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Serum levels of bilirubin, a strong antioxidant, may influence cancer risk. We aimed to assess the association between serum bilirubin levels and cancer risk. Data were retrieved from 10-year electronic medical records at Kyushu University Hospital (Japan) for patients aged 20 to 69 years old. The associations of baseline bilirubin levels with cancer risk (lung, colon, breast, prostate, and cervical) were evaluated using a gradient boosting decision tree (GBDT) model, a machine learning algorithm, and Cox proportional hazard regression model, adjusted for age, smoking, body mass index, and diabetes. The number of study subjects was 29,080. Median follow-up time was 4.7 years. GBDT models illustrated that baseline bilirubin levels were negatively and non-linearly associated with the risk of lung (men), colon, and cervical cancer. In contrast, a U-shaped association was observed for breast and prostate cancer. Cox hazard regression analyses confirmed that baseline bilirubin levels (P = 0.009) and cervical cancer risk (HR = 0.365, 95% CI 0.136–0.977, P = 0.045). Additionally, low bilirubin levels (P

Rural women in developing countries do not have any option but to visit the distant city to see the obstetricians and gynecologists in case of any maternal and child health issues. However, it becomes more difficult to travel during the COVID-19 pandemic situation. Thus, the telehealth service using the Portable Health Clinic can be very effective for maternal and child health care services. Since the PHC system provides home delivery services through the local health workers, the rural women can avail regular continuum of care services. This study found a 300% increase in participation in the continuum of care. This is not because they receive the service at home but also because they can receive consultancy from urban specialist doctors without travel during the pandemic situation.

Geographical variation in the standardized mortality ratio (SMR) for ischemic heart disease (IHD) among municipalities has not been assessed in Japan. Additionally, associations between area-level socioeconomic deprivation indices and IHD mortality have not been identified in Japan. The present study investigated this association.Information on IHD mortality was extracted from Vital Statistics data from 2018 to 2020 for each municipality in Japan. The socioeconomic deprivation level was derived from multiple socioeconomic characteristics. We classified municipalities into quintiles based on the deprivation level and investigated the association between the deprivation level and the SMR of IHD. Additionally, a Bayesian spatial regression model was used to investigate this association, adjusting for other municipal characteristics.Geographical variation in the SMR of IHD was revealed, and municipalities with high SMRs were spatially clustered. There was a weak negative correlation between the socioeconomic deprivation level and the SMRs (correlation coefficient, -0.057 for men and -0.091 for women). In contrast, the regression analysis showed a statistically significant positive association between deprived areas and the IHD mortality rate, and the relative risks for the most deprived municipalities compared with the least deprived municipalities were 1.184 (95% credible interval [CrI], 1.110 to 1.277) and 1.138 (95% CrI, 1.048 to 1.249) for men and women, respectively.A weak negative correlation between the socioeconomic deprivation level and the SMR was observed in the descriptive analysis, while the regression analysis showed that living in deprived areas was statistically positively associated with the IHD mortality rate.

Background/aim Albumin-bilirubin (ALBI) grade is an indicator of liver dysfunction and is useful for predicting postoperative prognosis of hepatocellular carcinomas. However, the significance of ALBI grade in non-small cell lung carcinoma (NSCLC) has not been elucidated. Patients and methods We analyzed 947 patients with pStage IA-IIIA NSCLC. We divided patients into ALBI grade 1 and grade 2/3 groups. We then analyzed the association of ABLI grade with clinicopathological characteristics and prognosis in NSCLC by using propensity-score matching. Results ALBI grade 2/3 was significantly associated with older age, male sex, advanced pT status, and histological type. Even after propensity-score matching, ALBI grade 2/3 patients had significantly worse cancer-specific survival (CSS) than ALBI grade 1 patients (5-year CSS: 87.3% versus 92.8%; p=0.0247). In multivariate analysis, ALBI grade 2/3 was an independent predictor of CSS (HR=1.9; 95%CI=1.11-3.11; p=0.0177). Conclusion ALBI grade was an independent prognostic factor in surgically resected NSCLC.

Objectives: No studies have examined the association between preterm birth rates and socioeconomic factors in Japan using nationwide statistical data. We analyzed the association between preterm birth rates and household occupation using Vital Statistics data.Methods: Aggregated Vital Statistics data from Japan from 2007 to 2019 were obtained from the Ministry of Health, Labour and Welfare. From the data, the number of births according to year, age group, gestational period, number of pregnancies, and household occupation were used in this study. Crude preterm birth rates and preterm birth rates adjusted by maternal age according to household occupation were calculated for each year. Poisson regression analysis was conducted to evaluate the association between household occupation and preterm births.Results: Unemployed households had the highest preterm birth rate, and households with an occupation classification of “full-time worker 2” (an employee at a large company, civil servant, or board member) had the lowest preterm birth rate throughout each period. Poisson regression analysis revealed that unemployed households were statistically significantly associated with a high preterm birth risk. In contrast, the preterm birth rate adjusted by maternal age remained stable throughout each period regardless of household occupation, and preterm birth rates were found not to have increased in recent years in Japan.Conclusions: Unemployed households had higher preterm birth rates than other household occupations. Further studies investigating the characteristics of unemployed households are needed to identify the reasons for this disparity.

Background and Purpose— Several stroke prognostic scores have been developed to predict clinical outcomes after stroke. This study aimed to develop and validate novel data-driven predictive models for clinical outcomes by referring to previous prognostic scores in patients with acute ischemic stroke in a real-world setting. Methods— We used retrospective data of 4237 patients with acute ischemic stroke who were hospitalized in a single stroke center in Japan between January 2012 and August 2017. We first validated point-based stroke prognostic scores (preadmission comorbidities, level of consciousness, age, and neurological deficit [PLAN] score, ischemic stroke predictive risk score [IScore], and acute stroke registry and analysis of Lausanne [ASTRAL] score in all patients; Houston intraarterial recanalization therapy [HIAT] score, totaled health risks in vascular events [THRIVE] score, and stroke prognostication using age and National Institutes of Health Stroke Scale-100 [SPAN-100] in patients who received reperfusion therapy) in our cohort. We then developed predictive models using all available data by linear regression or decision tree ensembles (random forest and gradient boosting decision tree) and evaluated their area under the receiver operating characteristic curve for clinical outcomes after repeated random splits. Results— The mean (SD) age of the patients was 74.7 (12.9) years and 58.3% were men. Area under the receiver operating characteristic curves (95% CIs) of prognostic scores in our cohort were 0.92 PLAN score (0.90–0.93), 0.86 for IScore (0.85–0.87), 0.85 for ASTRAL score (0.83–0.86), 0.69 for HIAT score (0.62–0.75), 0.70 for THRIVE score (0.64–0.76), and 0.70 for SPAN-100 (0.63–0.76) for poor functional outcomes, and 0.87 for PLAN score (0.85–0.90), 0.88 for IScore (0.86–0.91), and 0.88 ASTRAL score (0.85–0.91) for in-hospital mortality. Internal validation of data-driven prediction models showed that their area under the receiver operating characteristic curves ranged between 0.88 and 0.94 for poor functional outcomes and between 0.84 and 0.88 for in-hospital mortality. Ensemble models of a decision tree tended to outperform linear regression models in predicting poor functional outcomes but not in predicting in-hospital mortality. Conclusions— Stroke prognostic scores perform well in predicting clinical outcomes after stroke. Data-driven models may be an alternative tool for predicting poststroke clinical outcomes in a real-world setting.

