Simultaneous measurement of nascent transcriptome and translatome using 4-thiouridine metabolic RNA labeling and translating ribosome affinity purification.

Regulation of gene expression in response to various biological processes, including extracellular stimulation and environmental adaptation requires nascent RNA synthesis and translation. Analysis of the coordinated regulation of dynamic RNA synthesis and translation is required to determine functional protein production. However, reliable methods for the simultaneous measurement of nascent RNA synthesis and translation at the gene level are limited. Here, we developed a novel method for the simultaneous assessment of nascent RNA synthesis and translation by combining 4-thiouridine (4sU) metabolic RNA labeling and translating ribosome affinity purification (TRAP) using a monoclonal antibody against evolutionarily conserved ribosomal P-stalk proteins. The P-stalk-mediated TRAP (P-TRAP) technique recovered endogenous translating ribosomes, allowing easy translatome analysis of various eukaryotes. We validated this method in mammalian cells by demonstrating that acute unfolded protein response (UPR) in the endoplasmic reticulum (ER) induces dynamic reprogramming of nascent RNA synthesis and translation. Our nascent P-TRAP (nP-TRAP) method may serve as a simple and powerful tool for analyzing the coordinated regulation of transcription and translation of individual genes in various eukaryotes.

The disaster liaison for pediatric and perinatal medicine: A new system in Japan.

BACKGROUND: Worldwide, children, newborns, and pregnant or postpartum women are vulnerable to disasters and emergency situations, and providing support to this population is of great concern. Japan is located in a disaster-prone area, so disaster response and risk reduction strategies are important priorities. METHODS: We introduce a system called the Disaster Liaison for Pediatric and Perinatal Medicine (DLPPM). This was created with a specific focus on perinatal children and pregnant women in Japan. We report the details of its activities, discuss its challenges, and draw on lessons learned for the further development of perinatal support systems, particularly for children. RESULTS: The lessons learned from the activities of the DLPPM include the following: (1) establish a support system for emergency specialists beyond those with pediatric and perinatal specialties; (2) mitigate the risk of indirect damage caused by primary disasters; and (3) establish a networking function linked to existing pediatric and perinatal medicine facilities. CONCLUSIONS: By establishing similar systems, we believe that it will be feasible to address pediatric and perinatal care needs in disaster response contexts in other countries and regions around the world.

A Comprehensive Study of the Immunophenotype and its Clinicopathologic Significance in Adult T-Cell Leukemia/Lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a mature T-cell tumor caused by human T-lymphotropic virus type 1 (HTLV-1). The typical ATLL immunophenotypes are described in the 2017 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (positive: CD2, CD3, CD5, CD4, and CD25; negative: CD7, CD8, and cytotoxic markers; and partially positive: CD30, CCR4, and FOXP3). However, limited studies are available on the expression of these markers, and their mutual relationship remains unknown. Furthermore, the expression status of novel markers associated with T-cell lymphomas, including Th1 markers (T-bet and CXCR3), Th2 markers (GATA3 and CCR4), T follicular helper markers (BCL6, PD1, and ICOS), and T-cell receptor (TCR) markers, and their clinicopathologic significance is unclear. In this study, we performed >20 immunohistochemical stains in 117 ATLL cases to determine the comprehensive immunophenotypic profile of ATLL, which were compared on the basis of clinicopathologic factors, including morphologic variants (pleomorphic vs anaplastic), biopsy locations, treatments, Shimoyama classification-based clinical subtype, and overall survival. CD3+/CD4+/CD25+/CCR4+ was considered a typical immunophenotype of ATLL, but approximately 20% of cases did not conform to this pattern. Simultaneously, the following new findings were obtained: (1) most cases were negative for TCR-ß and TCR-δ (104 cases, 88.9%), indicating the usefulness of negative conversion of TCR expression to provide differentiation from other T-cell tumors; (2) the positivity of CD30 and CD15 and the negativity of FOXP3 and CD3 were significantly associated with anaplastic morphology; and (3) atypical cases, such as T follicular helper marker-positive (12 cases, 10.3%) and cytotoxic molecule-positive cases (3 cases, 2.6%), were identified. No single markers could predict the overall survival among patients with acute/lymphoma subtypes of ATLL. The results of this study illustrate the diversity of ATLL phenotypes. In T-cell tumors occurring in HTLV-1 carriers, the possibility of ATLL should not be eliminated even when the tumor exhibits an atypical phenotype, and the confirmation of HTLV-1 in the tissue is recommended.

