median follow-up time was 102.5 months (range, 5-179). The 10-year overall survival (10y-OS) rates in women with FIGO stage I/II disease were similar among HPV genotypes: 94.7% for HPV16 (n = 39), 95.2% for HPV18 (n = 26), and 96.4% for non-HPV16/18 (n = 29). However, the 10y-OS rates in women with FIGO stage III/IV tumors were 73.7% for HPV16 (n = 20), 45.7% for HPV18 (n = 7), and 35.7% for other types (n = 16), with significantly higher survival in HPV16-positive compared with HPV16-negative ICC (10y-OS; 73.7% vs. 39.5%, P = 0.04). This difference in FIGO stage III/IV tumors remained significant after adjusting for age and histology (hazard ratio 0.30, 95% confidence interval 0.09-0.86, P = 0.02). These results suggest that detection of HPV16 DNA may be associated with a favorable prognosis in patients with FIGO stage III/IV ICC. Given that most women with FIGO stage III/IV tumors received concurrent chemoradiotherapy, this finding may imply that HPV16-positive tumors are more chemoradiosensitive., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Persistent infection with oncogenic human papillomaviruses (HPVs) causes cervical cancer, accompanied by the accumulation of somatic mutations into the host genome. There are concomitant genetic changes in the HPV genome during viral infection; however, their relevance to cervical carcinogenesis is poorly understood. Here, we explored within-host genetic diversity of HPV by performing deep-sequencing analyses of viral whole-genome sequences in clinical specimens. The whole genomes of HPV types 16, 52, and 58 were amplified by type-specific PCR from total cellular DNA of cervical exfoliated cells collected from patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) and were deep sequenced. After constructing a reference viral genome sequence for each specimen, nucleotide positions showing changes with >0.5% frequencies compared to the reference sequence were determined for individual samples. In total, 1,052 positions of nucleotide variations were detected in HPV genomes from 151 samples (CIN1, n = 56; CIN2/3, n = 68; ICC, n = 27), with various numbers per sample. Overall, C-to-T and C-to-A substitutions were the dominant changes observed across all histological grades. While C-to-T transitions were predominantly detected in CIN1, their prevalence was decreased in CIN2/3 and fell below that of C-to-A transversions in ICC. Analysis of the trinucleotide context encompassing substituted bases revealed that TpCpN, a preferred target sequence for cellular APOBEC cytosine deaminases, was a primary site for C-to-T substitutions in the HPV genome. These results strongly imply that the APOBEC proteins are drivers of HPV genome mutation, particularly in CIN1 lesions. IMPORTANCE HPVs exhibit surprisingly high levels of genetic diversity, including a large repertoire of minor genomic variants in each viral genotype. Here, by conducting deep-sequencing analyses, we show for the first time a comprehensive snapshot of the within-host genetic diversity of high-risk HPVs during cervical carcinogenesis. Quasispecies harboring minor nucleotide variations in viral whole-genome sequences were extensively observed across different grades of CIN and cervical cancer. Among the within-host variations, C-to-T transitions, a characteristic change mediated by cellular APOBEC cytosine deaminases, were predominantly detected throughout the whole viral genome, most strikingly in low-grade CIN lesions. The results strongly suggest that within-host variations of the HPV genome are primarily generated through the interaction with host cell DNA-editing enzymes and that such within-host variability is an evolutionary source of the genetic diversity of HPVs., (Copyright © 2018 American Society for Microbiology.)

Objectives: Anma therapy (Japanese massage therapy, AMT) significantly reduces the severity of physical complaints in survivors of gynecologic cancer. However, whether this reduction of severity is accompanied by improvement in health-related quality of life is unknown., Methods: Forty survivors of gynecologic cancer were randomly allocated to either an AMT group that received one 40-min AMT session per week for 8 weeks or a no-AMT group. We prospectively measured quality of life by using the Japanese version of the European Organization for Research and Treatment of Cancer QLQ-C30 version 3.0 (EORTC QLQ-C30) at baseline and at 8-week follow-up. The QLQ-C30 response rate was 100%. Hospital Anxiety Depression Scale (HADS), Profile of Mood States (POMS), and Measure of Adjustment to Cancer were also prespecified and prospectively evaluated., Results: The QLQ-C30 Global Health Status and Quality of Life showed significant improvement at 8 weeks (P = 0.042) in the AMT group compared with the no-AMT group, and the estimated mean difference reached a minimal clinically important difference of 10 points (10.4 points, 95% CI = 1.2 to 19.6). Scores on fatigue and insomnia showed significant improvement in the AMT group compared with the no-AMT group (P = 0.047 and 0.003, respectively). There were no significant between-group improvements in HADS anxiety and depression scales; however, POMS-assessed anger-hostility showed significant improvement in the AMT group compared with the no-AMT group (p = 0.028)., Conclusions: AMT improved health-related quality of life in gynecologic cancer survivors. AMT can be of potential benefit for applications in oncology.