Background and aim The prevalence of ulcerative colitis (UC) is increasing in Japan. Validated claims-based definitions are required to investigate the epidemiology of UC and its treatment and disease course in clinical practice. This study aimed to develop a claims-based algorithm for UC in Japan. Methods A committee of epidemiologists, gastroenterologists, and internal medicine physicians developed a claims-based definition for UC, based on diagnostic codes and claims for UC treatments, procedures (cytapheresis), or surgery (post-operative claims). Claims data and medical records for a random sample of 200 cases per site at two large tertiary care academic centers in Japan were used to calculate the positive predictive value (PPV) of the algorithm for three gold standards of diagnosis, defined as physician diagnosis in the medical records, adjudicated cases, or registration in the Japanese Intractable Disease Registry (IDR). Results Overall, 1139 claims-defined UC cases were identified. Among 393 randomly sampled cases (mean age 44; 48% female), 94% had received ≥1 systemic treatment (immunosuppressants, tumor necrosis factor inhibitors, corticosteroids, or antidiarrheals), 4% had cytapheresis, and 2% had post-operative claims. When physician diagnosis was used as a gold standard, PPV was 90.6% (95% confidence interval [CI]: 87.7-93.5). PPV with expert adjudication was also 90.6% (95% CI: 87.7-93.5). PPVs with enrollment in the IDR as gold standard were lower at 41.5% (95% CI: 36.6-46.3) due to incomplete case registration. Conclusions The claims-based algorithm developed for use in Japan is likely to identify UC cases with high PPV for clinical studies using administrative claims databases.

Background Preoperative nutritional status is an important host-related prognostic factor for non-small cell lung carcinoma (NSCLC); however, the significance of postoperative changes in nutritional status remains unclear. This study aimed to elucidate the significance of postoperative decreases in serum albumin (ΔAlb) on the outcomes of early-stage NSCLC. Methods We analyzed 443 training cohort (TC) and 642 validation cohort (VC) patients with pStage IA NSCLC who underwent surgery and did not recur within 1 year. We measured preoperative serum albumin levels (preAlb) and postoperative levels 1 year after surgery (postAlb), and calculated ΔAlb as (preAlb − postAlb)/preAlb × 100%. A cutoff value of 11% for ΔAlb was defined on the basis of the receiver operating characteristic curve for the TC. Results Patients were divided into ΔAlb-Decreased and ΔAlb-Stable groups, including 100 (22.6%) and 343 (77.4%) in the TC, and 58 (9.0%) and 584 (90.1%) in the VC. ΔAlb-Decreased was associated with male sex (p = 0.0490), smoking (p = 0.0156), and non-adenocarcinoma (pp = 0.0169) and non-adenocarcinoma (p = 0.0251) in the VC. Multivariable analysis identified ΔAlb as an independent prognostic factor for disease-free survival (DFS) and overall survival (OS) in both cohorts (VC: DFS, HR = 1.9, 95%CI: 1.10–3.15, p = 0.0197; OS, HR = 2.0, 95%CI: 1.13–3.45, p = 0.0173). Moreover, subgroup analysis demonstrated that the prognostic value of ΔAlb was consistent for age, sex, smoking history, surgical procedure, and histological type. Conclusion We demonstrated a negative impact of postoperative decrease of the serum albumin on the prognosis of patients with early-stage NSCLC. Postoperative changes in nutritional status might be important in NSCLC outcomes.

Differences in low birth weight rate depending on maternal socioeconomic characteristics have not yet been demonstrated using the Vital Statistics in Japan; therefore, this study aimed to investigate these differences according to maternal occupations. “Report of Vital Statistics: Occupational and Industrial Aspects” and the Vital Statistics in Japan were used every five years from 1995 to 2015. Nine types of occupations were compared. The low birth weight rate was calculated according to maternal occupations and year. Also, the standardized low birth weight ratio was obtained by dividing the number of low-birth-weight infants for each maternal occupation by an expected number of low birth weight infants. The standardized low birth weight ratio for manual workers was the highest among all occupations from 2000 to 2015, and it was significantly higher than one throughout the years. The ratio for clerical workers was also significantly higher than one from 1995 to 2010. Whereas, the ratio for farmers was significantly lower than one in most of the years. It was suggested that health guidance and prenatal care are particularly needed for manual workers, and a study investigating the differences in prenatal characteristics among maternal occupations is necessary for finding a reason for disparity.

It is expected that a large amount of data related to diabetes and other chronic diseases will be generated. However, databases constructed without standardized data item sets can be limited in their usefulness. To address this, the Collaborative Committee of Clinical Informatization in Diabetes Mellitus was established in 2011 by the Japan Diabetes Society and Japan Association for Medical Informatics. The committee has developed core item sets and self-management item sets for diabetes mellitus, hypertension, dyslipidemia, and chronic kidney disease in collaboration with the Japanese Society of Hypertension, Japan Atherosclerosis Society, Japanese Society of Nephrology, and Japanese Society of Laboratory Medicine, as well as a mapping table that aligns the self-management item sets with the Japanese standardized codes for laboratory testing. The committee also determined detailed specifications for implementing the four self-management item sets in personal health record applications to facilitate risk stratification, the generation of alerts using information and communications technology systems, the avoidance of data input errors, and the generation of reminders to input the self-management item set data. The approach developed by the committee may be useful for combining databases for various purposes (such as for clinical studies, patient education, and electronic medical record systems) and for facilitating collaboration between personal health record administrators. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13340-019-00389-7) contains supplementary material, which is available to authorized users.

