Quality of Life in Japanese Patients with Dysmenorrhea or Endometriosis-Associated Pelvic Pain Treated with Extended Regimen Ethinylestradiol/Drospirenone in a Real-World Setting: A Prospective Observational Study.

INTRODUCTION: Dysmenorrhea and endometriosis are common gynecologic disorders among women of reproductive age that significantly impact health-related quality of life (HRQL) as well as productivity. Although there are treatment options listed in Japanese guidelines, a gap remains in unmet medical needs for maximizing treatment outcome. The extended regimen of ethinylestradiol and drospirenone (EE/DRSP) (taken daily for up to 120 consecutive days) has been available in Japan for treating dysmenorrhea and/or endometriosis-associated pain since 2016. Yet, the effectiveness of its usage on HRQL has not been investigated elsewhere to date. Therefore, in this study, we aim to observe changes in HRQL of Japanese women treated with an extended regimen of EE/DRSP for dysmenorrhea and/or endometriosis-associated pain. METHODS: As part of a 2-year post-marketing surveillance study, women with dysmenorrhea or endometriosis-associated pelvic pain were prescribed extended EE/DRSP during routine clinical practice. Data were collected 1 month before and 3 and 6 months after initiating treatment. Primary outcomes were the Menstrual Distress Questionnaire (MDQ) (before, during, and after menstruation) in patients with dysmenorrhea, and the Endometriosis Impact Scale (EIS) and European Quality of Life 5-dimensions 5-level instrument (EQ-5D-5L) in patients with endometriosis. RESULTS: The study cohort included 315 patients (mean age 28.9 years) with dysmenorrhea and 262 patients (mean age 31.3 years) with endometriosis. Mean MDQ total scores before and during menstruation decreased significantly after 6 months with extended EE/DRSP; there was no improvement in after-menstruation MDQ score. Mean EIS domain scores improved significantly by 6 months, with improvement in most EIS individual item scores. Mean EQ-5D-5L scores increased slightly during 6 months of treatment. CONCLUSIONS: Extended EE/DRSP treatment improved HRQL outcomes in Japanese women with dysmenorrhea or endometriosis-associated pelvic pain. TRIAL REGISTRATION: Registered at ClinicalTrials.gov (NCT03126747) on June 2017.

Quality of Life of Japanese Dysmenorrhea/Heavy Menstrual Bleeding Patients Treated with Levonorgestrel Intrauterine Delivery System in a Real-World Setting.

INTRODUCTION: The present study collected 1-year follow-up patient-reported outcome data from Japanese women with dysmenorrhea and/or heavy menstrual bleeding (HMB) who underwent insertion of the levonorgestrel-releasing intrauterine system (LNG-IUS) 52 mg. We aimed to evaluate the quality of life (QOL) of Japanese women over the course of the investigational period. METHODS: This was a multicenter, non-interventional, prospective, single-cohort, post-marketing surveillance study (J-MIRAI). The primary outcome was the median change in the Menstrual Distress Questionnaire (MDQ) and Menorrhagia Multi-Attribute Scale (MMAS) scores from baseline to 3 and 12 months after LNG-IUS insertion, with decreasing and increasing scores, respectively, indicating improvement. The secondary outcomes were the statistical relationships between the MDQ and menstrual pain (measured by a visual analog scale, VAS), and between the MMAS and pictorial blood loss assessment chart (PBAC) scores by regression analysis. RESULTS: In total, 593 patients were evaluated; 376, 467, and 250 patients were diagnosed with dysmenorrhea, HMB, or both, respectively. The median MDQ score decreased significantly at 3 and 12 months after LNG-IUS insertion in both the premenstrual and menstrual periods (both p < 0.001 vs baseline), and the median MMAS score showed a similar improvement during the menstrual period. Changes in median MDQ and MMAS scores were observed regardless of patient background. Correlations between MDQ and menstrual pain (VAS) and between MMAS and PBAC scores were found (estimated regression coefficients 0.29 and - 0.15, respectively). CONCLUSION: The LNG-IUS contributed to improvements in the QOL of patients with dysmenorrhea, HMB, and both, regardless of patient background characteristics. TRIAL REGISTRATION: Registered at ClinicalTrials.gov (NCT02475356) on 18 June 2015.

