Marine Pharmacology in 2019-2021: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action.

The current 2019-2021 marine pharmacology literature review provides a continuation of previous reviews covering the period 1998 to 2018. Preclinical marine pharmacology research during 2019-2021 was published by researchers in 42 countries and contributed novel mechanism-of-action pharmacology for 171 structurally characterized marine compounds. The peer-reviewed marine natural product pharmacology literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral mechanism-of-action studies for 49 compounds, 87 compounds with antidiabetic and anti-inflammatory activities that also affected the immune and nervous system, while another group of 51 compounds demonstrated novel miscellaneous mechanisms of action, which upon further investigation, may contribute to several pharmacological classes. Thus, in 2019-2021, a very active preclinical marine natural product pharmacology pipeline provided novel mechanisms of action as well as new lead chemistry for the clinical marine pharmaceutical pipeline targeting the therapy of several disease categories.

Two Onnamide Analogs from the Marine Sponge Theonella conica: Evaluation of Geometric Effects in the Polyene Systems on Biological Activity.

Two previously unreported onnamide analogs, 2Z- and 6Z-onnamides A (1 and 2), were isolated from the marine sponge Theonella conica collected at Amami-Oshima Is., Kagoshima Prefecture, Japan. Structures of compounds 1 and 2 were elucidated by spectral analysis. Structure-activity relationships (SARs) for effects on histone modifications and cytotoxicity against HeLa and P388 cells were characterized. The geometry in the polyene systems of onnamides affected the histone modification levels and cytotoxicity.

Histone modification dynamics as revealed by multicolor immunofluorescence-based single-cell analysis.

Post-translational modifications on histones can be stable epigenetic marks or transient signals that can occur in response to internal and external stimuli. Levels of histone modifications fluctuate during the cell cycle and vary among different cell types. Here, we describe a simple system to monitor the levels of multiple histone modifications in single cells by multicolor immunofluorescence using directly labeled modification-specific antibodies. We analyzed histone H3 and H4 modifications during the cell cycle. Levels of active marks, such as acetylation and H3K4 methylation, were increased during the S phase, in association with chromatin duplication. By contrast, levels of some repressive modifications gradually increased during G2 and the next G1 phases. We applied this method to validate the target modifications of various histone demethylases in cells using a transient overexpression system. In extracts of marine organisms, we also screened chemical compounds that affect histone modifications and identified psammaplin A, which was previously reported to inhibit histone deacetylases. Thus, the method presented here is a powerful and convenient tool for analyzing the changes in histone modifications.

Marine pharmacology in 2018: Marine compounds with antibacterial, antidiabetic, antifungal, anti-inflammatory, antiprotozoal, antituberculosis and antiviral activities; affecting the immune and nervous systems, and other miscellaneous mechanisms of action.

The 2018 marine pharmacology literature review represents a continuation of the previous 11 reviews of a series initiated in 1998. Preclinical marine pharmacology research during 2018 was performed by investigators in 44 countries and contributed novel pharmacology for 195 marine compounds. The peer-reviewed marine natural products pharmacology literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral activities for 53 compounds, 73 compounds which presented antidiabetic and anti-inflammatory activities as well as affecting the immune and nervous system, while in contrast 69 compounds were reported to show miscellaneous mechanisms of action which may contribute upon further investigation to several pharmacological classes. Thus, in 2018, the preclinical marine natural product pharmacology pipeline continued to report novel pharmacology as well as new lead compounds for the clinical marine pharmaceutical pipeline, which currently contributes to therapeutic strategies for several disease categories.

Marine Pharmacology in 2016-2017: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action.

The review of the 2016-2017 marine pharmacology literature was prepared in a manner similar as the 10 prior reviews of this series. Preclinical marine pharmacology research during 2016-2017 assessed 313 marine compounds with novel pharmacology reported by a growing number of investigators from 54 countries. The peer-reviewed literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral activities for 123 marine natural products, 111 marine compounds with antidiabetic and anti-inflammatory activities as well as affecting the immune and nervous system, while in contrast 79 marine compounds displayed miscellaneous mechanisms of action which upon further investigation may contribute to several pharmacological classes. Therefore, in 2016-2017, the preclinical marine natural product pharmacology pipeline generated both novel pharmacology as well as potentially new lead compounds for the growing clinical marine pharmaceutical pipeline, and thus sustained with its contributions the global research for novel and effective therapeutic strategies for multiple disease categories.