The coronavirus disease (COVID-19) pandemic has widely spread worldwide since 2020. Several countries have imposed lockdown or stay-at-home policies to prevent the infection. Bangladesh experienced a lockdown from March 2020 to May 2020, and internal travel was restricted. Such long and strict confinement may impact women’s health. Herein, we aimed to assess the impact of the COVID-19 pandemic on women’s health by comparing their health status before and during the pandemic. We conducted a prospective longitudinal study in two zones in the Chhaygaon union, rural district Shariatpur, Bangladesh. The study population comprised non-pregnant women aged 15–49 years. We visited the household of all eligible women and invited them for health checkups. The survey staff examined their health status at the checkup camps and conducted questionnaire interviews. In total, 121 non-pregnant women received health checkups both from June 2019 to July 2019 and in October 2020, before and during the COVID-19 pandemic, respectively. Compared with those during the 2019 health checkup, the medians of body mass index, systolic blood pressure, and diastolic blood pressure were significantly higher (22.7 kg/m2 to 23.6 kg/m2; 110.0 mmHg to 111.0 mmHg; and 73.0 mmHg to 75.0 mmHg, respectively, p

This study aimed to show geographical differences in esophageal cancer mortality in Japan and reveal an association of esophageal cancer mortality with municipal socioeconomic deprivation level. Esophageal cancer mortality data in the Vital Statistics from 2013 to 2017 for each municipality and corresponding population data were analyzed. The deprivation level was derived from the municipal socioeconomic variables by principal component analysis. Municipalities were classified into five quintiles based on the deprivation level, and an association between the level and esophageal cancer mortality was evaluated using a Bayesian spatial model. As a result of regression analysis, the relative risk of esophageal cancer mortality tended to become larger as the deprivation level increased irrespective of sex, and the relative risk of esophageal cancer mortality was significantly higher in quintile 5 (most deprived) than quintile 1 (least deprived) among men and women. These results suggest that the deprivation level increases the risk of esophageal cancer mortality in Japan.

The Japan Chronic Kidney Disease (CKD) Database (J-CKD-DB) is a large-scale, nation-wide registry based on electronic health record (EHR) data from participating university hospitals. Using a standardized exchangeable information storage, the J-CKD-DB succeeded to efficiently collect clinical data of CKD patients across hospitals despite their different EHR systems. CKD was defined as dipstick proteinuria ≥1+ and/or estimated glomerular filtration rate 2 base on both out- and inpatient laboratory data. As an initial analysis, we analyzed 39,121 CKD outpatients (median age was 71 years, 54.7% were men, median eGFR was 51.3 mL/min/1.73 m2) and observed that the number of patients with a CKD stage G1, G2, G3a, G3b, G4 and G5 were 1,001 (2.6%), 2,612 (6.7%), 23,333 (59.6%), 8,357 (21.4%), 2,710 (6.9%) and 1,108 (2.8%), respectively. According to the KDIGO risk classification, there were 30.1% and 25.5% of male and female patients with CKD at very high-risk, respectively. As the information from every clinical encounter from those participating hospitals will be continuously updated with an anonymized patient ID, the J-CKD-DB will be a dynamic registry of Japanese CKD patients by expanding and linking with other existing databases and a platform for a number of cross-sectional and prospective analyses to answer important clinical questions in CKD care.

BackgroundThe Japan Chronic Kidney Disease Database (J-CKD-DB) is a nationwide clinical database of patients with chronic kidney disease (CKD) based on electronic health records. The objective of this study was to assess the prevalences of hyperuricemia and electrolyte abnormalities in Japanese patients with CKD.MethodsIn total, 35,508 adult outpatients with estimated glomerular filtration rates of 5-60 ml/min/1.73 m2 in seven university hospitals were included this analysis. The proportions of patients with CKD stages G3b, G4, and G5 were 23.5%, 7.6%, and 3.1%, respectively.ResultsLogistic regression analysis showed that prevalence of hyperuricemia was associated with CKD stages G3b (adjusted odds ratio [95% confidence interval]: 2.12 [1.90-2.37]), G4 (4.57 [3.92-5.32]), and G5 (2.25 [1.80-2.80]). The respective prevalences of hyponatremia, hypercalcemia, hyperphosphatemia, and narrower difference between serum sodium and chloride concentrations were elevated in patients with CKD stages G3b, G4, and G5, compared with those prevalences in patients with CKD stage G3a. The prevalences of hyperkalemia were 8.3% and 11.6% in patients with CKD stages G4 and G5, respectively. In patients with CKD stage G5, the proportions of patients with optimal ranges of serum uric acid, potassium, corrected calcium, and phosphate were 49.6%, 73.5%, 81.9%, and 56.1%, respectively.ConclusionsWe determined the prevalences of hyperuricemia and electrolyte abnormalities in Japanese patients with CKD using data from a nationwide cohort study.

Objective We sought to examine whether the effect of treatment modality and drugs for cerebral vasospasm on clinical outcomes differs between elderly and non-elderly subarachnoid hemorrhage (SAH) patients in Japan. Methods We analyzed the J-ASPECT Study Diagnosis Procedure Combination database (n = 17,343) that underwent clipping or coiling between 2010 and 2014 in 579 hospitals. We stratified patients into two groups according to their age (elderly [≥75 years old], n = 3,885; non-elderly, n = 13,458). We analyzed the effect of treatment modality and anti-vasospasm agents (fasudil hydrochloride, ozagrel sodium, cilostazol, statin, eicosapentaenoic acid [EPA], and edaravone) on in-hospital poor outcomes (mRS 3–6 at discharge) and mortality using multivariable analysis. Results The elderly patients were more likely to be female, have impaired levels of consciousness and comorbidity, and less likely to be treated with clipping and anti-vasospasm agents, except for ozagrel sodium and statin. In-hospital mortality and poor outcomes were higher in the elderly (15.8% vs. 8.5%, 71.7% vs. 36.5%). Coiling was associated with higher mortality (odds ratio 1.43, 95% confidence interval 1.2–1.7) despite a lower proportion of poor outcomes (0.84, 0.75–0.94) in the non-elderly, in contrast to no effect on clinical outcomes in the elderly. A comparable effect of anti-vasospasm agents on mortality was observed between non-elderly and elderly for fasudil hydrochloride (non-elderly: 0.20, 0.17–0.24), statin (0.63, 0.50–0.79), ozagrel sodium (0.72, 0.60–0.86), and cilostazol (0.63, 0.51–0.77). Poor outcomes were inversely associated with fasudil hydrochloride (0.59, 0.51–0.68), statin (0.84, 0.75–0.94), and EPA (0.83, 0.72–0.94) use in the non-elderly. No effect of these agents on poor outcomes was observed in the elderly. Conclusions In contrast to the non-elderly, no effect of treatment modality on clinical outcomes were observed in the elderly. A comparable effect of anti-vasospasm agents was observed on mortality, but not on functional outcomes, between the non-elderly and elderly.

