Maternal-neonatal events resulting from medications for preventing hypertensive disorders in high-risk pregnant women: A systematic review and network meta-analysis.

BACKGROUND: There have been few studies reporting on maternal and neonatal events in high-risk pregnant women receiving medications for preventing hypertensive disorders of pregnancy (HDP). OBJECTIVE: To identify placental abruption, postpartum hemorrhage, neonatal intraventricular hemorrhage, and neonates with small for gestational age (SGA) or growth restriction resulting from medications for preventing HDP in high-risk pregnant women using a network meta-analysis. SEARCH STRATEGY: All randomized controlled trials comparing the most commonly used medications (antiplatelet agents, anticoagulants, antioxidants, nitric oxide, and calcium) for preventing HDP in high-risk pregnant women were searched from the Cochrane Pregnancy and Childbirth's Specialized Register of Controlled Trials until July 31, 2020, without language restriction. SELECTION CRITERIA: Two of the authors independently selected the eligible trials. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data and assessed the methodological quality of the included trials. Pairwise and network meta-analyses were used to determine comparative risk ratios and 95% confidence intervals. MAIN RESULTS: The 51 included trials involved 69 669 pregnant women. Compared with placebo/no treatment, antioxidants slightly reduced placental abruption with high-certainty evidence. Antiplatelet agents probably reduced SGA with low-certainty evidence and slightly increased neonatal intraventricular hemorrhage with moderate-certainty evidence. CONCLUSION: Antiplatelet agents probably reduce SGA, but neonatal intraventricular hemorrhage should be monitored. SYSTEMATIC REVIEW REGISTRATION: PROSPERO, CRD42018096276.

Parents' preferences for respite care of children with medical complexity.

BACKGROUND: The number of children with medical complexity (CMC) is increasing worldwide. For these children and their families, various forms of support are legislated; among them, short-stay respite care has a great unmet need. We examined such children's parents' preferences for respite care and their willingness to pay. METHODS: We used discrete choice experiments (DCEs) to estimate the parents' preferences and willingness to pay. Parents whose children used overnight short-stay respite services answered a questionnaire to compare two hypothetical facilities of respite care having seven attributes and three levels. The DCE data was analyzed using the conditional logit model. The willingness to pay was calculated based on DCE estimates. RESULTS: A total of 70 parents participated in this study and mean age of their children was 7.8 years (standard deviation [SD] 4.3). Among those children, 67 (96%) had the severest certification of disability, and 27 (38%) used a ventilator at home. We found that the parents' highest preferences was the best level of medical care level that can manage ventilators (coefficient 1.61, 95% confidence interval [CI]: 1.32-1.90). The better and best level of medical care, daily care, education/nursing, and emergency care were preferred over basic quality services. Willingness to pay for the best level of medical care was approximately 75,367 JPY per night. CONCLUSION: This study shows a need for respite care that can deliver high-level medical care, especially for the management of ventilators, to CMC. This finding can serve as a basis for promoting respite care services.

Detecting geographical clusters of low birth weight and/or preterm birth in Japan.

In Japan, mean birth weight has significantly decreased from 3152 g in 1979 to 3018 g in 2010 and the prevalence of preterm birth (PTB) has risen to 5.7% in the last thirty years. However, the presence and magnitude of geographical differences in low birthweight (LBW) and/or PTB in Japan is not well understood. We implemented spatial analysis to identify localized clusters and hot spots of LBW and/or PTB during 2012-2016. The Japan national birth database was used in this study. A total of 5,041,685 (male: 2,587,415, female: 2,454,270) births were used for spatial analysis using empirical Bayes estimates of the incidence rate of LBW and/or PTB and spatial scan tests to detect hot-spot areas with p values calculated from Monte Carlo iterations. The most and second likely clusters were located in two areas: (1) the small islands in south-west Japan (Amami and Okinawa, Relative risk = 1.09-1.67 with p < 0.001) and (2) the cities on the base of Mt. Fuji, stretching over three neighboring prefectures of Yamanashi, Shizuoka and Kanagawa (Relative risk = 1.10-1.55 with p < 0.001), respectively. We need to optimize the medical resource allocations based on the evidence in geographical clustering of LBW and/or PTB at specific locations in Japan.