A simple method for unsupervised anomaly detection: An application to Web time series data.

We propose a simple anomaly detection method that is applicable to unlabeled time series data and is sufficiently tractable, even for non-technical entities, by using the density ratio estimation based on the state space model. Our detection rule is based on the ratio of log-likelihoods estimated by the dynamic linear model, i.e. the ratio of log-likelihood in our model to that in an over-dispersed model that we will call the NULL model. Using the Yahoo S5 data set and the Numenta Anomaly Benchmark data set, publicly available and commonly used benchmark data sets, we find that our method achieves better or comparable performance compared to the existing methods. The result implies that it is essential in time series anomaly detection to incorporate the specific information on time series data into the model. In addition, we apply the proposed method to unlabeled Web time series data, specifically, daily page view and average session duration data on an electronic commerce site that deals in insurance goods to show the applicability of our method to unlabeled real-world data. We find that the increase in page view caused by e-mail newsletter deliveries is less likely to contribute to completing an insurance contract. The result also suggests the importance of the simultaneous monitoring of more than one time series.

The characteristics of influenza-like illness management in Japan.

BACKGROUND: This study aimed to make a quantitative assessment of the management of influenza-like illnesses (ILI) in Japanese healthcare settings. METHODS: We analysed participants' healthcare-seeking behaviour and physicians' practice in January 2019 using an online survey of 200 households in Japan. Quality of life score, quality-adjusted life years lost, the duration of symptoms, and the duration of absence from work were compared between the influenza ILI group and the non-influenza ILI group with one-to-one propensity score matching. Missing data were imputed using multiple imputation. RESULTS: In total, 261 of the 600 (43.5%) participants had at least one episode of influenza-like illness during January 2019. Of these, 194 (75.5%) visited healthcare facilities, 167 (86.1%) within 2 days of onset of symptoms. A total of 169 out of 191 (88.5%) received a rapid influenza diagnostic test and 101 were diagnosed with influenza, of whom 95.0% were treated with antivirals. The median quality-adjusted life-years (QALYs) lost was 0.0055 (interquartile range, IQR 0.0040-0.0072) and median absence from work for a single episode of influenza-like illness was 2 days (IQR 1-5 days). Albeit QALYs lost per episode was not different between two groups, the influenza ILI group showed longer duration of absence from work (5 days, IQR 4-6 days) than the non-influenza ILI group (2 days, IQR 1-3 days). CONCLUSIONS: In Japan, most people with influenza-like illnesses visit healthcare facilities soon after symptoms first occur and receive a diagnostic test. Those with influenza are usually treated with antivirals. Absence from work was longer for influenza than other similar illnesses.

Viral Etiology of Acute Lower Respiratory Tract Infections in Hospitalized Children in Nagasaki, a Regional City of Japan in 2013-2015.

BACKGROUND: Acute lower respiratory tract infections (ALRIs) are the most common disease for hospitalized children in Japan. The aim of this study was to identify viruses in children hospitalized for ALRIs and to demonstrate epidemiologic and clinical characteristics in Japan. METHODS: During a 2-year period from February 2013 to January 2015, we collected nasopharyngeal swab specimens from almost all hospitalized children with ALRIs in Nagasaki, a regional city of Japan, and its environs. Viruses were detected by multiplex polymerase chain reaction from these samples. RESULTS: We detected one or more viruses from 259 (69%) of 374 patients, 227 of whom were infected with a single virus, 30 with 2, and 2 with 3 viruses. Detected viruses in this study were rhinovirus (46.4%), respiratory syncytial virus (29.7%), human metapneumovirus (6.8%), parainfluenza virus (5.5%), enterovirus D68 (3.4%), influenza virus (2.7%), adenovirus (2.4%), bocavirus (2.0%) and Coxsackie virus (1.0%). We detected a seasonal shift in respiratory syncytial virus outbreaks from the 2013-2014 to the 2014-2015 seasons. There was no significant difference in clinical course and severity among those viruses. Patients with a history of asthma or underlying diseases were older and more frequently required oxygen therapy than previously healthy patients. CONCLUSIONS: Viral etiology in hospitalized children with ALRIs in Nagasaki, Japan, was similar to that in many other countries. Enterovirus D68, which was recently recognized as a causative agent of severe ALRIs, was also identified in this study area. Severity of ALRIs may depend on underlying disease rather than type of etiologic virus.