Background and objective Regular health checkups are important for mothers and newborns to detect health problems at an early stage; however, this is often difficult in resource-limited settings. Therefore, the portable health clinic (PHC) for maternal and child health (MCH), a telemedicine health checkup system, was introduced as an intervention study in a rural area in Bangladesh. The aim of this research project was to report findings that we had observed at a mid-point of the intervention period. Methods This was an intervention study conducted in Shariatpur, Bangladesh. The study population included pregnant/parturient women aged 15–49 years and their newborns. With the help of the newly created PHC for MCH, health workers, with a set of sensor devices in an attache case, visited mothers and newborns at home to examine their health status. Their health status was triaged into four categories using a data management application, and in cases of affected or emergent health status, they were placed on remote video consultation with a doctor. Results In total, 94 women were included in the PHC for MCH intervention. The rate of participants who received antenatal care at least four times or postnatal care at least once increased (from 29% to 51%, and from 27% to 78%, respectively) compared with before introducing PHC for MCH. Using the PHC for MCH, we detected health problems in pregnant/parturient women; a relatively high percentage had anemia (45–54%) and/or abnormal pulse rate (20–40%). Moreover, after introducing the PHC for MCH, more than 40% of women who received multiple antenatal care or postnatal care checkups improved their health status. Conclusions The PHC for MCH could be an effective system to improve the health of mothers and newborns by increasing the availability of care. In the future, this system is expected to be used as a primary resource for maternity healthcare, not only in rural areas but also in other social environments.

Osteoporosis has become a worldwide public health problem, in part due to the fact that it increases the risk of fragility hip fractures (FHFs). The epidemiological assessment of FHFs is critical for their prevention; however, datasets for FHFs in Japan remain scarce. This was a multicenter, prospective, observational study in the northern district of Kyushu Island. Inclusion criteria were age > 60 years with a diagnosis of FHF and acquisition of clinical data by an electronic data capture system. Of 1294 registered patients, 1146 enrolled in the study. Nearly one third of patients (31.8%) had a history of previous fragility fractures. The percentage of patients receiving osteoporosis treatment on admission was 21.5%. Almost all patients underwent surgical treatment (99.1%), though fewer than 30% had surgery within 48 h after hospitalization. Bone mineral density (BMD) was evaluated during hospitalization in only 50.4% of patients. The rate of osteoporosis treatment increased from 21.5% on admission to 39.3% during hospitalization. The main reasons that prescribers did not administer osteoporosis treatment during hospitalization were forgetfulness (28.4%) and clinical judgment (13.6%). Age and female ratio were significantly higher in patients with previous FHFs than in those without. There was a significant difference in the rate of osteoporosis treatment or L-spine BMD values in patients with or without previous FHFs on admission. In conclusion, this study confirmed that the evaluation and treatment of osteoporosis and FHFs is still suboptimal in Japan, even in urban districts.

What is known and objective Since its introduction in April 2012, denosumab has been administered to approximately 7,300 patients as of August 2012, and 32 cases of serious hypocalcaemia after denosumab administration, including two deaths, have been reported in Japan. A Dear Healthcare Professional Letter of Rapid Safety Communication ('Blue letter') was released to warn about the risks of hypocalcaemia associated with denosumab. The goal of this study therefore was to measure the impact of regulatory action on denosumab-induced hypocalcaemia in Japan by using an electronic medical information database (MID). Methods We used two different aggregated data sets based on MIDs (data sets one and two). The patients studied were those who were newly prescribed denosumab or zoledronic acid between April 2012 and September 2014. We assessed four indicators: (a) the proportion of patients with calcium supplementation at the initial denosumab treatment, (b) the proportion of patients who underwent a serum calcium test, (c) the average number of serum calcium tests performed and (d) the prevalence of hypocalcaemia. All indices were aggregated by every 3 months. To evaluate the impact of regulatory action, we used difference in difference (DID) analysis. Results and discussion The proportion of patients with calcium supplementation at the initial denosumab treatment increased year by year in both data sets. The average number of serum calcium tests increased year by year in data set two. There was a significant difference in the prevalence of hypocalcaemia in data set two. This suggests that the estimate of impact of the regulatory action may vary according to the database. In DID analysis, however, significant influences of the regulatory action on combination use with a calcium supplement were detected in both data sets. What is new and conclusion There was a significant influence on combination use of denosumab with vitamin D and/or calcium supplement in both data sets. That there was no apparent increase in the prevalence of denosumab-induced hypocalcaemia, suggests that the regulatory action had an impact in the clinical setting studied. Such regulatory actions may play an important role in the promotion of drug safety.

BackgroundThe Japan Chronic Kidney Disease Database (J-CKD-DB) is a nationwide clinical database of patients with chronic kidney disease (CKD) based on electronic health records. The objective of this study was to assess the prevalence of anemia and the utilization rate of erythropoiesis-stimulating agents (ESAs) in Japanese patients with CKD.MethodsIn total, 31,082 adult outpatients with estimated glomerular filtration rates of 5-60 ml/min/1.73 m2 in seven university hospitals were included this analysis. The proportions of patients with CKD stages G3b, G4, and G5 were 23.5%, 7.6%, and 3.1%, respectively.ResultsThe mean (standard deviation) hemoglobin level of male patients was 13.6 (1.9) g/dl, which was significantly higher than the mean hemoglobin level of female patients (12.4 (1.6) g/dl). The mean (standard deviation) hemoglobin levels were 11.4 (2.1) g/dl in patients with CKD stage G4 and 11.2 (1.8) g/dl in patients with CKD stage G5. The prevalences of anemia were 40.1% in patients with CKD stage G4 and 60.3% in patients with CKD stage G5. Logistic regression analysis showed that diagnoses of CKD stage G3b (adjusted odds ratio [95% confidence interval]: 2.32 [2.09-2.58]), G4 (5.50 [4.80-6.31]), and G5 (9.75 [8.13-11.7]) were associated with increased prevalence of anemia. The utilization rates of ESAs were 7.9% in patients with CKD stage G4 and 22.4% in patients with CKD stage G5.ConclusionsWe determined the prevalence of anemia and utilization rate of ESAs in Japanese patients with CKD using data from a nationwide cohort study.