Labor risk factors for fetal heart rate abnormality after combined spinal-epidural analgesia.

OBJECTIVE: To explore the association between obstetric factors or outcomes and fetal heart rate (FHR) abnormalities after combined spinal-epidural analgesia (CSEA). METHODS: Women with singleton term deliveries who received CSEA at our institution between January 1 and December 31, 2017, were analyzed using medical records. We performed a logistic regression analysis to compare factors and outcomes between cases with and without new FHR abnormalities within 1 h after CSEA. RESULTS: Of the 393 women, 163 showed the new occurrence of FHR abnormality after CSEA. Rupture of the membrane (odds ratio [OR] 2.49; 95% confidence interval [CI] 1.52-4.09; P < 0.01) and dilatation of the cervix (OR 1.24; 95% CI 1.07-1.44; P < 0.01) were significantly associated with FHR abnormalities. There were significant differences in FHR abnormality rates between women with cervical dilatation of 2 cm or less and 3 cm or more (OR 2.20; 95% CI 1.01-4.81; P = 0.047) and 6 cm or less and 7 cm or more (OR 2.46; 95% CI 1.01-6.01; P = 0.048). FHR abnormalities were not significantly associated with cesarean delivery during labor, instrumental delivery, APGAR score below 7 at 1 or 5 min, or umbilical arterial blood gas pH less than 7.2. CONCLUSION: Rupture of the membrane and an advanced dilated cervix were risk factors for FHR abnormality when CSEA was initiated.

Factors associated with reversals of COVID-19 vaccination willingness: Results from two longitudinal, national surveys in Japan 2021-2022.

Background: Research characterizing changes of heart with respect to vaccine intention is scarce, and very little research considers those who were initially vaccine willing but became hesitant. Here, we sought to assess the factors related to reversals of vaccine willingness. Methods: We conducted a longitudinal, national survey on vaccination intention among Japanese adults aged 20 years or older, with the first questionnaire performed in February-March 2021 (N = 30,053) and the follow-up in February 2022 (N = 19,195, response rate 63.9%). The study population comprised those who reported vaccine willingness in the first survey, with the outcome variable being development of vaccine hesitancy at follow-up. We performed a regression analysis of vaccination status using sociodemographic, health-related, psychologic/attitudinal, and information-related variables as predictors. We used the sparse group minimax concave penalty (MCP) to select the optimum group of covariates for the logistic regression. Findings: Of 11,118 (57.9%) respondents who previously expressed interest in vaccination, 10,684 (96.1%) and 434 (3.9%) were in the vaccine willing and hesitant groups, respectively. Several covariates were found to significantly predict vaccine hesitancy, including marital status, influenza vaccine history, COVID-19 infection/testing history, engagement in COVID-19 preventive measures, perceived risks/benefits of the COVID-19 vaccine, and attitudes regarding vaccination policies and norms. The use of certain information sources was also associated with vaccine hesitancy. Interpretation: Sociodemographic, health-related, psychologic/attitudinal, and information-related variables predicted the development of vaccine hesitancy among those with prior willingness. Most of these predictors were also associated with vaccination status. Funding: The present work was supported in part by a grant from the Kanagawa Prefectural Government of Japan and by AIST government subsidies.

Characterising reasons for reversals of COVID-19 vaccination hesitancy among Japanese people: One-year follow-up survey.