Marine Pharmacology in 2014-2015: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, Antiviral, and Anthelmintic Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action.

The systematic review of the marine pharmacology literature from 2014 to 2015 was completed in a manner consistent with the 1998-2013 reviews of this series. Research in marine pharmacology during 2014-2015, which was reported by investigators in 43 countries, described novel findings on the preclinical pharmacology of 301 marine compounds. These observations included antibacterial, antifungal, antiprotozoal, antituberculosis, antiviral, and anthelmintic pharmacological activities for 133 marine natural products, 85 marine compounds with antidiabetic, and anti-inflammatory activities, as well as those that affected the immune and nervous system, and 83 marine compounds that displayed miscellaneous mechanisms of action, and may probably contribute to novel pharmacological classes upon further research. Thus, in 2014-2015, the preclinical marine natural product pharmacology pipeline provided novel pharmacology as well as new lead compounds for the clinical marine pharmaceutical pipeline, and thus continued to contribute to ongoing global research for alternative therapeutic approaches to many disease categories.

Kakeromamide A, a new cyclic pentapeptide inducing astrocyte differentiation isolated from the marine cyanobacterium Moorea bouillonii.

Kakeromamide A (1), a new cyclic pentapeptide encompassing a thiazole ring moiety and a ß-amino acid, was isolated from the marine cyanobacterium Moorea bouillonii. Its structure was elucidated by the spectral analysis and the modified Marfey's method. Compound 1 induced differentiation of neural stem cells into astrocytes at the concentration of 10 µM.

Impact of a direct-to-consumer information campaign on prescription patterns for overactive bladder.

BACKGROUND: Direct-to-consumer information (DTCI) campaign is a new medium to inform and empower patients in their decision-making without directly promoting specific drugs. However, little is known about the impact of DTCI campaigns, expanding rapidly in developed countries, on changes in prescription patterns. We sought to determine whether a DTCI campaign on overactive bladder increases the prescription rate for overactive bladder treatment drugs. METHODS: We performed a 3-year retrospective cohort study of 1332 participants who were diagnosed overactive bladder but not prescribed treatment drugs prior to the examined DTCI campaign (exposure), using the health insurance claims dataset of the Japan Medical Data Center (November 19, 2010 to November 18, 2013). The DTCI campaign for overactive bladder included television, Internet, and print advertising (November 19, 2011 to December 22, 2011). We divided the study period into Pre-Campaign Year (2010-2011), Year 1 (2011-2012), and Year 2 (2012-2013). Each year began on November 19 and included Period 1 (weeks 1-5) through Period 10 (weeks 46-50). The main outcome was first-time prescription of the treatment drug for each patient, measured by 5-week periods. Using Period 10 in the Pre-Campaign Year as the referent period, we applied the Cox proportional hazard model for each period. Additionally, we performed the interrupted time series analysis (ITSA) for the first-time prescription rate per 5-week period. RESULTS: Following the DTCI campaign, patients were about seven times more likely to receive a first prescription of a treatment drug during Period 4 in Year 1 (hazard ratio 7.09; 95% CI, 2.11-23.8; p-value<.01) compared with the reference period. Similar increases were also observed for subsequent Periods 5 and 6 in Year 1. The ITSA confirmed the DTCI campaign impact on the level of prescription rate (one-time increase in the regression-intercept) that increased by 1128.1 [per standardized 100,000 persons] (p < .05) during Period 4 in Year 1. CONCLUSIONS: The examined DTCI campaign appeared to increase the prescription rate among patients with overactive bladder for 15 weeks with a 15-week delay. Clinical outcomes of the patients with targeted diseases need to be monitored after DTCI campaigns by a future study.