The safety of plasma apheresis from donors recovering from COVID-19 infection in Japan.

PURPOSE: Since 2020, the novel coronavirus infection (COVID-19) has spread globally. A few studies have investigated the safety of COVID-19 convalescent plasma (CCP) apheresis from COVID-19. This study was the first retrospective observational study of CCP in Japan. METHODS: We recruit donors from April 2020 to November 2021 and plasmapheresis in our center (NCGM: national center for global health and medicine). We set the primary endpoint as the Donors Adverse Event (DAE) occurrence at the time of the CCP collection. Variable selection was used to explore the determinants of DAE. RESULTS: Mean and SD age was 50.5 (10.6) years old. Seventy-three (42.2 %) were female, and 87 (33.3 %) were multiple-times donors. Twelve (6.97 % by donors and 4.6 % in total collections) adverse events occurred. The DAEs were VVR (Vaso Vagal Reaction), paresthesia, hypotension, agitation, dizziness, malaise, and hearing impairment/paresthesia. Half of them were VVR during apheresis. DAE occurred only in first-time donors and more in severe illnesses such as using ventilation and ECMO. From the donor characteristics and variable selection, the risk factors are as follows: younger age, female, the severity of disease at the time of the disease, and lower SBP before initiation. Our DAE incidence did not differ from previous studies. DAEs were more likely to occur in CCP apheresis than in healthy donors. CONCLUSION: We confirm the safety of CCP apheresis in this study, although DAEs were more than healthy donors. More caution should be exercised in the plasma collection for future outbreaks of emerging infectious diseases.

Time course of adverse reactions following BNT162b2 vaccination in healthy and allergic disease individuals aged 5-11 years and comparison with individuals aged 12-15 years: an observational and historical cohort study.

We aimed to investigate the type and frequency of adverse events over 7 days following the first and second BNT162b2 vaccination. This observational and historical cohort study included patients aged 5-11 years who received two doses of BNT162b2 and provided consent along with their guardians. We collected data on sex, age, height, weight, blood type, history of Bacille Calmette-Guerin vaccination, allergic disease, medication, history of coronavirus disease 2019 (COVID-19), and adverse reactions 7 days following the first and second BNT162b2 vaccination using a questionnaire. Our results were compared with previously reported results for individuals aged 12-15 years. A total of 421 participants were eligible for this study. Among the 216 patients with allergic disease, 48 (22.2%) had experienced worsening of their chronic diseases, and the frequency of fatigue and dizziness after the second dose was higher than that of healthy individuals. The experience of systemic adverse reactions was associated with asthma. The frequency of headache, diarrhea, fatigue, muscle/joint pain, and fever after the second BNT162b2 vaccination was lower in individuals aged 5-11 years than in those aged 12-15 years. Fever was the only systemic adverse reaction that lasted longer than 5 days (1.0% of participants). CONCLUSIONS: Individuals with allergic diseases, who are potentially susceptible to COVID-19, may experience worsening of their chronic diseases and more frequent adverse reactions after BNT162b2 vaccination than healthy individuals. To ensure that children with allergic diseases receive the vaccine safely, further information needs to be collected. WHAT IS KNOWN: • Adverse reactions after BNT162b2 vaccination among individuals aged 5-11 years are generally nonserious, more common after second vaccination, and substantially less common compared to those observed among individuals aged 12-15 years. WHAT IS NEW: • Individuals with allergic diseases experienced worsening of their chronic diseases and more frequent adverse reactions after BNT162b2 vaccination than healthy individuals. • Systemic adverse reactions were associated with asthma. Fever was the only systemic adverse reaction that lasted longer than 5 days.

Risk of low birthweight associated with the timing and frequency of antenatal care visits in Lao PDR: a retrospective cohort study.