Background: Vaccine hesitancy is a global public health threat. We present unique data that characterises those who experienced reversals of COVID-19 vaccination hesitancy in Japan. Methods: We administered a questionnaire on vaccination intention among 30053 Japanese adults aged 20 years or older before the COVID-19 vaccination was available to the general population (first survey) and conducted a follow-up survey on vaccination status one year later in February 2022 (second survey). Those who responded in the first survey that they did not intend to be vaccinated or were unsure and then responded in the second survey that they were vaccinated or intend to be vaccinated were asked about the reasons for their change of heart. Based on previous literature and expert opinion, 31 reasons for changing vaccination intention were compiled and respondents were asked to choose which among them applied to themselves, with multiple responses possible. Based on the results of those responses, each individual was then clustered using the Uniform Manifold Approximation and Projection (UMAP) dimensionality reduction technique and Ordering Points To Identify the Clustering Structure (OPTICS) algorithm. We then identified unique characteristics among each of the sub-populations (clusters). Findings: In the second survey we received 19195 responses (response rate 63.9%), of which 8077 responded 'no' or 'not sure' in the first survey regarding their intention to be vaccinated. Of these, 5861 responded having received or intending to receive the vaccine (72.6%). We detected six and five sub-populations (clusters) among the 'no' group and 'not sure' group, respectively. The clusters were characterized by perceived benefits of vaccination, including the COVID-19 vaccine, awareness of the COVID-19 vaccination status of those close to them, recognition of the social significance of COVID-19 vaccination for the spread of infection, and dispelled concerns about short-term adverse reactions and the safety of the COVID-19 vaccine. Work and personal relationship reasons were also found to be a unique overarching reason for vaccination changes of heart only among those who did not intend to vaccinate. Interpretation: Those who changed their intention to accept COVID-19 vaccination as well as their unique characteristics as detailed in this study will be important entry points when discussing how to promote vaccination to those who are hesitant to vaccinate in the future. Funding: The present work was supported in part by a grant from the Kanagawa Prefectural Government of Japan and by AIST government subsidies.

Medications for preventing hypertensive disorders in high-risk pregnant women: a systematic review and network meta-analysis.

OBJECTIVES: To determine the relative effectiveness of medications for preventing hypertensive disorders in high-risk pregnant women and to provide a ranking of medications using network meta-analysis. METHODS: All randomized controlled trials comparing the most commonly used medications to prevent hypertensive disorders in high-risk pregnant women that are nulliparity and pregnant women having family history of preeclampsia, history of pregnancy-induced hypertension in previous pregnancy, obstetric risks, or underlying medical diseases. We received the search results from the Cochrane Pregnancy and Childbirth's Specialised Register of Controlled Trials, searched on 31st July 2020. At least two review authors independently selected the included studies and extracted the data and the methodological quality. The comparative risk ratios (RR) and 95% confidence intervals (CI) were analyzed using pairwise and network meta-analyses, and treatment rankings were estimated by the surface under the cumulative ranking curve for preventing preeclampsia (PE), gestational hypertension (GHT), and superimposed preeclampsia (SPE). Safety of the medications is also important for decision-making along with effectiveness which will be reported in a separate review. RESULTS: This network meta-analysis included 83 randomized studies, involving 93,864 women across global regions. Three medications, either alone or in combination, probably prevented PE in high-risk pregnant women when compared with a placebo or no treatment from network analysis: antiplatelet agents with calcium (RR 0.19, 95% CI 0.04 to 0.86; 1 study; low-quality evidence), calcium (RR 0.61, 95% CI 0.47 to 0.80; 13 studies; moderate-quality evidence), antiplatelet agents (RR 0.69, 95% CI 0.57 to 0.82; 31 studies; moderate-quality evidence), and antioxidants (RR 0.77, 95% CI 0.63 to 0.93; 25 studies; moderate-quality evidence). Calcium probably prevented PE (RR 0.63, 95% CI 0.46 to 0.86; 11 studies; moderate-quality evidence) and GHT (RR 0.89, 95% CI 0.84 to 0.95; 8 studies; high-quality evidence) in nulliparous/primigravida women. Few included studies for the outcome of superimposed preeclampsia were found. CONCLUSION: Antiplatelet agents, calcium, and their combinations were most effective medications for preventing hypertensive disorders in high-risk pregnant women when compared with a placebo or no treatment. Any high-risk characteristics for women are important in deciding the best medications. The qualities of evidence were mostly rated to be moderate. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018096276.