Development and validation of a score for evaluating comprehensive stroke care capabilities: J-ASPECT Study.

BACKGROUND: Although the Brain Attack Coalition recommended establishing centers of comprehensive care for stroke and cerebrovascular disease patients, a scoring system for such centers was lacking. We created and validated a comprehensive stroke center (CSC) score, adapted to Japanese circumstances. METHODS: Of the selected 1369 certified training institutions in Japan, 749 completed an acute stroke care capabilities survey. Hospital performance was determined using a 25-item score, evaluating 5 subcategories: personnel, diagnostic techniques, specific expertise, infrastructure, and education. Consistency and validity were examined using correlation coefficients and factorial analysis. RESULTS: The CSC score (median, 14; interquartile range, 11-18) varied according to hospital volume. The five subcategories showed moderate consistency (Cronbach's α = 0.765). A strong correlation existed between types of available personnel and specific expertise. Using the 2011 Japanese Diagnosis Procedure Combination database for patients hospitalized with stroke, four constructs were identified by factorial analysis (neurovascular surgery and intervention, vascular neurology, diagnostic neuroradiology, and neurocritical care and rehabilitation) that affected in-hospital mortality from ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The total CSC score was related to in-hospital mortality from ischemic stroke (odds ratio [OR], 0.973; 95% confidence interval [CI], 0.958-0.989), intracerebral hemorrhage (OR, 0.970; 95% CI, 0.950-0.990), and subarachnoid hemorrhage (OR, 0.951; 95% CI, 0.925-0.977), with varying contributions from the four constructs. CONCLUSIONS: The CSC score is a valid measure for assessing CSC capabilities, based on the availability of neurovascular surgery and intervention, vascular neurology, diagnostic neuroradiology, and critical care and rehabilitation services.

Association Between Nonrestorative Sleep and Risk of Diabetes: A Cross-Sectional Study.

Although insufficient sleep or poor sleep quality has been reported to be associated with the development of type 2 diabetes, the relation of type 2 diabetes with nonrestorative sleep (NRS), a subjective feeling, has been overlooked. We used a large-scale medical checkup database to investigate whether there is a cross-sectional association between NRS and type 2 diabetes risk in Japanese individuals. We extracted data for 14,476 individuals who were not receiving therapeutic drugs for diabetes. About 36.8% of individuals were identified as having NRS. In a multiple logistic regression analysis, NRS was significantly associated with the risk of developing diabetes. Thus, this line of research may have implications for diabetes prevention.

Monitoring and evaluating the quality of cancer care in Japan using administrative claims data.

The importance of measuring the quality of cancer care has been well recognized in many developed countries, but has never been successfully implemented on a national level in Japan. We sought to establish a wide-scale quality monitoring and evaluation program for cancer by measuring 13 process-of-care quality indicators (QI) using a registry-linked claims database. We measured two QI on pre-treatment testing, nine on adherence to clinical guidelines on therapeutic treatments, and two on supportive care, for breast, prostate, colorectal, stomach, lung, liver and cervical cancer patients who were diagnosed in 2011 from 178 hospitals. We further assessed the reasons for non-adherence for patients who did not receive the indicated care in 26 hospitals. QI for pretreatment testing were high in most hospitals (above 80%), but scores on adjuvant radiation and chemoradiation therapies were low (20-37%), except for breast cancer (74%). QI for adjuvant chemotherapy and supportive care were more widely distributed across hospitals (45-68%). Further analysis in 26 hospitals showed that most of the patients who did not receive adjuvant chemotherapy had clinically valid reasons for not receiving the specified care (above 70%), but the majority of the patients did not have sufficient reasons for not receiving adjuvant radiotherapy (52-69%) and supportive care (above 80%). We present here the first wide-scale quality measurement initiative of cancer patients in Japan. Patients without clinically valid reasons for non-adherence should be examined further in future to improve care.

Influence of Differently Licensed KIR2DL1-Positive Natural Killer Cells in Transplant Recipients with Acute Leukemia: A Japanese National Registry Study.