Evolutionary dynamics of influenza B strains detected from paediatric acute respiratory infections in central Vietnam.

Influenza virus B belongs to the family Orthomyxoviridae with segmented negative-sense RNA genomes. Since 1970s, influenza B has diverged intoVictoria and Yamagata, which differs in antigenic and evolutionary characteristics. Yet, molecular-epidemiological information of influenza B from developing nations is limited. In central Vietnam, influenza A subtype-specific circulation pattern and clinical characteristics were previously described. However, molecular evolutionary characteristics of influenza B has not been discussed to date. We utilized the influenza B positives obtained from paediatric ARI surveillance during 2007-2013. Influenza B HA and NA genes were amplified, sequenced, and phylogenetic/molecular evolutionary analysis was performed using Maximum Likelihood and Bayesian MCMC. Phylodynamics analysis was performed with Bayesian Skyline Plot (BSP). Furthermore, we performed selection pressure analysis and estimated N-glycosylation sites. In the current study, overall positive rate for influenza B was 3.0%, and Victoria lineage immediately became predominant in post-A/H1N1pdm09 period. The noticeable shift in Victoria lineage WHO Group occurred. With respect to the evolutionary rate (substitutions/site/year), Victoria lineage HA gene was evolving faster than Yamagata lineage (2.43 × 10-3 vs 2.00 × 10-3). Furthermore, the evolutionary rate of Victoria Group 5 was greater than Group 1. BSP presented the rapid growth in Effective Population Size (EPS) of Victoria lineage occurred soon after the 1st A/H1N1pdm09 case was detected whereas the EPS of Yamagata lineage was stable for both genes. N-glycosylation pattern between lineages and among WHO Groups were slightly different, and HA gene had a total of 6 amino acid substitutions under positive section pressure (4 for Victoria and 2 for Yamagata). The current results highlight the importance of Victoria lineage in post-A/H1N1pdm09 period. Difference in evolutionary characteristics and phylodynamics may indicate lineage and WHO Group-specific evolutionary dynamics. It is necessary to further continue the molecular-epidemiological surveillance in local setting to gain a better understanding of local evolutionary characteristics of influenza B strains.

Diphtheria Outbreaks in Schools in Central Highland Districts, Vietnam, 2015-2018.

During 2015-2018, seven schools in rural Vietnam experienced diphtheria outbreaks. Multilocus sequence types were the same within schools but differed between schools. Low vaccine coverage and crowded dormitories might have contributed to the outbreaks. Authorities should consider administering routine vaccinations and booster doses for students entering the school system.

Challenges in diagnosing scrub typhus among hospitalized patients with undifferentiated fever at a national tertiary hospital in northern Vietnam.

BACKGROUND: Scrub typhus (ST) is a leading cause of non-malarial febrile illness in Southeast Asia, but evidence of its true disease burden is limited because of difficulties of making the clinical diagnosis and lack of adequate diagnostic tests. To describe the epidemiology and clinical characteristics of ST, we conducted an observational study using multiple diagnostic assays at a national tertiary hospital in Hanoi, Vietnam. METHODOLOGY/PRINCIPAL FINDINGS: We enrolled 1,127 patients hospitalized with documented fever between June 2012 and May 2013. Overall, 33 (2.9%) patients were diagnosed with ST by PCR and/or screening of ELISA for immunoglobulin M (IgM) with confirmatory tests: 14 (42.4%) were confirmed by indirect immunoperoxidase assay (IIP), and 19 (57.6%) were by IIP and PCR. Living by farming, conjunctival injection, eschar, aspartate aminotransferase elevation, and alanine aminotransferase elevation were significantly associated with ST cases (adjusted odds ratios (aORs): 2.8, 3.07, 48.8, 3.51, and 4.13, respectively), and having a comorbidity and neutrophilia were significantly less common in ST cases (aORs: 0.29 and 0.27, respectively). The majority of the ST cases were not clinically diagnosed with rickettsiosis (72.7%). Dominant IIP reactions against a single antigen were identified in 15 ST cases, whereas indistinguishably high reactions against multiple antigens were seen in 11 ST cases. The most frequently observed dominant IIP reaction was against Karp antigen (eight cases) followed by Gilliam (four cases). The highest diagnostic accuracy of IgM ELISA in acute samples was 78%. In a phylogenetic analysis of the 56-kDa type-specific antigen gene, the majority (14 cases) were located in the Karp-related branch followed by the Gilliam-related (two cases), Kato-related (two cases), and TA763-related clades (one case). CONCLUSIONS/SIGNIFICANCE: Both the clinical and laboratory diagnoses of ST remain challenging at a tertiary hospital. Implementation of both serological and nucleic acid amplification assays covering endemic O. tsutsugamushi strains is essential.