BACKGROUND: Antenatal care (ANC) plays an important role in preventing low birthweight (LBW). Whereas the government of Lao People's Democratic Republic (Lao PDR) has committed to increasing the usage of ANC, little attention has been given to the early initiation of ANC. The present study assessed the influence of delayed and fewer ANC visits on LBW in the country. METHODS: This is a retrospective cohort study conducted at Salavan Provincial Hospital. Study participants were all pregnant women who gave birth at the hospital between 1 August 2016 and 31 July 31 2017. Data were collected from medical records. Logistic regression analyses were performed to quantify the relationship between ANC visits and LBW. We also investigated factors associated with inadequate ANC visits: first ANC visit after the first trimester or < 4 ANC visits. RESULTS: The mean birth weight was 2808.7 g [standard deviation: SD 455.6]. Among 1804 participants, 350 (19.4%) had babies with LBW, and 147 (8.2%) had inadequate ANC visits. In multivariate analyses, compared to participants with adequate ANC visits, those with ≥ 4 ANC visits and the first ANC visit after the second trimester, those with < 4 ANC visits, and those with no ANC visits had higher odds ratios (ORs) of LBW: 3.77 (95% confidence interval: CI = 1.66-8.57), 2.39 (95% CI = 1.18-4.83) and 2.22 (95% CI = 1.08-4.56), respectively. Younger maternal age (OR 1.42; 95% CI = 1.07-1.89), government subsidisation (OR 2.69; 95% CI = 1.97-3.68) and ethnic minority (OR 1.88; 95% CI = 1.50-2.34) were associated with increased risk of insufficient number of ANC visits after adjusting for covariates. CONCLUSIONS: Frequent and early initiation of ANC was associated with a reduction in LBW in Lao PDR. Encouraging childbearing-aged women to receive sufficient ANC at proper timing may lead to a reduction in LBW and improvement in short- and long-term health outcomes of neonates. Special attention will be needed for ethnic minorities and women in lower socioeconomic classes.

Difficulties experienced by health care professionals who performed home visits to screen for postpartum depression during the COVID-19 pandemic: a qualitative study in Japan.

BACKGROUND: Postpartum depression is a risk factor for suicide and maltreatment of children, and its early detection and appropriate intervention are issues to be resolved. In Japan, local governments are working to detect postpartum depression early by conducting home visits to families with infants within 4 months postpartum, but home-visit professionals have faced new difficulties due to the coronavirus disease 2019 (COVID-19) pandemic that started in 2020. The purpose of this study was to clarify the difficulties experienced by health care professionals who perform home visits to screen for postpartum depression. METHODS: Focus-group interviews were conducted during the COVID-19 pandemic with health care professionals (n = 13) who make postpartum home visits to families with infants within 4 months. Data were analyzed using thematic analysis. RESULTS: Four main categories were identified that describe the difficulties experienced by health care professionals: "Lack of support for partners," "Difficulty in talking face-to-face," "Inability to offer family assistance," and "Anxiety about being a source of infection." CONCLUSIONS: This study shed light on the difficulties faced by professionals in supporting mothers and children in the community during the COVID-19 pandemic. Although these difficulties were considered to have become apparent during the pandemic, the results may offer an important perspective for postpartum mental health support even after the pandemic ends. Accordingly, it may be necessary for these professionals to receive supported through multidisciplinary collaboration in order to improve postpartum care in the community.

Situation analyses of caregivers' knowledge on infant liquid formula in Japan: a cross-sectional questionnaire-based study.

BACKGROUND: Sales of the first domestic liquid infant milk formula in Japan started in March 2019, and some local governments have started to stockpile the formula in case of disasters. This study aimed to assess caregivers' knowledge of liquid formula to promote better utilization during disaster situations. METHODS: A cross-sectional, questionnaire-based study was conducted between August 26 and October 4, 2019, in Aiiku Hospital and Aiiku Clinic (Minato Ward, Tokyo, Japan). Caregivers of infants at their 1-, 3-4-, and 6-7-month medical check-ups participated. Caregivers' knowledge about the cup feeding method and handling of residual (left over) formula was evaluated. Caregivers were divided into high or low knowledge groups. Logistic regression analysis was performed to analyze the relation between caregivers' information sources on liquid formula and each caregiver's level of knowledge (high or low). RESULTS: Only 10.5% of caregivers were included in the high knowledge group regarding the cup feeding method, whereas 83.1% of caregivers were included in the high knowledge group regarding handling of residual liquid formula. Only 8.1% of caregivers were included in the high knowledge group regarding both cup feeding and handling of residual liquid formula. Logistic regression analysis showed that none of the information sources (hospital/clinic, TV/newspaper/magazine/website, milk company's website/advertisements, retail store, study meeting/event/social networking service, friend/infant's grandmother, workplace) affected the caregivers' knowledge. CONCLUSIONS: Caregivers' knowledge on the cup feeding method and handling of left over liquid formula was insufficient. Proactive and correct provision of information is required to improve caregivers' knowledge as this is an urgent infant safety issue in disaster situations.