Licensing by self MHC class I ligands is required for proper natural killer (NK) cell response. NK cells with inhibitory killer cell immunoglobulin-like receptors for nonself MHC exhibit transient alloreactivity after hematopoietic stem cell transplantation (HSCT). We analyzed 3866 recipients in the Japan national registry who underwent their first allogeneic HSCT for acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) from HLA-A, -B, and -DRB1 allele-genomatched unrelated donors. By classifying them into 5 independent groups based on HLA-C group matching and assumed donor NK cell status, we found that for HLA-C-matched HSCT for AML in HLA-C1/C1 recipients, in whom transient alloreactivity against HLA-C2-negative leukemic cells was expected, the relapse rate was significantly lower than it was in HLA-C-matched HSCT for AML in HLA-C1/C2 recipients (hazard ratio [HR], .72; P = .011). This difference was not observed in HLA-C-matched HSCT for ALL. Compared with HLA-C-matched HSCT, significantly higher mortality was observed in HLA-C1/C1 AML patients who received transplants from HLA-C-mismatched HLA-C1/C1 donors (HR, 1.37; P = .001) and in HLA-C1/C1 ALL patients who received transplants from HLA-C2-positive donors (HR, 2.13; P = .005). In conclusion, donor selection based on leukemic subtype and donor HLA-C group matching improves transplantation outcome after HLA-C-mismatched HSCT.

Association between novel arterial stiffness indices and risk factors of cardiovascular disease.

BACKGROUND: Prevention and early detection of arterial stiffness are required to avoid severe cardiovascular events. Recently, new noninvasive arterial stiffness indices, the arterial pressure volume index (API) and the arterial velocity pulse index (AVI), have been developed. The purpose of this study was to examine the clinical validity of these new indices by investigating the association between known risk factors of cardiovascular disease (CVD) and API or AVI in a large population. METHODS: This cross-sectional survey included 7248 adults who underwent an annual medical checkup at a single medical institution. API and AVI were measured using cuff oscillometry by trained nurses. We used correlation coefficients, t-tests, and multiple regression analyses to evaluate associations, and calculated intraclass correlation coefficients (ICC) to examine test-retest reliabilities of these indices. RESULTS: Mean age was 45.5 years (SD = 5.8), and 4083 (56.3 %) participants were men, while 3165 were women. Mean values of API and AVI were 25.1 (SD = 7.0) and 16.6 (SD = 5.4), respectively. API was strongly correlated with body mass index (BMI), systolic blood pressure (sBP), and diastolic blood pressure (dBP) (r > 0.3, p < 0.001). AVI was strongly correlated with age, sBP, and API (r > 0.3, p < 0.001). Multiple regression analyses showed that sex, age, BMI, and sBP were independently associated with API. Sex, age, BMI, sBP, fasting plasma glucose (FPG), and smoking condition were also independently associated with AVI. As reliabilities of measurements, the ICC of API was 0.74, and the ICC of AVI was 0.80. CONCLUSIONS: These new noninvasive arterial stiffness indices, which had high test-retest reliabilities, were associated with known risk factors of CVD. Further study is warranted to determine the clinical validity of these indices.

Risk of Alcohol Consumption in Bladder Cancer: Case-Control Study from a Nationwide Inpatient Database in Japan.

Bladder cancer is common in Western countries, but not in Japan. Established risk factors are smoking and high-risk jobs such as printing and manufacturing. The risk of alcohol consumption in bladder cancer has been the recent focus; however, available literature on alcohol consumption and bladder cancer has been limited from Japanese population, thought to have a weak genetic tolerance to acetaldehyde. We aimed to determine whether alcohol consumption is an independent risk factor for bladder cancer among Japanese. The study was a matched case-control study from the nationwide Japanese clinical database administered by the Rosai Hospital group. We identified 739 cases of bladder cancer diagnosed between 2005 (when the database was established) and 2014 and 7,196 controls matched by sex, age, hospital, and admission period. We estimated the odds ratio of alcohol consumption for bladder cancer adjusted for the amount of smoking, high-risk occupations, and comorbidities (hypertension, hyperlipidemia, diabetes, hyperuricemia, and obesity) with conditional logistic regression. The risk of bladder cancer was significantly higher in ever drinkers than in never drinkers (odds ratio, 1.33; 95% confidence interval, 1.06 to 1.66). Furthermore, the risk threshold for alcohol consumption was more than 15 g of alcohol intake per day (one, 180-mL cup equivalent to 6 ounces of Japanese sake containing 23 grams of alcohol). Among Japanese, alcohol consumption may be an independent risk factor for bladder cancer, with a lower risk threshold.