Molecular Evolution of the Protease Region in Norovirus Genogroup II.

Noroviruses are a major cause of viral epidemic gastroenteritis in humans worldwide. The protease (Pro) encoded in open reading frame 1 (ORF1) is an essential enzyme for proteolysis of the viral polyprotein. Although there are some reports regarding the evolutionary analysis of norovirus GII-encoding genes, there are few reports focused on the Pro region. We analyzed the molecular evolution of the Pro region of norovirus GII using bioinformatics approaches. A time-scaled phylogenetic tree of the Pro region constructed using a Bayesian Markov chain Monte Carlo method indicated that the common ancestor of GII diverged from GIV around 1680 CE [95% highest posterior density (HPD), 1607-1749]. The GII Pro region emerged around 1752 CE (95%HPD, 1707-1794), forming three further lineages. The evolutionary rate of GII Pro region was estimated at more than 10-3 substitutions/site/year. The distribution of the phylogenetic distances of each genotype differed, and showed genetic diversity. Mapping of the negative selection and substitution sites of the Pro structure showed that the substitution sites in the Pro protein were mostly produced under neutral selection in positions structurally adjacent to the active sites for proteolysis, whereas negative selection was observed in residues distant from the active sites. The phylodynamics of GII.P4, GII.P7, GII.P16, GII.P21, and GII.P31 indicated that their effective population sizes increased during the period from 2005 to 2016 and the increase in population size was almost consistent with the collection year of these genotypes. These results suggest that the Pro region of the norovirus GII evolved rapidly, but under no positive selection, with a high genetic divergence, similar to that of the RNA-dependent RNA polymerase (RdRp) region and the VP1 region of noroviruses.

Influenza B associated paediatric acute respiratory infection hospitalization in central vietnam.

BACKGROUND: Influenza B is one of the major etiologies for acute respiratory infections (ARI) among children worldwide; however, its clinical-epidemiological information is limited. We aimed to investigate the hospitalization incidence and clinical-epidemiological characteristics of influenza B-associated paediatric ARIs in central Vietnam. METHODS: We collected clinical-epidemiological information and nasopharyngeal swabs from ARI children hospitalized at Khanh Hoa General Hospital, Nha Trang, Vietnam from February 2007 through June 2013. Nasopharyngeal samples were screened for 13 respiratory viruses using Multiplex-PCRs. Influenza B-confirmed cases were genotyped by Haemagglutinin gene sequencing. We analyzed the clinical-epidemiological characteristics of influenza B Lineages (Victoria/Yamagata) and WHO Groups. RESULTS: In the pre-A/H1N1pdm09 period, influenza B-associated ARI hospitalization incidence among children under five was low, ranging between 14.7 and 80.7 per 100 000 population. The incidence increased to between 51.4 and 330 in the post-A/H1N1pdm09. Influenza B ARI cases were slightly older with milder symptoms. Both Victoria and Yamagata lineages were detected before the A/H1N1pdm09 outbreak; however, Victoria lineage became predominant in 2010-2013 (84% Victoria vs 16% Yamagata). Victoria and Yamagata lineages did not differ in demographic and clinical characteristics. In Victoria lineage, Group1 ARI cases were clinically more severe compared to Group5, presenting a greater proportion of wheeze, tachypnea, and lower respiratory tract infection. CONCLUSIONS: The current results highlight the increased incidence of influenza B-related ARI hospitalization among children in central Vietnam in the post-A/H1N1pdm09 era. Furthermore, the difference in clinical severity between Victoria lineage Group1 and 5 implies the importance of influenza B genetic variation on clinical presentation.