Health screening system to ensure children's health and development in Japan.

BACKGROUND: The establishment of health screening systems for children is important, however, such systems are not always well-established in developing countries. This study aimed to improve child health screening systems in developing countries by analyzing the factors that contribute to enabling continuous and proper screenings at various governmental levels in Japan. METHODS: We reviewed the history of child health and development screening systems in Japan and examined factors that enabled their regular and nationwide implementation. RESULTS: We identified the six enabling factors: (i) the existence of relevant laws and regulations in health and education systems for health checkups, (ii) mandated and detailed conditions for health checkups within both school and community health, (iii) the provision of guidelines and manuals for health checkups, (iv) a sufficient number of professionals to carry out the health checkups, (v) clear criteria for evaluating and interpreting the checkup results, and (vi) understanding among teachers, children, and guardians of the importance of health checkups. CONCLUSION: We proposed the following six requirements to the governments in developing countries for establishing their own health screening programs: (i) a clear description of the need for regular and continuous health checkups in the relevant laws, regulations, and policies, (ii) mandate as essential activity and detailed requirements of the screening activities, (iii) provision of relevant manuals for health workers and teachers, (iv) provision of enough well-trained professionals and a training system, (v) studying growth and development curves for children, and (vi) promoting understanding among stakeholders about the importance of health checkups.

Dermatopathic reaction of lymph nodes in HTLV-1 carriers: a spectrum of reactive and neoplastic lesions.

AIMS: Dermatopathic reaction is a histopathological finding of lymph nodes that usually occurs in patients with inflammatory pruritic cutaneous lesions. However, it is sometimes seen in patients with cutaneous T cell lymphoma. Adult T cell leukaemia/lymphoma (ATLL) is a T cell malignancy caused by infection with human T cell leukaemia virus type I (HTLV-1), which is frequently accompanied by cutaneous lesions. However, the detailed clinicopathological characteristics of the dermatopathic reaction of lymph nodes in ATLL patients and HTLV-1 carriers, addressed in this study, remains to be clarified. METHODS AND RESULTS: We retrospectively analysed 18 nodal lesions with dermatopathic reaction in HTLV-1 carriers. Axillary and inguinal lymph nodes were the primary affected tissues. Three cases with atypical lymphoid cell infiltration were defined as ATLL with dermatopathic reaction (ATLL-D), showing an abnormal T cell immunophenotype and T cell monoclonality. Two of the three ATLL-D patients died 14 and 7 months after diagnosis (the third case had a very short follow-up). The other 15 patients were indistinguishable from reactive lesions and were defined as HTLV-1-associated lymphadenitis with dermatopathic reaction (HAL-D). They showed an indolent clinical course, with only one case eventually transforming to aggressive disease. CONCLUSIONS: Lymph node lesions accompanied by dermatopathic reaction in HTLV1 carriers represent a spectrum that includes reactive and neoplastic conditions. HAL-D should be distinguished from ATLL-D, especially to avoid overtreatment.

Hair abnormality in Netherton syndrome observed under polarized light microscopy.

BACKGROUND: Trichorrhexis invaginata, the main diagnostic feature of Netherton syndrome, is often difficult to detect, especially in adult patients. OBJECTIVE: We sought to describe a characteristic feature of hairs in Netherton syndrome using a polarized light microscope and the underlying histopathologic changes. METHODS: Hairs obtained from 8 patients with Netherton syndrome were observed under polarized light, and we evaluated the correlation between number of band-like patterns and disease severity. RESULTS: Under polarized microscopy, the hair shafts of 8 patients showed a characteristic band-like pattern under polarized light that was not observed in healthy control individuals or patients with atopic dermatitis. This discontinuity of polarized light shows a band-like pattern in which the bands mostly ranged from 0.1 to 1.0 mm in width. The observed ratio of this finding was significantly higher than that of trichorrhexis invaginata observed under light microscopy, and patients with severe dermatitis tended to have a higher ratio than those with less severe dermatitis. LIMITATIONS: Comparative examination among other congenital ichthyoses was not performed. CONCLUSIONS: A band-like pattern in hairs with polarized light microscopy can be seen in Netherton syndrome and may have potential utility as a diagnostic marker.