The distribution of hospital nurses and associated factors.

Objectives With the increasing aging population in Japan, the demand for medical and long-term care is expected to grow. Consequently, it is important to secure sufficient nursing personnel for medical care facilities. Careful monitoring of the allocation of nurses is crucial for providing services that match the needs of the population. However, few studies have examined the distribution of nurses by the type of facility in which they work or identified any associated factors. The objectives of this study are to examine trends in the distribution of nurses working in hospitals and to identify any associated factors such as policy changes, local socioeconomic characteristics, and nurse supply-and-demand-related factors.Methods We conducted an ecological study using public survey data from 2002 to 2011. We focused on 274 secondary medical areas (SMAs) in 38 prefectures from which we could obtain continuous data over the study period. We calculated the number of hospital nurses per 100,000 of the population in each SMA as well as the Gini coefficient. The explained variable was the number of hospital nurses per 100,000 of the population. We employed the following explanatory variables: SMA population, aging population ratio, population density category, per capita income, region, number of nursing school graduates, and nurse wages offered during the previous year. We then examined the association by applying multilevel analysis.Results The number of hospital nurses per 100,000 of the population in the SMAs increased during the period. The Gini coefficient decreased as a general trend but increased in 2007 and 2008. After adjusting for the SMA population and its increase, depending on the year, the number of hospital nurses was positively correlated with higher income per capita, higher aging population ratio, regions other than Kanto, higher number of nursing school graduates, and higher previous-year wages.Conclusion Although the differences in the numbers of hospital nurses across SMAs were lower, and thus improved, the differences tended to expand for 2 years after revision of the medical payment system in 2006. The results show the possibility of the influence of policy changes such as the revision of the medical payment system. The local socioeconomic characteristics, the number of nursing school graduates, and nurse wages were also factors affecting the distribution of hospital nurses.

Prescription of potentially inappropriate medications to elderly hemodialysis patients: prevalence and predictors.

BACKGROUND: In elderly hemodialysis (HD) patients, the risk of medication-related problems is particularly high. Thus, certain medications should generally not be prescribed to those patients. The Beers criteria for potentially inappropriate medications (PIMs) have been publicized. Still, with regard to elderly HD patients, the prevalence and risk factors for prescription of PIMs are unknown. METHODS: This was a cross-sectional study of data from the Japan Dialysis Outcomes and Practice Patterns Study (2002-08). Patients were included if they were 65 years old or older and were currently receiving HD treatment at a hospital or clinic. We counted the number of patients who were prescribed at least one PIM, as defined by the modified Beers criteria. We used multiple logistic regression analysis to determine which patient characteristics and facility characteristics were associated with prescription of PIMs. RESULTS: Data from 1367 elderly patients were analyzed. More than half of the patients (57%) had been prescribed a PIM. The three most frequently prescribed PIMs were H2 blockers (33%), antiplatelet agents (19%) and α-blockers (13%). PIM prescriptions were less likely at facilities that conducted multidisciplinary rounds {adjusted odds ratio (AOR): 0.67 [95% confidence interval (CI): 0.48-0.93]} and at teaching hospitals [AOR: 0.59 (95% CI, 0.39-0.90)]. PIM prescriptions are more likely if more than one physician has clearance to alter the HD regimen [AOR: 1.65 (95% CI, 1.12-2.44)]. CONCLUSIONS: PIMs were prescribed to many elderly HD patients in Japan. Nephrologists should become more aware of PIMs. Multidisciplinary rounds could benefit patients by reducing the prescription of PIMs.