An Alarmingly High Proportion of HIV-1 Isolates Carrying Mutations Corresponding to Resistance to Antiretroviral Drugs among HIV-Positive High-Risk Groups in Central Vietnam: a Substudy of the National Sentinel Survey.

We studied the prevalence of HIV drug resistance among high-risk groups such as injecting drug users (IDUs), female sex workers (FSWs), and men having sex with men (MSM) in central Vietnam. We used HIV-positive blood samples from 2012-2013 sentinel surveillance surveys. Study subjects were screened for HIV infection by standardized screening assays, and the HIV-positive samples were further tested for HIV viral load and drug-resistance mutations (DRMs) by in-house assays. DRMs were identified using the Stanford University online sequence analysis tool. Their risk behaviors were also investigated. During the study period, 6,016 (high-risk) subjects were screened, and 97 tested positive for HIV infection (IDUs: n = 63, 3.0%; FSWs: n = 24, 0.9%; and MSM: n = 10, 1.0%). Ninety-two of the 97 samples (45 from 2012 and 47 from 2013) were available for further testing. HIV RNA was detected in 56 (60.9%) of the 92 samples, and drug resistance genotyping was successfully performed on 40 (71.4%) samples. All these isolates were subtype CRF01_AE, except for 1 (2.5%) IDU whose HIV belongs to subtype B. Thirteen individuals (32.5%) were carrying HIV with at least 1 DRM: 9 IDUs, 1 FSW, and 3 MSM. Thus, HIV seroprevalence among high-risk individuals in central Vietnam is low, but a high proportion of drug resistant HIV-1 isolates is observed in the high-risk group.

Molecular evolution of respiratory syncytial virus subgroup A genotype NA1 and ON1 attachment glycoprotein (G) gene in central Vietnam.

We performed molecular evolutionary analyses of the G gene C-terminal 3rd hypervariable region of RSV-A genotypes NA1 and ON1 strains from the paediatric acute respiratory infection patients in central Vietnam during the 2010-2012 study period. Time-scaled phylogenetic analyses were performed using Bayesian Markov Chain Monte Carlo (MCMC) method, and pairwise distances (p-distances) were calculated. Bayesian Skyline Plot (BSP) was constructed to analyze the time-trend relative genetic diversity of central Vietnam RSV-A strains. We also estimated the N-glycosylation sites within G gene hypervariable region. Amino acid substitutions under positive and negative selection pressure were examined using Conservative Single Likelihood Ancestor Counting (SLAC), Fixed Effects Likelihood (FEL), Internal Fixed Effects Likelihood (IFEL) and Mixed Effects Model for Episodic Diversifying Selection (MEME) models. The majority of central Vietnam ON1 strains detected in 2012 were classified into lineage 1 with few positively selected substitutions. As for the Vietnamese NA1 strains, four lineages were circulating during the study period with a few positive selection sites. Shifting patterns of the predominantly circulating NA1 lineage were observed in each year during the investigation period. Median p-distance of central Vietnam NA1 strains was wider (p-distance=0.028) than that of ON1 (p-distance=0.012). The molecular evolutionary rate of central Vietnam ON1 strains was estimated to be 2.55×10-2 (substitutions/site/year) and was faster than NA1 (7.12×10-3 (substitutions/site/year)). Interestingly, the evolutionary rates of both genotypes ON1 and NA1 strains from central Vietnam were faster than the global strains respectively. Furthermore, the shifts of N-glycosylation pattern within the G gene 3rd hypervariable region of Vietnamese NA1 strains were observed in each year. BSP analysis indicated the rapid growth of RSV-A effective population size in early 2012. These results suggested that the molecular evolution of RSV-A G gene detected in central Vietnam was fast with unique evolutionary dynamics.

Association of RSV-A ON1 genotype with Increased Pediatric Acute Lower Respiratory Tract Infection in Vietnam.