Factors affecting the provision of analgesia during childbirth, Japan.

Japan's universal health-care system means that it is a very safe country in which to give birth. Perinatal outcomes in Japan are excellent, with low infant mortality and neonatal mortality. However, childbirth remains a challenge for many Japanese women, who are faced with a scarcity of places to give birth, limited availability of analgesia and social norms that favour natural birth. The number of birth facilities in Japan continues to decrease as fewer children are born. The numbers of qualified medical staff remain inadequate, with a continuing lack of female physicians, perpetuated by a pervasive negative gender bias. Recruitment efforts are underway, but few doctors want to specialize in obstetrics or gynaecology. Furthermore, around half of female obstetricians and gynaecologists in Japan's male-dominated medical system stop practising when they have their own children. The difficulty of obtaining analgesia during labour is another problem. Although low uptake of labour pain relief in Japan is said to be due to cultural influences, the root of the problem is a lack of qualified anaesthesiologists and the inflexibility of a system that will not allow other staff to be trained to administer labour analgesia. Problems with labour anaesthesia have been linked to 14 maternal deaths since 2010. Japanese policy-makers need to act to renovate the nation's obstetric facilities, reorganize regional perinatal care systems, train more obstetricians and anaesthesiologists, promote task-shifting and better integrate biomedical and traditional, non-medical care for pregnant women.

Le système de soins de santé universel du Japon en fait un pays très sûr pour les accouchements. Les résultats en matière de santé périnatale au Japon sont excellents, avec une mortalité infantile et une mortalité néonatale faibles. Néanmoins, l'accouchement reste problématique pour de nombreuses Japonaises, qui doivent faire face à un manque d'établissements adaptés pour les accouchements, à une disponibilité limitée de l'analgésie et à des normes sociales qui favorisent les accouchements naturels. Le nombre de maternités au Japon ne cesse de baisser, à mesure de la diminution du nombre de naissances. Les effectifs en personnel médical qualifié restent inappropriés, avec une pénurie persistante de femmes médecins, perpétuée par des préjugés négatifs généralisés liés au genre. Des efforts de recrutement sont en cours, mais peu de médecins souhaitent se spécialiser en obstétrique ou en gynécologie. Par ailleurs, dans le système médical japonais dominé par les hommes, près de la moitié des femmes obstétriciennes et gynécologues cessent de pratiquer dès qu'elles ont elles-mêmes des enfants. La difficulté à bénéficier d'une analgésie obstétricale pendant l'accouchement constitue un autre problème. Même si, au Japon, le faible recours au soulagement de la douleur pendant le travail est généralement imputé à des influences culturelles, le fond du problème est une pénurie d'anesthésistes qualifiés et le manque de souplesse d'un système qui ne permet pas de former d'autres professionnels de santé pour pouvoir pratiquer l'analgésie obstétricale. Les problèmes liés à la réalisation d'une analgésie obstétricale ont donné lieu à 14 décès maternels depuis 2010. Au Japon, les décideurs politiques doivent agir pour rénover les installations obstétricales du pays, réorganiser les systèmes régionaux de santé périnatale, former davantage d'obstétriciens et d'anesthésistes, promouvoir le transfert des tâches et mieux intégrer les soins biomédicaux et les soins traditionnels, non médicaux, pour les femmes enceintes.