Reproductive, maternal, newborn, and child health (RMNCH) care services could be critical entry points for preventing non-communicable diseases in women and children. In high-income countries, non-communicable diseases screening has been integrated into both the medical and public health systems. To integrate these services in low- and middle-income countries, it is necessary to closely examine its effectiveness and feasibility. In this systematic review, we evaluated the effectiveness of integrating gestational and non-gestational non-communicable diseases interventions and RMNCH care among women and children in low- and middle-income countries. This systematic review included randomized and quasi-randomized controlled trials published from 2000 to 2015. Participants included reproductive-age women, children < 5 years old, and RMNCH care providers. The included interventions comprised packaged care/services that integrated RMNCH services with non-communicable disease care. The outcomes were maternal and/or infant mortality and complications, as well as health care service coverage. We analyzed six studies from 7,949 retrieved articles. Yoga exercise (p < 0.01) and nutritional improvements (p < 0.05) were effective in reducing gestational hypertension and diabetes. Additionally, integrating cervical cancer and RMNCH services was useful for identifying potential cervical cancer cases. Interventions that integrate non-communicable disease care/screening and RMNCH care may positively impact the health of women and children in low- and middle-income countries. However, as primary evidence is scarce, further research on the effectiveness of integrating non-communicable disease prevention and RMNCH care is warranted. (Review Registration: PROSPERO International prospective register of systematic reviews (CRD42015023425).).

In South-East Asia, the maternal and child mortality rate has declined over the past decades; however, it varies among and within the countries in the region, including Cambodia. The continuum of care is an integrated series of care that women and children are required to avail continuously from pregnancy to the child/motherhood period. This study aimed to assess the completion rate of the continuum of care and examine the factors associated with the continuum of care in Ratanakiri, Cambodia. A cross-sectional study was conducted in Ratanakiri. Overall, 377 women were included, and data were collected via face-to-face interviews using a semi-structured questionnaire. Among them, 5.0% completed the continuum of care (antenatal care at least four times, delivery by skilled birth attendant, and postnatal care at least once). Meanwhile, 18.8% did not receive any care during pregnancy, delivery, and after birth. The highest discontinuation rate was at the postnatal care stage (73.6%). Not receiving any perinatal care was associated with neonatal complications at 6 weeks after birth (adjusted odds ratio [AOR]: 3.075; 95% confidence interval [CI]: 1.310–7.215). Furthermore, a long distance to the health center was negatively associated with completion of the continuum of care (AOR: 0.877; 95% CI: 0.791–0.972). This study indicates the need for efforts to reduce the number of women who discontinue from the continuum of care, as well as who do not receive any care to avoid neonatal complications. Since the discontinuation rate was highest at the postnatal care, postnatal care needs to be promoted more through the antenatal care and delivery services. Furthermore, given that long distance to health facilities was a barrier for receiving the care continuously, our findings suggest the need for a village-based health care system that can provide the basic continuum of care in remote areas.

Background We examined the association between pre-admission risk scores and severity on admission and functional outcome in acute ischemic stroke with atrial fibrillation (AF). Methods Between September 2011 and April 2014, we retrospectively extracted consecutive ischemic stroke patients with AF whose pre-admission modified Rankin Scale (mRS) score was 2 or less from our prospective database. Pre-admission CHADS 2 , CHA 2 DS 2 -VASc, and R 2 CHADS 2 scores were calculated in each patient, and their association with the National Institutes of Health Stroke Scale (NIHSS) score on admission or unfavorable outcome (mRS ≥3 at 3 months from the onset) was assessed. Results A total of 344 patients (189 were men; age, 77.7 ± 10.0 years) were included in the analysis. The median pre-admission CHADS 2 , CHA 2 DS 2 -VASc, and R 2 CHADS 2 scores were 2, 4, and 4, respectively. NIHSS score on admission was positively correlated with pre-admission CHADS 2 (ρ = .116, P = .031), CHA 2 DS 2 -VASc (ρ = .166, P = .020), and R 2 CHADS 2 scores (ρ = .106, P = .049). Receiver operating characteristic (ROC) curve analysis revealed that pre-admission CHADS 2 score of 2 or more (sensitivity, 80%; specificity, 45%; area under the ROC curve [AUC], .654), CHA 2 DS 2 -VASc score of 3 or more (sensitivity, 86%; specificity, 44%; AUC, .683), and R 2 CHADS 2 score of 4 or more (sensitivity, 61%; specificity, 62%; AUC, .657) were associated with unfavorable outcome. The pre-admission CHA 2 DS 2 -VASc score was better than the pre-admission CHADS 2 score in estimating unfavorable outcome ( P = .017). In multivariate analysis, cutoffs of these scores, female sex, higher NIHSS score, and internal carotid artery occlusion were associated with unfavorable outcome. Conclusions Pre-admission CHADS 2 , CHA 2 DS 2 -VASc, and R 2 CHADS 2 scores were associated with onset severity and functional outcome in acute ischemic stroke with AF.