Factors associated with the risk perception of COVID-19 infection and severe illness: A cross-sectional study in Japan.

Understanding COVID-19 risk perception may help inform public health messaging aimed at encouraging preventive measures and improving countermeasures against the pandemic. We conducted an online survey of 29,708 Japanese adults in February 2021 and estimated the associations between COVID-19 risk perception and a broad array of individual factors. Two logistic regressions were constructed to estimate factors associated with the risk perception of COVID-19 (defined as responding that one might become infected within the next 6 months), and of severe illness among those who responded that they might become infected (defined as responding that one would become severely ill). After adjusting for covariates, those with a higher perceived risk of the COVID-19 vaccine had higher odds of risk perception for both infection and severe illness. Interestingly, those with higher odds of risk perception of being infected were more likely to report obtaining their information from healthcare workers whereas those with lower odds were more likely to report obtaining their information from the Internet or the government; those with lower odds of risk perception of being severely ill were more likely to report obtaining their information from the Internet. The higher the trust level in the government as a COVID-19 information source, the lower the odds of both risk perception of being infected and becoming severely ill. The higher the trust levels in social networking services as a COVID-19 information source, the higher the odds of risk perception of becoming severely ill. Public health messaging should address the factors identified in our study.

Implementation Degree Assessment Sheet for Health Program in Japan by Customizing CFIR: Development and Validation.

PURPOSE: More than 70% of public health nurses in Japan belong to government agencies, and there is a need for further evidence-based capacity development for program implementation. The purpose of this research was to develop an Implementation Degree Assessment Sheet (IDAS) by customizing the Consolidated Framework for Implementation Research (CFIR) to health programs in Japan. METHODS: The draft IDAS (five domains, 31 constructs) created by customizing the CFIR was refined by the researchers and modified through pre-testing. The survey covered full-time public health nurses (PHNs) affiliated to all prefectures and the cities with health centers of Japan. The survey was conducted as an anonymous, self-administered questionnaire survey by mail. RESULTS: One hundred eighty-five of the 334 institutions (55.4%) agreed to participate in our survey. Of the 966 questionnaire forms distributed, 709 forms (73.4%) were collected, of which 702 responses (72.7%) were valid. No item required consideration of deletion based on the results of item analysis, and our confirmatory factor analysis on model fitness between the five IDAS domains and CFIR showed sufficient fit indices after modification. With regard to reliability, Cronbach's coefficient alpha, a measure of internal consistency, stayed above 0.8 overall. Our verification of stability with the split-half (odd/even) method resulted in a Spearman-Brown reliability coefficient of 0.95. The correlation coefficient between the IDAS scores and the research utilization competency score, used as an external criterion, was 0.51 (p<0.001), supporting the coexistence validity of the criterion-related validity of the IDAS. The significant differences were observed between known-groups, supporting the known-group validity of the IDAS. CONCLUSION: This study developed the IDAS and confirmed constant reliability and validity. Hereafter, it is necessary to promote the required capacity development based on the actual degree of implementation in order to use the IDAS for the competency development of public health nurses and related professions to deliver health programs.

Association of low birthweight and premature birth with hypertensive disorders in pregnancy: a systematic review and meta-analysis.

BACKGROUND: Growing evidence suggests that women born preterm or small have an increased risk of experiencing hypertensive disorders during pregnancy; however, a quantitative summary of the evidence on this issue is unavailable. OBJECTIVE: We aimed to systematically review the literature to describe the association between being born preterm, low birthweight (LBW), or small for gestational age (SGA), and future gestational hypertension, preeclampsia, or eclampsia. METHODS: We searched the MEDLINE, Embase, CINAHL, ClinicalTrials.gov, and ICTRP databases. We included all cohort and case-control studies examining the association between LBW, preterm birth, or SGA and hypertensive disorders in pregnancy. We pooled the odds ratios and 95% confidence intervals using the DerSimonian and Laird random-effects model. We assessed the certainty of evidence for each outcome using the Grading of Recommendations, Assessment, Development, and Evaluation criteria. RESULTS: Eleven studies were identified, totalling 752 316 participants. Being born preterm, LBW, or SGA was associated with gestational hypertension [pooled odds ratio (OR), 1.31; 95% confidence interval (CI) 1.15-1.50; moderate certainty of evidence] and preeclampsia (pooled OR, 1.35; 95% CI 1.23-1.48; moderate certainty of evidence). No study measured eclampsia as an outcome. CONCLUSION: Women born preterm, LBW, or SGA have an increased risk of gestational hypertension and preeclampsia. The course of the mother's own birth might be used to identify women at risk of gestational hypertension and preeclampsia.