Since the initial discovery of RSV-A ON1 in Canada in 2010, ON1 has been reported worldwide, yet information regarding its clinical impact and severity has been controversial. To investigate the clinical relevance of RSV-A ON1,acute respiratory infection (ARI) cases enrolled to our population-based prospective pediatric ARI surveillance at Khanh Hoa General Hospital, Central Vietnam from January 2010 through December 2012 were studied. Clinical-epidemiological information and nasopharyngeal samples were collected. Multiplex PCR assays were performed for screening 13 respiratory viruses. RSV-positive samples were further tested for subgroups (A/B) and genotypes information by sequencing the G-glycoprotein 2nd hypervariable region. Statistical analysis was performed to evaluate the clinical-epidemiological characteristics of RSV-A ON1. A total of 1854 ARI cases were enrolled and 426 (23.0%) of them were RSV-positive. During the study period, RSV-A and B had been co-circulating. NA1 was the predominant RSV-A genotype until the appearance of ON1 in 2012. RSV-related ARI hospitalization incidence significantly increased after the emergence of ON1. Moreover, multivariate analysis revealed that risk of lower respiratory tract infection was 2.26 (95% CI: 1.37-3.72) times, and radiologically-confirmed pneumonia was 1.98 (95% CI: 1.01-3.87) times greater in ON1 compared to NA1 cases. Our result suggested that ON1 ARI cases were clinically more severe than NA1.

A prospective multi-center observational study of children hospitalized with diarrhea in Ho Chi Minh City, Vietnam.

We performed a prospective multicenter study to address the lack of data on the etiology, clinical and demographic features of hospitalized pediatric diarrhea in Ho Chi Minh City (HCMC), Vietnam. Over 2,000 (1,419 symptomatic and 609 non-diarrheal control) children were enrolled in three hospitals over a 1-year period in 2009-2010. Aiming to detect a panel of pathogens, we identified a known diarrheal pathogen in stool samples from 1,067/1,419 (75.2%) children with diarrhea and from 81/609 (13.3%) children without diarrhea. Rotavirus predominated in the symptomatic children (664/1,419; 46.8%), followed by norovirus (293/1,419; 20.6%). The bacterial pathogens Salmonella, Campylobacter, and Shigella were cumulatively isolated from 204/1,419 (14.4%) diarrheal children and exhibited extensive antimicrobial resistance, most notably to fluoroquinolones and third-generation cephalosporins. We suggest renewed efforts in generation and implementation of policies to control the sale and prescription of antimicrobials to curb bacterial resistance and advise consideration of a subsidized rotavirus vaccination policy to limit the morbidity due to diarrheal disease in Vietnam.

Correlation between doctor's belief on the patient's self-determination and medical outcomes in obtaining informed consent.

We employed a questionnaire survey to assess attitudes toward informed consent (IC) among hospital doctors. Based on the result of the correlation analysis, the following two hypotheses were identified. The first hypothesis is that "the doctor's belief that the patient's self-determination is possible promotes cure of illness by obtaining IC." The second hypothesis is that "the doctor's belief that the patient's self-determination is possible has a positive influence on patient's quality of life by obtaining IC." We clarified the rationale for explaining these two hypotheses by applying cross tabulation analysis, discriminant analysis and principal component analysis (PCA). The doctors were divided into two groups in terms of their position on the patient's self-determination. One group of doctors believed the possibility of patient's self-determination, and the other did not. Through our statistical analyses, the characteristics that discriminate these two groups were identified. It was revealed that the former group placed a great importance on the hospitality value, while the latter placed an importance on the service value. Agreement or rejection of the concept of IC has been demonstrated as a key distinguishing factor between the two groups. The results of PCA showed that the doctor's belief on the patient's self-determination in obtaining IC had a significant effect on medical outcomes, and the two above-mentioned hypotheses were revealed.

Laser reflector arrangement on H2A-lRE satellite for monitoring spin rate and optical degradation.

We devised a unique array of cube-corner reflectors on a spherical satellite so that laser ranging could be used to detect the spin rate and the optical degradation. On the H2A-LRE satellite, there are reflectors made of synthetic silica and ones made of BK7 glass. We report that the degradation of the BK7 reflectors, as well as the spin rate of the satellite, can be monitored through a spectral analysis of laser-ranging data. The center-of-mass correction of the Laser Ranging Equipment satellite was calculated at 210 +/- 10 mm for all possible systems and throughout the degradation process of the BK7 reflectors.