El sistema universal de atención sanitaria de Japón hace que sea un país muy seguro para dar a luz. Los resultados perinatales en Japón son excelentes, con baja mortalidad infantil y mortalidad neonatal. Sin embargo, el parto sigue siendo un problema para muchas mujeres japonesas, que se enfrentan a la escasez de lugares para dar a luz, la limitada disponibilidad de analgesia y las normas sociales que favorecen el parto natural. El número de centros de maternidad en Japón sigue disminuyendo a medida que nacen menos niños. El número de personal médico cualificado sigue siendo insuficiente, con una continua falta de mujeres médicas, perpetuada por un prejuicio de género negativo generalizado. Los esfuerzos de reclutamiento están en marcha, pero pocos médicos quieren especializarse en obstetricia o ginecología. Además, alrededor de la mitad de las obstetras y ginecólogas del sistema médico japonés dominado por los hombres dejan de ejercer cuando tienen sus propios hijos. La dificultad para obtener analgesia durante el trabajo de parto es otro problema. Aunque se dice que la baja aceptación del alivio del dolor del trabajo de parto en Japón se debe a influencias culturales, la raíz del problema es la falta de anestesiólogos calificados y la inflexibilidad de un sistema que no permitirá que otro personal esté capacitado para administrar la analgesia del trabajo de parto. Los problemas con la anestesia del trabajo de parto se han relacionado con 14 muertes maternas desde 2010. Los responsables de formular políticas en Japón deben actuar para renovar las instalaciones obstétricas del país, reorganizar los sistemas regionales de atención perinatal, capacitar a más obstetras y anestesiólogos, promover el cambio de tareas e integrar mejor la atención biomédica y la atención no médica tradicional para las mujeres embarazadas.

Prevalence and Risk Factors of Internet Addiction Among Employed Adults in Japan.

BACKGROUND: The prevalence of Internet addiction (IA) among employed adults has not been reported using a large sample. To clarify the actual status of addictive Internet use among employed adults, this study aimed to evaluate the prevalence and the risk factors of IA and at-risk IA among employed adults in Japan. METHODS: This cross-sectional study surveyed all junior and senior high school personnel in Shimane Prefecture, a rural area in Japan. Eligible participants included 3,211 junior and senior high school personnel (1,259 men and 1,952 women). Participants completed a questionnaire on their activities and factors related to Internet use. RESULTS: The prevalence of IA and at-risk IA was 0.03% and 4.82%, respectively. Furthermore, game playing was shown to be the Internet activity most closely associated with at-risk IA. CONCLUSIONS: This study showed that around 5% of school personnel in a rural area in Japan are at risk for developing addiction to the Internet and that using the Internet for game playing is related to at-risk IA. Our results suggest that employed adults should be instructed to use the Internet properly.

Socioeconomic determinants of accessibility to birth registration in Lao PDR.

BACKGROUND: The global coverage rate of birth registration is only around 65% for the population of children under five although birth registration secures protection and access to health services that are fundamental rights for all babies. This study aimed to perform a basic analysis of the accessibility to birth registration to better understand how to improve the birth registration system in the Lao PDR. METHODS: For the analysis of birth registration and related socioeconomic factors, 9576 mother-child pairs were chosen from the data set of The Lao Social Indicator Survey 2011-12. After bivariate analysis with statistical tests including the chi-square test were conducted, logistic regression was performed to determine the variables that statistically influence accessibility to birth registration. RESULTS: Ethno-geographic factors and place of delivery were observed to be the factors associated with birth registration in this analysis. CONCLUSION: Many mothers in the Lao PDR deliver in their local communities. Therefore, capacity development of various human resources, such as Skilled Birth Attendant, to support the local administrative procedure of birth registration in their communities could be one option to overcoming the bottlenecks in the birth registration process in the Lao PDR.

Study protocol of a cluster randomized controlled trial to evaluate effectiveness of a system for maintaining high-quality early essential newborn care in Lao PDR.