Gestational diabetes mellitus in women born small or preterm: Systematic review and meta-analysis.

PURPOSE: There is some evidence that women born preterm or with low birth weight (LBW) have an increased future risk of gestational diabetes mellitus (GDM) during pregnancy; however, a quantitative summary of evidence is lacking. In this systematic review and meta-analysis, we examined the published data to investigate whether being born preterm, with LBW or small for gestational age (SGA) are associated with GDM risk. METHODS: We searched the MEDLINE, Embase, and CINAHL databases and study registries, including ClinicalTrials.gov and ICTRP, from launch until 29 October 2020. Observational studies examining the association between birth weight or gestational age and GDM were eligible. We pooled the odds ratios and 95% confidence intervals using the DerSimonian and Laird random-effects model. RESULTS: Eighteen studies were included (N = 827,382). The meta-analysis showed that being born preterm, with LBW or SGA was associated with increased risk of GDM (pooled odds ratio = 1.84; 95% confidence interval: 1.54-2.20; I2 = 78.3%; τ2 = 0.07). Given a GDM prevalence of 2.0, 10, and 20%, the absolute risk differences were 1.6%, 7.0%, and 11.5%, respectively. The certainty of the evidence was low due to serious concerns of risk of bias and publication bias. CONCLUSIONS: Women born prematurely, with LBW or SGA status, may be at increased risk for GDM. However, whether this should be considered in clinical decision-making depends on the prevalence of GDM.

Identification of optimum combinations of media channels for approaching COVID-19 vaccine unsure and unwilling groups in Japan.

BACKGROUND: Optimizing media campaigns for those who were unsure or unwilling to take coronavirus disease (COVID-19) vaccines is required urgently to effectively present public health messages aimed at increasing vaccination coverage. We propose a novel framework for selecting tailor-made media channels and their combinations for this task. METHODS: An online survey was conducted in Japan during February to March, 2021, with 30,053 participants. In addition to their sociodemographic characteristics, it asked the attitude toward vaccination and information sources (i.e., media channels) for COVID-19 issues. Multinomial logic regression was fitted to estimate the combinations of the media channels and their odds ratio (OR) associated with vaccination attitudes. FINDINGS: The proportion of respondents who were unsure or unwilling to take the vaccination was skewed toward younger generation: 58.1% were aged under 35, while 28.1% were 65 years or older. Media channels such as "Non-medical and Non-TV" and "Non-medical and Non-government" were associated with the unsure group: OR (95% Confidence intervals, (CI)) = 1.75 (1.62, 1.89) and 1.53 (1.44, 1.62), respectively. In addition, media channels such as "Newspapers or the Novel Coronavirus Expert Meeting", "Medical or Local government", and "Non-TV" were associated with the unwilling group: OR (95% CI) were 2.00 (1.47, 2.75), 3.13 (2.58, 3.81), and 2.25 (1.84, 2.77), respectively. INTERPRETATION: To effectively approach COVID-19 vaccine unsure and unwilling groups, generation-specific online and offline media campaigns should be optimized to the type of vaccine attitude. FUNDING: Funded by the Ministry of Health, Labour and Welfare of Japan (H29-Gantaisaku-ippan-009) and the Japan Agency for Medical Research and Development (AMED) (JP20fk0108535).

Reasons for being unsure or unwilling regarding intention to take COVID-19 vaccine among Japanese people: A large cross-sectional national survey.