Purpose: Fragility hip fractures (FHFs) are associated with a high risk of mortality, but the relative contribution of various factors remains controversial. This study aimed to evaluate predictive factors of mortality at 1 year after discharge in Japan. Methods: A total of 497 patients aged 60 years or older who sustained FHFs during follow-up were included in this study. Expected variables were finally assessed using multivariable Cox proportional hazards models. Results: The 1-year mortality rate was 9.1% (95% confidence interval: 6.8–12.0%, n = 45). Log-rank test revealed that previous fractures ( p = 0.003), Barthel index (BI) at discharge ( p = 0.011), and place-to-discharge ( p = 0.004) were significantly associated with mortality for male patients. Meanwhile, body mass index (BMI; p = 0.023), total Charlson comorbidity index (TCCI; p = 0.005), smoking ( p = 0.007), length of hospital stay (LOS; p = 0.009), and BI ( p = 0.004) were the counterparts for females. By multivariate analyses, previous vertebral fractures (hazard ratio (HR) 3.33; p = 0.044), and BI 2 (HR 2.70, p = 0.023), TCCI ≥5 (HR 2.61, p = 0.032), smoking history (HR 3.59, p = 0.018), LOS Conclusions: Previous vertebral fractures and BI 2, TCCI ≥5, smoking history, LOS

Preterm low-birth-weight infants remain difficult to manage based on adequate laboratory tests. The aim of this study was to establish blood reference intervals (RIs) in those newborns who were admitted to and survived in the neonatal intensive care unit (NICU). A multicenter prospective study was conducted among all infants admitted to 11 affiliated NICUs from 2010 to 2013. The clinical information and laboratory data were registered in a network database designed for this study. The RIs for 26 items were derived using the parametric method after applying the latent abnormal values exclusion method. The influence of birth weight (BW) and gestational age (GA) on the test results was expressed in terms of the standard deviation ratio (SDR), as SDRBW and SDRGA, respectively. A total of 3189 infants were admitted during the study period; 246 were excluded due to a lack of blood sampling data, and 234 were excluded for chromosomal abnormalities (n = 108), congenital anomalies requiring treatment with surgical procedures (n = 76), and death or transfer to another hospital (n = 50). As a result, 2709 infants were enrolled in this study. Both the SDRGA and SDRBW were above 0.4 in the test results for total protein (TP), albumin (ALB), alanine aminotransferase (ALT), and red blood cells (RBC); their values increased in proportion to the BW and GA. We derived 26 blood RIs for infants who were admitted to NICUs. These RIs should help in the performance of proper clinical assessments and research in the field of perinatal-neonatal medicine.

Background: We aimed to determine the predictive factors for excellent or extremely poor functional outcome in patients with first-ever atrial fibrillation (AF)-related cardioembolic stroke. Methods: Retrospective observational study from a database. Patients with AF-related cardioembolic stroke with a premorbid modified Rankin Scale (mRS) score of 0 or 1 and without a previous history of stroke were included. Results: Factors associated with excellent functional outcome (mRS scores of 0 or 1; n = 77; 30.4% of patients) included age >78 years (OR 0.31, 95% CI 0.15-0.61), male sex (OR 2.16, 95% CI 1.04-4.60), absence of hypertension (OR 0.46, 95% CI 0.22-0.94) and initial National Institutes of Health Stroke Scale (NIHSS) score of >9 (OR 0.08, 95% CI 0.03-0.16). Factors associated with extremely poor functional outcome (mRS scores of 5 or 6; n = 63; 24.9%) included age >78 years (OR 3.30, 95% CI 1.54-7.39), initial NIHSS score of >9 (OR 12.38, 95% CI 5.40-32.56), congestive heart failure (OR 4.82, 95% CI 2.00-12.19) and ischemic heart disease (OR 4.02, 95% CI 1.18-14.69). Conclusions: Predictive factors exist to delineate excellent and extremely poor functional outcomes after a first-time stroke associated with AF.

Atrial fibrillation (AF)-related cardioembolic stroke is a serious problem in the aging society. The present study examined the clinical characteristics and outcomes of AF-related cardioembolic stroke in patients aged ≥80 years.Between September 2011 and April 2014, consecutive patients with ischemic stroke and AF were retrospectively extracted from the multicenter database. Clinical characteristics were compared between patients aged ≥80 years and80 years. Multivariate cox proportional hazard models were used to estimate hazard ratios and 95% confidential intervals on 90-day mortality for age of ≥80 years.A total of 253 patients aged ≥80 years (87 men, 86.4 ± 5.0 years) and 196 patients aged80 years (134 men, 70.4 ± 7.1 years) were included. Patients aged ≥80 years were more frequently female, and more likely to have higher premorbid modified Rankin Scale score (mRS), lower body mass index, previous history of stroke, prior antiplatelet therapy, congestive heart failure, and persistent AF. Patients aged ≥80 years had higher initial National Institutes of Health Stroke Scale score and were more likely to have occlusion of the cervicocephalic arteries, but less likely to receive thrombolysis. Patients aged ≥80 years had a higher mRS and mortality after 3 months. Age of ≥80 years was a significant predictor of 90-day mortality after adjustment for sex (hazard ratio 2.20, 95% confidential interval 1.25-4.09), but was no longer significant after further adjustment for other clinical characteristics and stroke severity.In AF-related cardioembolic stroke, patients aged ≥80 years had different clinical characteristics and poorer outcome compared with patients aged80 years. Geriatr Gerontol Int 2017; 17: 708-713.

Background Pure dysarthria (PD) and dysarthria-facial paresis syndrome (DFP) mainly result from lenticulostriate artery territory infarction. PD and DFP are rare clinical entities, often grouped without distinction. The purpose of this study was to examine clinical and radiographic differences between PD and DFP due to unilateral internal capsule and/or corona radiata infarction. Methods Using a database that included consecutive patients with ischemic stroke admitted to the neurological stroke units of three hospitals within 7 days from onset between September 2011 and April 2014, we retrospectively extracted first-ever stroke patient data, who presented with PD or DFP with a single ischemic lesion localized in the internal capsule and/or corona radiata. Patients with weakness, ataxia, sensory deficit, or cortical symptoms were excluded. Ischemic lesion volume was calculated by the ABC/2 method on diffusion-weighted imaging (DWI). DWI images were normalized and superimposed to the template for PD and DFP. We compared patients' characteristics between PD and DFP. Results A total of 2126 patients, including 65 patients (3.1 %) with PD or DFP, were registered. Of these, 13 PD patients and 18 patients with DFP due to unilateral internal capsule and/or corona radiata infarction were included for analysis. Compared with DFP patients, PD patients had longer onset-to-door time (median 37.5 vs. 10.8 h, p = 0.031), shorter vertical length (C component) of ischemic lesions (median 12.0 vs. 18.8 mm, p = 0.007), and smaller ischemic lesion volume (median 285 vs. 828 mm3, p = 0.023). Ischemic lesions causing PD were located more frequently in the left hemisphere than DFP (92 % vs. 56 %, p = 0.045). The superimposed lesion pattern indicated that DFP had lesions more medial and involving posterior portions of the putamen and the caudate body, as well as more of the genu and posterior limb of the internal capsule, than PD. Ninety days after onset, symptoms disappeared in 21 (72 %) out of 29 patients. Conclusions In cerebral infarction limited to the internal capsule and/or corona radiata, PD is derived from smaller and left-sided lesions with delay in diagnosis compared with DFP. The clinical course of those with PD and DFP might be benign.