Are hospitals in Japan with larger patient volume treating younger and earlier-stage cancer patients? An analysis of hospital-based cancer registry data in Japan.

OBJECTIVE: Differences in hospital case-mix have not been adequately accounted for in hospital volume and patient outcome studies in Japan. We aimed to examine whether differences may exist by investigating the distribution of patients' stage and age across designated cancer treatment hospitals of varying patient volume across Japan. METHODS: We analyzed data of gastric, breast, colorectal, lung and liver cancer patients who were included in the national database of hospital-based cancer registries between 2008 and 2011. We investigated the association between hospital volume, cancer stage and patient age. Hospitals were classified into five groups according to patient volume. RESULTS: In total, 676 713 patients met the inclusion criteria. The proportion of patients with early-stage (tumor-node-metastasis Stage 0 or I) cancer was higher among high-volume hospitals for all cancer types except small cell lung cancer. The proportion of older patients (age >75 years) was smaller among high-volume hospitals for all cancer types. The difference in the proportion of patients with early-stage cancers between very low-volume and very high-volume hospitals was greatest for non-small cell lung cancer (26.5% for very low and 43.5% for very high). This difference for the proportion of older patients was also greatest for non-small cell lung cancer (48.9% for very low and 30.3% for very high). CONCLUSIONS: We showed that the proportions of early-stage cancer patients and younger patients are greater in higher-volume hospitals compared with lower-volume hospitals in Japan. Researchers conducting volume-outcome studies and policymakers analyzing hospital performance should be cautious when making interhospital comparisons.

Differences in medical schools' regional retention of physicians by school type and year of establishment: effect of new schools built under government policy.

BACKGROUND: Physician maldistribution is an ongoing concern globally. The extent of medical schools retaining graduates within their geographical areas has rarely been explored in Japan or in other countries. This study aimed to investigate whether the proportion of medical school graduates practicing in the vicinity of medical school (retention rate) differs by the year of the school's establishment and by the school's funding source. METHODS: This cross-sectional study used a set of databases on medical institutions and personnel. We analyzed a sample of 168,594 clinically active physicians practicing in institutions as of May 2014, who passed the National Medical Practitioners Examination between 1985 and 2013. We assessed the retention rate and the schools' establishment period and funding source (pre-1970/post-1970, private/public), using a hierarchical regression model with random intercept unique to each medical school. We used the following factors as covariates: gender, physicians' length of professional experience, and the geographical features of the medical schools. RESULTS: The retention rate was widely distributed from 16.2 to 81.5 % (median: 48.4 %). Physicians who graduated from post-1970 medical schools were less likely to practice in the prefecture of their medical school location, relative to those who graduated from pre-1970 medical schools (adjusted odds ratio: 0.75; 95 % confidence interval: 0.62-0.90). Physicians who graduated from private medical schools were also less likely to practice in the prefecture of their medical school location, relative to those who graduated from public medical schools (adjusted odds ratio: 0.63; 95 % confidence interval: 0.51-0.77). In addition, the ability to retain graduates varied by school according to the school's characteristics. CONCLUSIONS: There was a considerable difference between medical schools in retaining graduates locally. The study results may have significant implications for government policy to alleviate maldistribution of physicians in Japan.

A cross sectional study on fertility knowledge in Japan, measured with the Japanese version of Cardiff Fertility Knowledge Scale (CFKS-J).