A few studies previously suggested that human papillomavirus (HPV) E6 messenger RNA (mRNA) may exist uniformly in all grades of cervical intraepithelial neoplasia (CIN), whereas the detection rate of E7 mRNA may increase with disease progression from low-grade CIN to invasive carcinoma. The aim of this study was to clarify the different roles of E6 and E7 mRNAs in cervical carcinogenesis. The presence of each E6 and E7 mRNA was analyzed in 171 patients with pathologically-diagnosed CIN or cervical carcinoma. We utilized a RT-PCR assay based on consensus primers which could detect E6 mRNA (full-length E6/E7 transcript) and E7 mRNAs (spliced E6*/E7 transcripts) separately for various HPV types. E7 mRNAs were detected in 6% of CIN1, 12% of CIN2, 24% of CIN3, and 54% of cervical carcinoma. The presence of E7 mRNAs was significantly associated with progression from low-grade CIN to invasive carcinoma in contrast with E6 mRNA or high-risk HPV (HR-HPV) DNA (p = 0.00011, 0.80 and 0.54). The presence of both E6 and E7 mRNAs was significantly associated with HPV16/18 DNA but not with HR-HPV DNA (p = 0.0079 and 0.21), while the presence of E6 mRNA was significantly associated with HR-HPV DNA but not with HPV16/18 DNA (p = 0.036 and 0.089). The presence of both E6 and E7 mRNAs showed high specificity and low sensitivity (100% and 19%) for detecting CIN2+ by contrast with the positivity for HR-HPV DNA showing low specificity and high sensitivity (19% and 89%). The positive predictive value for detecting CIN2+ was even higher by the presence of both E6 and E7 mRNAs than by the positivity for HR-HPV DNA (100% vs. 91%). In 31 patients followed up for CIN1-2, the presence of both E6 and E7 mRNAs showed significant association with the occurrence of upgraded abnormal cytology in contrast with E6 mRNA, HR-HPV DNA, or HPV16/18 DNA (p = 0.034, 0.73, 0.53, and 0.72). Our findings support previous studies according to which E7 mRNA is more closely involved in cervical carcinogenesis than E6 mRNA. Moreover, the separate analysis of E6 and E7 mRNAs may be more useful than HR-HPV DNA test for detecting CIN2+ precisely and predicting disease progression. Further accumulation of evidence is warranted to validate our findings.

Background: Human papillomavirus genotypes 52 and 58 (HPV52/58) are frequently detected in patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) in East Asian countries including Japan. As with other HPV genotypes, HPV52/58 consist of multiple lineages of genetic variants harboring less than 10% differences between complete genome sequences of the same HPV genotype. However, site variations of nucleotide and amino acid sequences across the viral whole-genome have not been fully examined for HPV52/58. The aim of this study was to investigate genetic variations of HPV52/58 prevalent among Japanese women by analyzing the viral whole-genome sequences., Methods: The entire genomic region of HPV52/58 was amplified by long-range PCR with total cellular DNA extracted from cervical exfoliated cells isolated from Japanese patients with CIN or ICC. The amplified DNA was subjected to next generation sequencing to determine the complete viral genome sequences. Phylogenetic analyses were performed with the whole-genome sequences to assign variant lineages/sublineages to the HPV52/58 isolates. The variability in amino acid sequences of viral proteins was assessed by calculating the Shannon entropy scores at individual amino acid positions of HPV proteins., Results: Among 52 isolates of HPV52 (CIN1, n  = 20; CIN2/3, n  = 21; ICC, n  = 11), 50 isolates belonged to lineage B (sublineage B2) and two isolates belonged to lineage A (sublineage A1). Among 48 isolates of HPV58 (CIN1, n  = 21; CIN2/3, n  = 19; ICC, n  = 8), 47 isolates belonged to lineage A (sublineages A1/A2/A3) and one isolate belonged to lineage C. Single nucleotide polymorphisms specific for individual variant lineages were determined throughout the viral genome based on multiple sequence alignments of the Japanese HPV52/58 isolates and reference HPV52/58 genomes. Entropy analyses revealed that the E1 protein was relatively variable among the HPV52 isolates, whereas the E7, E4, and L2 proteins showed some variations among the HPV58 isolates., Conclusions: Among the HPV52/58-positive specimens from Japanese women with CIN/ICC, the variant distributions were strongly biased toward lineage B for HPV52 and lineage A for HPV58 across histological categories. Different patterns of amino acid variations were observed in HPV52 and HPV58 across the viral whole-genome.