BACKGROUND: Reduction in neonatal deaths has been a major challenge globally. To prevent neonatal deaths, improvements in newborn care have been promoted worldwide. The World Health Organization Western Pacific Regional Office has been promoting the Early Essential Newborn Care (EENC), a package of specific simple and cost-effective interventions, in their region. However, mere introduction of EENC cannot reduce neonatal deaths unless quality of care is ensured. In Lao PDR, the government introduced self-managed continuous monitoring as a sustainable way to improve the quality of care described in the EENC. METHODS: A clustered randomized controlled trial was designed to compare the effectiveness of self-managed continuous monitoring with external supervisory visits to monitor health workers' satisfactory EENC performance and their knowledge and skills related to the EENC in Lao PDR. Determinants of EENC performance will be measured with a structured questionnaire developed based on the Theory of Planned Behaviour, which predicts future behaviour. During self-managed continuous monitoring activities, health workers in each district hospital will conduct periodical peer reviews and feedback sessions. Fifteen district hospitals will be randomly allocated into the self-managed continuous monitoring (intervention) and the supervision (control) groups. Fifteen health workers routinely involved in maternity and newborn care including physicians, midwives and other health staff will be recruited from each hospital (effect size 0.6, intra-cluster correlation coefficient 0.06, 5% alpha error and 80% power). We will compare the change in the mean score of the determinants before and one year after randomisation between the two groups. We will also compare the retention of knowledge and skills related to the EENC between the two groups. The expected enrolment period is July 20th, 2017 to July 20th, 2018. DISCUSSION: This is the first cluster randomized trial to evaluate a self-managed continuous monitoring system for quality maintenance of newborn care in a resource-limited country. This research is conducted in collaboration with the Ministry of Health and international organizations; therefore, if effective, this intervention would be applied in larger areas of the country and the region. TRIAL REGISTRATION: This trial was registered at UMIN-CTR on 15th of June, 2017. Registration number is UMIN000027794 .

High Prevalence of Distinct Human Herpesvirus 8 Contributes to the High Incidence of Non-acquired Immune Deficiency Syndrome-Associated Kaposi's Sarcoma in Isolated Japanese Islands.

Background: Non-acquired immune deficiency syndrome (AIDS) Kaposi's sarcoma (KS) is extremely rare in Japan but highly endemic in Okinawa, especially in Miyako Islands. We aimed to elucidate the exact incidence and cause of this high prevalence. Methods: Non-AIDS KS cases in Okinawa Prefecture over the past 31 years were reviewed, and human herpesvirus 8 (HHV8) seroprevalence in Miyako Islands was determined. We examined whole-genome sequences of 3 HHV8 strains and performed whole-exome sequencing of 4 male patients from Miyako Islands. Results: Approximately half of the non-AIDS KS cases in Okinawa Prefecture were from Miyako Islands. The age-adjusted incidence rate was 0.87/105 per year for Miyako Islands and 0.056/105 per year for the rest of Okinawa. Human herpesvirus 8 seroprevalence was 15.4% in Miyako Islands. The 3 HHV8 genomes isolated from Miyako islanders formed a phylogenetically branch distinct from those of previously sequenced HHV8 strains and shared specific mutations in 9 proteins. These mutations were verified in Okinawan patients other than those from Miyako Islands. Whole-exome sequencing of the 4 male Miyako Islanders did not reveal shared pathogenic mutations. Conclusions: Miyako Islands are an endemic area of non-AIDS KS. The high rate of a distinct HHV8 may contribute to the high incidence of KS in the region.

Survivin: A novel marker and potential therapeutic target for human angiosarcoma.

Human angiosarcoma is a rare malignant vascular tumor associated with extremely poor clinical outcome and generally arising in skin of the head and neck region. However, little is known about the molecular pathogeneses and useful immunohistochemical markers of angiosarcoma. To investigate the mechanisms of angiosarcoma progression, we collected 85 cases of human angiosarcoma specimens with clinical records and analyzed ISO-HAS-B patient-derived angiosarcoma cells. As control subjects, 54 cases of hemangioma and 34 of pyogenic granuloma were collected. Remarkably, consistent with our recent observations regarding the involvement of survivin expression following Hippo pathway inactivation in the neoplastic proliferation of murine hemangioendothelioma cells and human infantile hemangioma, nuclear survivin expression was observed in all cases of angiosarcoma but not in hemangiomas and pyogenic granulomas, and the Hippo pathway was inactivated in 90.3% of yes-associated protein (YAP) -positive angiosarcoma cases. However, survivin expression modes and YAP localization (Hippo pathway activation modes) were not correlated with survival. In addition, we confirmed that survivin small interference RNA (siRNA) transfection and YM155, an anti-survivin drug, elicited decreased nuclear survivin expression and cell proliferation in ISO-HAS-B cells which expressed survivin consistently. Conclusively, these findings support the importance of survivin as a good marker and critical regulator of cellular proliferation for human angiosarcoma and YM155 as a potential therapeutic agent.