The residents of several cities and villages in Bangladesh underwent e-health checkups. The distribution of Hb increased from the first hemoglobin (Hb) measurement to the second, and some women recovered from severe anemia. A strong effect was observed in subjects who were prescribed iron supplements. The mean blood pressure improved after the first health examination, and the blood sugar level increased. In countries with shortages of health practitioners and health care providers, e-health examinations and instructions may be useful interventions because they make people health conscious and improve their health status.

Management system of chronic diseases in developing countries and post-disaster situation has been required. Body area network (BAN, IEEE 802.15.6) is expected to be useful in medical field. To evaluate BAN standard, we are implementing BAN in our attaché case type sensor set named "Portable Health Clinic" (PHC), and conducting systematic health checkup in rural and urban areas in Bangladesh. (Methods) In the PHC, we packed weight scale, blood pressure meter, blood sugar meter, body thermometer, pulse oxymeter, as electrical devices, and tape measure (for height, waist and hip), urine test tape (for urine sugar, urine protein and urobilinogen) as no-electrical devices. We provided checkup in rural villages and urban companies in Bangladesh by PHC, and transmitted data by cellphone network to the data center in Dhaka. Individual health condition was categorized into 4 grades, green (healthy), yellow (caution), orange (affected), and red (emergent) by international diagnosis standards of diseases. We provided telemedicine for orange and red, and tele-prescription for hypertensive patients. We are making all sensor devices implemented with BAN. (Results) The health checkup was provided to 5498 subjects until the end of 2012 and categorized green 14%, yellow 66%, orange 17%, and red 3%. The result shows its potency as an effective healthcare system in developing countries and in a chronic phase after disaster. We continue to provide the e-health service for 10K-15 K people each year until March 2014.

Mutation of the insulin receptor gene can compromise the ability of the receptor to mediate insulin action. A homozygous point mutation that results in the substitution of histidine for arginine 252 in the insulin receptor alpha-subunit has now been identified by polymerase chain reaction and single stranded conformational polymorphism analysis in a 20-yr-old Japanese woman with type A syndrome and severe insulin resistance. The proband's consanguineous parents (diabetic mother and normal father) and her sister (impaired glucose tolerance), each of whom showed an exaggerated insulin response to an oral glucose load, were heterozygous for this mutation. Her brother showed a normal insulin response and lacked the mutation, as did 50 healthy Japanese control subjects. The chronic sc administration of insulin-like growth factor I (IGF-I) improved the patient's hyperglycemia and corrected certain metabolic abnormalities over a 9-month period, even though the binding of 125I-labeled IGF-I to her cultured fibroblasts was decreased by 40% relative to that to cells from healthy controls. Studies of the binding of 125I-labeled insulin to the proband's cultured fibroblasts, to COS-I cells transfected with complementary DNA encoding the mutant insulin receptor, and to partially purified mutant receptors revealed that the Arg252--His mutation decreased both cell surface expression and the affinity for insulin for the receptor. These observations suggest that the homozygous Arg252--His mutation is responsible for the type A insulin resistance of the proband, whereas in the heterozygous state, the mutation results in mild insulin resistance indistinguishable from that observed in noninsulin-dependent diabetes mellitus.

Cerebrotendinous xanthomatosis (CTX) is a rare familial disorder characterized by progressive neurological dysfunction, atherosclerosis, and xanthomas with sterol storage in the nervous system, vessels, and tendons. Increased serum cholestanol, derived from intermediates of cholesterol catabolism, may possibly be a major cause of the disease. An examination was made of the cDNA encoding cytochrome P450 sterol 27-hydroxylase (CYP27) in hepatic mitochondria, considered a defective enzyme inducing CTX, in a Japanese housewife afflicted with CTX and her family. The proposita and one of her brothers, who also had CTX symptoms and hypercholestanolemia, were found to be homozygotic, carrying a point mutation in the CYP27 gene at Arg104 (CGG) to Trp104 (TGG). The mutant position has a 100% conserved positive charge in all known vertebrate cytochrome P450s and even in bacterial cytochrome P450cam. The mother of the proposita and another brother were both free of CTX symptoms and were heterozygotic for the mutation, although their plasma cholesterol increased moderately. An increase in plasma cholestanol alone would, thus, not appear to be a direct cause of sterol storage in CTX, while CTX is strongly suggested to be caused by defects in both alleles of the CYP27 gene.

Deceased donor liver transplantation has been an established surgical procedure since the 1960s. More recently, the technique of living donor liver transplantation (LDLT) was introduced, and it is being performed with increasing frequency. However, there is a paucity of information on the clinical outcomes of donor patients. In this study, which was conducted at a single university hospital, the relationship between potentially relevant factors (eg, patient characteristics, preoperative status, and operation characteristics) and postoperative developments in donor patients was examined. We used electronic critical pathways, which are charts of medical process that include favorable states (defined as outcomes) to be achieved during the hospital stay of a patient; predefined outcomes that are not achieved are recorded as variances. With the electronic critical pathway system, objective data about the conditions of patients and relevant clinical processes could be collected readily. Using data from the electronic critical pathways for LDLT donor patients and applying multiple logistic regression analysis, we examined factors that were related to the variance of each outcome measure for postoperative developments. Among the various donor characteristics, the duration of the operation was related to variance in 5 types of health outcomes, age and blood loss volume were related to variance in 2 types of health outcomes, and other characteristics (ie, sex, body surface area, operation urgency, and volume ratio of the remnant liver) were related to variance in 1 type of health outcome. In conclusion, the findings in this study may facilitate improvements in the postoperative status of LDLT donor patients. Further studies that incorporate analogous data from other medical facilities are necessary to verify these findings.