BACKGROUND: Identifying and understanding reasons for being unsure or unwilling regarding intention to be vaccinated against coronavirus disease (COVID-19) may help to inform future public health messages aimed at increasing vaccination coverage. We analyzed a broad array of individual's psychological dispositions with regard to decision-making about COVID-19 vaccination in Japan. METHODS: A nationally representative cross-sectional web survey was conducted with 30053 Japanese adults aged 20 years or older at the end of February 2021. In addition to the question on the individual's intention to be vaccinated against COVID-19, respondents were asked about their sociodemographic, health-related, and psychological characteristics as well as information sources about COVID-19 and their levels of trust. Also, those who responded 'not sure' or 'no' regarding intention to take COVID-19 vaccine were asked why. Multinomial logistic regression with sparse group Lasso (Least Absolute Shrinkage and Selection Operator) penalty was used to compute adjusted odds ratios for factors associated with the intention (not sure/no versus yes). FINDINGS: The percentages of respondents who answered 'not sure' or 'no' regarding intention to be vaccinated against COVID-19 vaccine were 32.9% and 11.0%, respectively. After adjusting for covariates, the perceived risks of COVID-19, perceived risk of a COVID-19 vaccine, perceived benefits of a COVID-19 vaccine, trust in scientists and public authorities, and the belief that healthcare workers should be vaccinated were significantly associated with vaccination intention. Several sources of information about COVID-19 were also significantly associated with vaccination intention, including physicians, nurses, and television, medical information sites with lower odds of being unsure or unwilling, and internet news sites, YouTube, family members, and scientists and researchers with higher odds. The higher the level of trust in television as a source of COVID-19 information, the higher the odds of responding 'not sure' (odds ratio 1.11, 95% confidence interval 1.01-1.21). We also demonstrated that many respondents presented concerns about the side effects and safety of a COVID-19 vaccine as a major reason for being unsure or unwilling. To decide whether or not to get the vaccine, many respondents requested more information about the compatibilities between the vaccine and their personal health conditions, whether other people had been vaccinated, the effectiveness of vaccines against variants, and doctors' recommendations. INTERPRETATION: Our findings suggest that public health messaging based on the sociodemographic and psychological characteristics of those who are unsure or unwilling regarding intention to be vaccinated against COVID-19 vaccine may help to increase vaccine uptake amongst this population. FUNDING: The present work was supported in part by a grant from the Ministry of Health, Labour and Welfare of Japan (H29-Gantaisaku-ippan-009).

How do Japanese rate the severity of different diseases and injuries?-an assessment of disability weights for 231 health states by 37,318 Japanese respondents.

BACKGROUND: Disability weights (DWs) are weight factors that reflect the severity of health states for estimates of disability-adjusted life years. A new set of global DWs was published for the Global Burden of Diseases and Injuries (GBD) 2013 study, which relied on sampling from various world regions, but included little data for countries in East Asia. This study aimed to measure DWs in Japan using comparable methods, and compare the results with previous estimates from the GBD 2013 DW study. METHODS: We conducted a web-based survey in 2019 to estimate DWs for 231 health states for the Japanese population. The survey included five new health states but otherwise followed the method of the GBD DW measurement study. The survey consisted of 15 paired comparison (PC) questions and 3 population health equivalence questions (PHE) per respondent. We analyzed PC data using probit regression and rescaled results to DW units between 0 (equivalent to full health) and 1 (equivalent to death). FINDINGS: We considered 37,318 nationally representative respondents. The values of the resulting DWs ranged from 0.707 (95% uncertainty interval (UI) 0.527-0.842) for spinal cord injury at neck level (untreated) to 0.004 (UI 0.001-0.009) for mild anemia. High correlation between Japanese DW and GBD 2013 DW was observed, but there was considerable disagreement. Out of 226 comparable health states, 55 (24.3%) showed more than a factor-of-two difference, of which 41 (74.6%) had a higher value in Japanese DW. Many of the health states with higher DW in the Japan study were injuries, including amputation and fracture, and hearing and vision loss, while mental, behavioral, and substance use disorders generally tended to be lower. CONCLUSIONS: This study has created an empirical basis for assessment of Japanese DWs of health status. The findings from this study based on the Japanese population suggest that there might be contextual differences in rating the severity of health states compared to previous surveys conducted elsewhere.