Objective: We conducted a pooled analysis of published studies to compare the performance of human papillomavirus (HPV) testing and cytology in detecting residual or recurrent diseases after treatment for cervical intraepithelial neoplasia grade 2 or 3 (CIN 2/3)., Methods: Source articles presenting data on posttreatment HPV testing were identified from the National Library of Medicine (PubMed) database. We included 5,319 cases from 33 articles published between 1996 and 2013., Results: The pooled sensitivity of high-risk HPV testing (0.92; 95% confidence interval [CI], 0.90 to 0.94) for detecting posttreatment CIN 2 or worse (CIN 2+) was much higher than that of cytology (0.76; 95% CI, 0.71 to 0.80). Co-testing of HPV testing and cytology maximized the sensitivity (0.93; 95% CI, 0.87 to 0.96), while HPV genotyping (detection of the same genotype between pre- and posttreatments) did not improve the sensitivity (0.89; 95% CI, 0.82 to 0.94) compared with high-risk HPV testing alone. The specificity of high-risk HPV testing (0.83; 95% CI, 0.82 to 0.84) was similar to that of cytology (0.85; 95% CI, 0.84 to 0.87) and HPV genotyping (0.83; 95% CI, 0.81 to 0.85), while co-testing had reduced specificity (0.76; 95% CI, 0.75 to 0.78). For women with positive surgical margins, high-risk HPV testing provided remarkable risk discrimination between test-positives and test-negatives (absolute risk of residual CIN 2+ 74.4% [95% CI, 64.0 to 82.6] vs. 0.8% [95% CI, 0.15 to 4.6]; p<0.001)., Conclusion: Our findings recommend the addition of high-risk HPV testing, either alone or in conjunction with cytology, to posttreatment surveillance strategies. HPV testing can identify populations at greatest risk of posttreatment CIN 2+ lesions, especially among women with positive section margins.

We investigated Southern rice black-streaked dwarf virus (SRBSDV) accumulation in a vector insect, the whitebacked planthopper (Sogatella furcifera), to elucidate the association of virus accumulation in the vector with virus transmission efficiency. Real-time quantitative reverse transcription polymerase chain reaction analysis confirmed that this virus is transmitted in a persistent-propagative manner. SRBSDV was successfully transmitted by S. furcifera males in which RNA accumulation of the capsid protein gene of SRBSDV was >10(3) in the whole body of S. furcifera, indicating that the threshold accumulation of the virus RNA for virus transmission is 10(3) in an S. furcifera male. The SRBSDV detection rate in the immigrant population of S. furcifera was high in 2011 (39.5%); however, most of the insects contained fewer than 10(3) RNAs of the capsid protein gene. This result indicates that the risk of SRBSDV epidemics could be estimated from the proportion of virus-transmissible S. furcifera (i.e., S. furcifera that contained more than 10(3) RNAs of the virus capsid protein gene) rather than the SRBSDV detection rate in S. furcifera.

The biological and genetic diversity of Wheat yellow mosaic virus (WYMV) isolates in Japan was characterized. On the basis of wheat cultivar reactions, 14 WYMV isolates from various places were classified into pathotypes I, II, or III. These were distributed in central, northern, and southern areas of Japan, respectively. WYMV isolates comprised three genotypes (A, A' and B) based on amino acid differences in RNA1 and two genotypes (a and b) based on amino acid differences in RNA2. A correlation was found between the WYMV RNA1-based genotype and pathotype, suggesting that factors associated with pathogenicity map to RNA1. Genotype Aa and A'a were distributed mainly in the central to southern areas of Japan, and genotype Bb was found in northern areas of Japan, as shown by reverse-transcription polymerase chain reaction restriction fragment length polymorphism analysis. Chinese isolates YA and YZ were closely related to genotypes Bb and Aa, respectively. Wheat was introduced from China to Japan in the 4th and 5th centuries, and the two genotypes of WYMV might also have been introduced with the crop from China and later adapted to local wheat cultivars in Japan.