BACKGROUND: A recent survey of 79 countries showed that fertility knowledge was lower in Japan than in any other developed country. Given the fertility decline in Japan and the importance of fertility knowledge, we conducted an online survey to examine fertility knowledge and the related factors for effective public education. METHODS: We studied people aged 18-59 years old, n = 4,328 (the "General" group), and also people who had been trying to conceive for at least six months, 18-50 years old, n = 618 (the "Triers" group). Fertility knowledge was assessed using the Japanese version of the 13-item Cardiff Fertility Knowledge Scale (CFKS-J). All participants provided socio-demographic and fertility information. Participants also completed a 14-item health literacy scale and an 11-item health numeracy scale. We asked participants who were aware of age-related decline in fertility when and where they first acquired that knowledge. RESULTS: The average percentages of CFKS-J items answered correctly were 53.1% in the Triers group and 44.4% in the General group (p < 0.001). Multivariate linear regression models showed in the Triers group greater fertility knowledge was associated with greater health literacy and prior medical consultation regarding their fertility. In the General group greater fertility knowledge was associated with being female, younger, university educated, currently trying to conceive, non-smoking, having higher household income, having higher health literacy and having higher health numeracy. Of those who were aware of the age-related decline in fertility, around 3% first learned the fact "at school", and around 65% first learned it "through mass media" or "via the Internet". More than 30% of the respondents first learned it "less than 5 years before" the survey. CONCLUSIONS: Although fertility knowledge had improved since a previous study, possibly due to recent media coverage of age-related infertility, it was still low. Educational interventions, both in schools and in the community, may be needed to increase fertility knowledge in the general population because most people obtain fertility knowledge from mass media, which has been shown to often present distorted and inaccurate fertility information.

Association of Bystander Interventions With Neurologically Intact Survival Among Patients With Bystander-Witnessed Out-of-Hospital Cardiac Arrest in Japan.

IMPORTANCE: Neurologically intact survival after out-of-hospital cardiac arrest (OHCA) has been increasing in Japan. However, associations between increased prehospital care, including bystander interventions and increases in survival, have not been well estimated. OBJECTIVE: To estimate the associations between bystander interventions and changes in neurologically intact survival among patients with OHCA in Japan. DESIGN, SETTING, AND PARTICIPANTS: Retrospective descriptive study using data from Japan's nationwide OHCA registry, which started in January 2005. The registry includes all patients with OHCA transported to the hospital by emergency medical services (EMS) and recorded patients' characteristics, prehospital interventions, and outcomes. Participants were 167,912 patients with bystander-witnessed OHCA of presumed cardiac origin in the registry between January 2005 and December 2012. EXPOSURES: Prehospital interventions by bystander, including defibrillation using public-access automated external defibrillators and chest compression. MAIN OUTCOMES AND MEASURES: Neurologically intact survival was defined as Glasgow-Pittsburgh cerebral performance category score 1 or 2 and overall performance category scores 1 or 2 at 1 month or at discharge. The association between the interventions and neurologically intact survival was evaluated. RESULTS: From 2005 to 2012, the number of bystander-witnessed OHCAs of presumed cardiac origin increased from 17,882 (14.0 per 100,000 persons [95% CI, 13.8-14.2]) to 23,797 (18.7 per 100,000 persons [95% CI, 18.4-18.9]), and neurologically intact survival increased from 587 cases (age-adjusted proportion, 3.3% [95% CI, 3.0%-3.5%]) to 1710 cases (8.2% [95% CI, 7.8%-8.6%]). The rates of bystander chest compression increased from 38.6% to 50.9%, bystander-only defibrillation increased from 0.1% to 2.3%, bystander defibrillation combined with EMS defibrillation increased from 0.1% to 1.4%, and EMS-only defibrillation decreased from 26.6% to 23.5%. Performance of bystander chest compression, compared with no bystander chest compression, was associated with increased neurologically intact survival (8.4% [6594 survivors/78,592 cases] vs 4.1% [3595 survivors/88,720 cases]; odds ratio [OR], 1.52 [95% CI, 1.45-1.60]). Compared with EMS-only defibrillation (15.0% [6445 survivors/42,916 cases]), bystander-only defibrillation (40.7% [931 survivors/2287 cases]) was associated with increased neurologically intact survival (OR, 2.24 [95% CI, 1.93-2.61]), as was combined bystander and EMS defibrillation (30.5% [444 survivors/1456 cases]; OR, 1.50 [95% CI, 1.31-1.71]), whereas no defibrillation (2.0% [2369 survivors/120,653 cases]) was associated with reduced survival (OR, 0.43 [95% CI, 0.39-0.48]). CONCLUSIONS AND RELEVANCE: In Japan, between 2005 and 2012, the rates of bystander chest compression and bystander defibrillation increased and were associated with increased odds of neurologically intact survival.