Analysis of preventability of malignancy-related maternal death from the nationwide registration system of maternal deaths in Japan.

Objective: We reviewed malignancy related maternal deaths in Japan to ascertain if there were avoidable factors.Methods: Malignancy-related maternal death in Japan reported to the Maternal Death Exploratory Committee, from 2010 to 2016 inclusive.Results: There were 12 cases of maternal death caused by malignancy. There were four gastric cancers (two poorly differentiated adenocarcinoma, one signet ring cell carcinoma with adenocarcinoma, one histology not available), 3 leukemia (two acute myeloid leukemia, one aggressive NK cell leukemia), two ureteral cancers (histology not available), one malignant lymphoma (diffuse large B-cell lymphoma with translocation), one brain tumor (gliomatosis cerebri), and one cervical cancer (glassy cell carcinoma). Two gastric cancer patients had chronic gastric pain before conception. In two cases the physicians commented that they had avoided computed tomography and the brain biopsy needed for diagnosis because the patient was pregnant. At diagnosis, the clinical stages were II-IV in 9, and the performance status was 3-5 in 8. Indication for delivery was exacerbated maternal condition in 5, for treatment in 3, spontaneous labor in 3, and one patient declined elective delivery. Median [interquartile rage] (range) gestational weeks of delivery was 29 [24-30] (19-40). One cervical cancer patient had a radical hysterectomy and chemotherapy for 10 months. However, three leukemia and one gastric cancer patients had chemotherapy within 10 d because they deteriorated rapidly. Another seven cases did not have any treatment because of poor general condition or because they remained undiagnosed. In all cases, the Committee considered that there was no evidence of substandard care.Conclusion: In these cases, both the clinical stages and biological degree of malignancy were high. In two-thirds of cases, early termination of the pregnancy was indicated because of deteriorating maternal condition. Chemotherapy was not effective because of short available time for therapy and the advanced stage of the cancers when diagnosed. Encouraging women to have a thorough medical assessment before conception, and early diagnosis and treatment before pregnancy, appears to be the only practical way to reduce deaths from malignancy while a woman is pregnant.

Cell-to-cell transmission of HSV-1 in differentiated keratinocytes promotes multinucleated giant cell formation.

BACKGROUND: Herpes simplex virus (HSV) infection in the skin causes small grouped vesicles characterized by acantholytic cells and multinucleated giant cells (MGCs). Although viral factors have been studied as fusion proteins, little is known how the differentiation status of keratinocytes is involved in the formation of MGCs by HSV-1 infection. OBJECTIVE: As the human epidermis is composed of several layers of keratinocytes that undergo terminal differentiation, we aimed to elucidate whether the differentiation status of keratinocytes affects viral entry, propagation, cell-to-cell transmission of HSV-1, and MGC formation. METHODS: HaCaT cells and normal human epidermal keratinocytes were cultured in either low- or high-Ca2+ medium. After HSV-1 infection, cellular morphology, viral propagation, and expression of cytoskeletal and intercellular adhesion molecules were examined sequentially. Viral entry, replication, and expression of HSV receptors were analyzed. Cell-to-cell transmission and fusion after HSV-1 infection was evaluated using the Cell Tracker™ Red CMTPX dye system. RESULTS: Keratinocytes in high-Ca2+ medium formed MGCs, but those in low-Ca2+ medium formed single nuclear round cells in response to HSV-1 infection. HSV-1 entered the keratinocytes more effectively in low-Ca2+ than in high-Ca2+ medium, although transcripts of HSV receptors were comparable in both conditions. HSV-1 could replicate more efficiently in high-Ca2+ than in low-Ca2+ medium. A cell-to-cell fusion assay showed that HSV-1-infected and adjacent-uninfected keratinocytes were involved in MGCs in high-Ca2+ but not in low-Ca2+ medium. CONCLUSION: Differentiated keratinocytes promote MGC formation by cell-to-cell fusion with resolution of cell membrane and cell-to-cell transmission of HSV-1 from infected keratinocytes to neighboring uninfected keratinocytes.