We present the unusual case of a 17-year-old female with insulin-resistant diabetes, acanthosis nigricans, hirsutism, amenorrhea, dental dysplasia and lipopexia on the extremities. She had been diagnosed as having border line diabetes with hyperinsulinemia at age 12 when she was not obese and diabetes mellitus at age 13. On admission, she was obese and had lipopexia only on the extremities. The presence of hyperinsulinemia and poor response to exogenous insulin suggested severe insulin resistance. Insulin binding to transformed B-lymphoblasts derived from her was extremely low compared to the normal control, showing decreased receptor affinity. Her parents and sister exhibited hypersecretion of insulin in response to a 75 g oral glucose tolerance test. Her mother was diabetic, and her father and sister had border line diabetes, whereas her brother had a normal response. These findings support strongly the diagnosis of a type A syndrome with severe insulin resistance associated with lipopexia on the extremities. A genetic defect in the insulin receptor gene may be responsible.

Serum 1,5-anhydro-D-glucitol (AG) levels, which have been reported to decrease specifically in diabetics, were measured in 102 patients with non-insulin-dependent diabetes mellitus (NIDDM). The mean of serum AG levels was 7.9 +/- 0.7 micrograms/ml (mean +/- S.E.). It was found a significant negative correlation between serum AG level and HbA1c or fasting blood sugar level. The decrease in serum AG levels inversely correlated with the extent of glycemic control in the patients with NIDDM. Additionally, the changes of serum AG levels negatively correlated with the changes of HbA1c levels during long-term (2 years) treatment. Furthermore, serum AG levels were compared between the patients with and without diabetic complication such as retinopathy, proteinuria or neuropathy. It was found that each group of the patients with complication had significantly decreased serum AG level compared with the complication free group. On the other hand, however, no differences were found in serum AG levels corrected by HbA1c levels using the linear regression formula between the group of the patients with and without diabetic complication.

The molecular mechanisms by which triglycerides in lipid droplets (LDs) are synthesized, stored, and degraded need to be elucidated.The objectives were to report siblings with neutral lipid storage disease with myopathy (NLSDM) with a novel mutation of adipose triglyceride lipase (ATGL) and determine whether the C-terminal part of ATGL containing the hydrophobic region plays a role in the interaction with LDs.Skin fibroblasts and peripheral blood leukocytes were obtained from NLSDM patients. In vitro experiments were performed with fibroblasts and COS7 cells.Transfection studies were used to assess the effects of various recombinant ATGL proteins on lipase activities and lipid contents. Fluorescence microscopy were used for determination of intracellular distribution of ATGL proteins.The direct sequence of ATGL cDNA reveals that a patient is a homozygote for the 4-bp deletion, leading to a premature stop codon and causes the lack of the C terminus of the protein including the hydrophobic domain. Overexpressed control ATGL in NLSDM fibroblasts was found around the rims of LDs and caused significantly reduced cellular lipid accumulation. In contrast, NLSDM ATGL was homogeneously located in the cytoplasm despite the presence of LDs and had almost no effect on LD degradation despite its similar lipase activity. A series of C-terminal truncated ATGLs without the intact hydrophobic domain failed to localize around and degrade LDs.These findings indicate that the domain including the hydrophobic region of ATGL was essential for association with LDs.

Background: Wild-type p53 is increased during cellular responses to various stresses. Mdm2, which is induced by p53, regulates p53 protein concentrations through the ubiquitin–proteasome pathway. Aim: To investigate whether the Mdm2 mediated ubiquitination of p53 is associated with epithelial cell apoptosis in idiopathic pulmonary fibrosis (IPF). Methods: Immunohistochemistry and western blot analysis were carried out on lung samples obtained by lung biopsy from patients with IPF and non-specific interstitial pneumonia (NSIP). Results: The expression of p53, phosphorylated p53, Mdm2, p21, and Bax was upregulated in epithelial cells from patients with IPF and NSIP compared with normal lung parenchyma. Except for p21, there was a significant increase in the expression of these factors in IPF compared with NSIP. In addition, the number of apoptotic cells and the number of p53 and Bax positive cells was increased compared with controls. p53 conjugated with Mdm2 was decreased in IPF compared with NSIP and controls. Ubiquitinated p53 was increased in both IPF and NSIP compared with controls. Conclusions: Signalling molecules associated with p53 mediated apoptosis may participate in epithelial cell apoptosis, and the attenuation of p53–Mdm2 conjugation and of p53 degradation may be involved in the epithelial cell apoptosis seen in IPF. Augmented epithelial apoptosis in IPF may lead to the poor prognosis compared with NSIP.

Dehydroepiandrosterone (DHEA) and its sulfate derivative (DHEA-S) reportedly have antidiabetic and antiobesity effects. The effect of DHEA on glucose uptake in cultured human fibroblasts was examined. Incubation of cells with supraphysiologic concentrations of DHEA (10(-5) mol/L) foror = 10 hours enhanced 2-deoxyglucose (2-DG) uptake significantly (P.05). Supraphysiologic concentrations of insulin (10(-7) mol/L) increased the sensitivity of glucose uptake to DHEA. Conversely, the sensitivity of glucose uptake to insulin was increased by incubating cells with 10(-6) mol/L DHEA. Both the abundance of transcripts encoding glucose transporter-1 (Glut-1) and the maximal velocity (Vmax) of 2-DG transport were increased in cultured fibroblasts incubated with DHEA. Cultured fibroblasts expressed a specific binding factor with low affinity for [3H]DHEA (maximal number of binding sites, 18,496 sites per cell; Kd, 298 nmol/L). Other androgen hormones exerted a less-marked effect on glucose uptake; DHEA-S had no effect. These results suggested that DHEA increases Glut-1 mRNA through binding to a specific factor in cultured human fibroblasts and thereby stimulates glucose uptake in these cells.

In the present study, we examined the levels of plasma lipids and apolipoproteins in patients with non-insulin dependent diabetes mellitus (NIDDM) with hypercholesterolemia in different apolipoprotein E (apo E) phenotypes. We also examined the influences of apo E polymorphism on the response to pravastatin. The patients were divided into three groups, E4/E3, E3/E3, and E3/E2. There were no differences in the baseline levels of plasma lipids and apolipoproteins, except that the level of triglycerides in E3/E2 heterozygotes was significantly higher than E3/E3 homozygotes. Three months of pravastatin administration significantly reduced plasma levels of total cholesterol and low-density lipoprotein cholesterol in each group to the same degree. We observed a significant reduction of apo B both in the E4/E3 and E3/E3 groups and apo E in the E3/E3 group. Such reduction was not observed in the E3/E2 group. We conclude that pravastatin is a potent drug to correct lipid abnormalities, particularly in NIDDM patients with apo E4/E3 and E3/E3. In the E3/E2 group, its effectiveness may be diminished.