Involvement of S-type anion channels in disease resistance against an oomycete pathogen in Arabidopsis seedlings.

Pharmacological indications suggest that anion channel-mediated plasma membrane (PM) anion efflux is crucial in early defense signaling to induce immune responses and programmed cell death in plants. Arabidopsis SLAC1, an S-type anion channel required for stomatal closure, is involved in cryptogein-induced PM Cl- efflux to positively modulate the activation of other ion fluxes, production of reactive oxygen species and a wide range of defense responses including hypersensitive cell death in tobacco BY-2 cells. We here analyzed disease resistance against several pathogens in multiple mutants of the SLAC/SLAH channels of Arabidopsis. Resistance against a biotrophic oomycete Hyaloperonospora arabidopsidis Noco2 was significantly enhanced in the SLAC1-overexpressing plants than in the wild-type, while that against a bacteria Pseudomonas syringae was not affected significantly. Possible regulatory roles of S-type anion channels in plant immunity and disease resistance against bacterial and oomycete pathogens is discussed.

Contribution of the S-type Anion Channel SLAC1 to Stomatal Control and Its Dependence on Developmental Stage in Rice.

Rice production depends on water availability and carbon fixation by photosynthesis. Therefore, optimal control of stomata, which regulate leaf transpiration and CO2 absorption, is important for high productivity. SLOW ANION CHANNEL-ASSOCIATED 1 (SLAC1) is an S-type anion channel protein that controls stomatal closure in response to elevated CO2. Rice slac1 mutants showed significantly increased stomatal conductance (gs) and enhanced CO2 assimilation. To discern the contribution of stomatal regulation to rice growth, we compared gs in the wild type (WT) and two mutants, slac1 and the dominant-positive mutant SLAC1-F461A, which expresses a point mutation causing an amino acid substitution (F461A) in SLAC1, at different growth stages. Because the side group of F461 is estimated to function as the channel gate, stomata in the SLAC1-F461A mutant are expected to close constitutively. All three lines had maximum gs during the tillering stage, when the gs values were 50% higher in slac1 and 70% lower in SLAC1-F461A, compared with the WT. At the tillering stage, the gs values were highest in the first leaves at the top of the stem and lower in the second and third leaves in all three lines. Both slac1 and SLAC1-F461A retained the ability to change gs in response to the day-night cycle, and showed differences in tillering rate and plant height compared with the WT, and lower grain yield. These observations show that SLAC1 plays a crucial role in regulating stomata in rice at the tillering stage.

The Transmembrane Region of Guard Cell SLAC1 Channels Perceives CO2 Signals via an ABA-Independent Pathway in Arabidopsis.

The guard cell S-type anion channel, SLOW ANION CHANNEL1 (SLAC1), a key component in the control of stomatal movements, is activated in response to CO2 and abscisic acid (ABA). Several amino acids existing in the N-terminal region of SLAC1 are involved in regulating its activity via phosphorylation in the ABA response. However, little is known about sites involved in CO2 signal perception. To dissect sites that are necessary for the stomatal CO2 response, we performed slac1 complementation experiments using transgenic plants expressing truncated SLAC1 proteins. Measurements of gas exchange and stomatal apertures in the truncated transgenic lines in response to CO2 and ABA revealed that sites involved in the stomatal CO2 response exist in the transmembrane region and do not require the SLAC1 N and C termini. CO2 and ABA regulation of S-type anion channel activity in guard cells of the transgenic lines confirmed these results. In vivo site-directed mutagenesis experiments targeted to amino acids within the transmembrane region of SLAC1 raise the possibility that two tyrosine residues exposed on the membrane are involved in the stomatal CO2 response.