Early initiation of oral beta-blocker improves long-term survival in patients with acute myocardial infarction who underwent primary percutaneous coronary intervention.

BACKGROUND: The optimal timing for the initiation of oral beta-blockers after acute myocardial infarction (MI) remains unclear within the context of current primary percutaneous coronary intervention (PCI) practice. METHODS: This retrospective cohort study included 412 consecutive patients admitted with a diagnosis of acute MI between January 2007 and August 2016 who underwent successful primary PCI and were given oral carvedilol during hospitalization. Early and late carvedilol groups were based on initiation within the first 24 h or after. Propensity score matching (1:1) incorporating 21 baseline characteristics yielded 47 matched pairs. Timing of carvedilol initiation was evaluated in relation to patient outcomes including time to all-cause mortality, using Kaplan-Meier estimates on the matched cohort and additional confirmation in multivariable regression analysis among the entire cohort. RESULTS: Median follow-up period was 828 days. All-cause death occurred in 14 patients (4.7%) and 18 patients (15.8%) of the early and late carvedilol groups. After propensity score matching, initiation of oral carvedilol within the first 24 h was associated with lower all-cause mortality (6.4% vs. 25.5%, hazard ratio 0.28, 95% confidence interval 0.06 - 0.89, p = 0.036), as well as lower in-hospital mortality (0 vs. 14.9%, p = 0.018). CONCLUSIONS: These results provide evidence that initiation of oral carvedilol within the first 24 h reduces the risk of long-term mortality, in acute MI patients who underwent primary PCI, supporting current guidelines recommendation.

Acquired copy number amplification at the MYC enhancer in human B-precursor acute lymphoblastic leukemia cell lines.

Our study highlights the discovery of recurrent copy number alterations in noncoding regions, specifically blood enhancer cluster (BENC-CNA), in B-precursor acute lymphoblastic leukemia (BCP-ALL) cell lines. We demonstrate that BENC-CNA acts as a super-enhancer, driving MYC expression and possibly contributing to the immortalization and proliferative advantage of BCP-ALL cells in vitro.

Barriers to conservative kidney management for Japanese healthcare professionals involved in the treatment of end-stage renal disease.

BACKGROUND: Conservative kidney management (CKM) is a treatment alternative for patients with end-stage kidney disease (ESKD). Despite the increasing population of elderly dialysis patients in Japan, CKM is not as readily available compared with that in North America and Europe. Therefore, it is important to clarify the barriers to CKM in Japan. METHODS: We interviewed 11 experts to explore their beliefs and issues regarding CKM. Based on the interviews, we categorized the CKM barriers into eight categories and created a 24-item questionnaire. A questionnaire survey was conducted among 112 medical professionals involved in ESKD management. To investigate the types of barriers, we conducted an exploratory factor analysis using the questionnaire results. RESULTS: Responses were obtained from 53 (47.3%) of 112 subjects (18 doctors, 29 nurses, 6 clinical engineers), with 94.3% considering CKM as a treatment option for ESKD. Factor analysis categorized the questions into the following: (1) Lack of palliative care experience, (2) Ethics and responsibility, (3) Patient's problem, (4) Dialog with patients and families, and (5) Lack of support system. Regarding barriers to CKM, "lack of experience in palliative care" and "lack of support system" scored the highest, and "ethics and responsibility" scored the lowest. CONCLUSIONS: Barriers to CKM may be classified into five factors, with "lack of experience in palliative care" and "lack of support system" being the important barriers to overcome. Additionally, most healthcare professionals consider CKM as the fourth option for renal replacement therapy.

Folate Metabolism and Risk of Childhood Acute Lymphoblastic Leukemia: A Genetic Pathway Analysis from the Childhood Cancer and Leukemia International Consortium.

BACKGROUND: Prenatal folate supplementation has been consistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Previous germline genetic studies examining the one carbon (folate) metabolism pathway were limited in sample size, scope, and population diversity and led to inconclusive results. METHODS: We evaluated whether ∼2,900 single-nucleotide polymorphisms (SNP) within 46 candidate genes involved in the folate metabolism pathway influence the risk of childhood ALL, using genome-wide data from nine case-control studies in the Childhood Cancer and Leukemia International Consortium (n = 9,058 cases including 4,510 children of European ancestry, 3,018 Latinx, and 1,406 Asians, and 92,364 controls). Each study followed a standardized protocol for quality control and imputation of genome-wide data and summary statistics were meta-analyzed for all children combined and by major ancestry group using METAL software. RESULTS: None of the selected SNPs reached statistical significance, overall and for major ancestry groups (using adjusted Bonferroni P-value of 5 × 10-6 and less-stringent P-value of 3.5 × 10-5 accounting for the number of "independent" SNPs). None of the 10 top (nonsignificant) SNPs and corresponding genes overlapped across ancestry groups. CONCLUSIONS: This large meta-analysis of original data does not reveal associations between many common genetic variants in the folate metabolism pathway and childhood ALL in various ancestry groups. IMPACT: Genetic variants in the folate pathway alone do not appear to substantially influence childhood acute lymphoblastic leukemia risk. Other mechanisms such as gene-folate interaction, DNA methylation, or maternal genetic effects may explain the observed associations with self-reported prenatal folate intake.

Effect of postpartum depression and role of infant feeding practices on relative weight of child at 1 and 3 years of age.

BACKGROUND: Childhood obesity has increased and is considered one of the most serious public health challenges of the 21st century globally, and may be exacerbated by postpartum depression (PPD). The purpose of this study was to examine the association between PPD at 1st and 6th month postpartum, infant feeding practices, and body mass index (BMI) z-score of the child at one and three years of age. METHODS: This study used data from an ongoing prospective maternal-child birth cohort performed at the National Center for Child Health and Development (NCCHD) in suburban Tokyo, Japan with the period of recruitment from May 13, 2010 to November 28, 2013. Out of 2,309 total number of mothers, 1,279 mother-child dyads were assessed in the study. We performed multivariable linear regression analysis to examine the association between PPD and child's BMI z-score stratified by the child's age at 1 year and 3 years of age. RESULTS: The prevalence of PPD at 1 month postpartum (17%) was found to be higher than at 6 months (12%). In multivariable linear regression analysis we observed that children at 3 years who had mothers with PPD at 6 months had, on average, a BMI z-score 0.25 higher than children of mothers who did not have PPD at 6 months (ß coefficient 0.25, 95% CI [0.04 to 0.46], p value 0.02), holding all other covariates constant. Also, initiation of weaning food when child is at six months of age was associated with higher BMI z-score of the child at 3 years after adjusting for all covariates (ß coefficient = 0.18, 95% CI [0.03 to 0.34], p-value < 0.05). CONCLUSION: The significant association between PPD at 6 months and child's BMI z-score at 3 years of age, in conjunction with birth trends and high prevalence of PPD, can add to the body of evidence that there is need for multiple assessment across the first postpartum year to rule out PPD as early screening and early interventions may benefit both maternal health and child development outcomes. These findings can indicate the need for establishing support systems for care-giving activities for mothers with PPD.

Rare TCF3 variants associated with pediatric B cell acute lymphoblastic leukemia.

Germline genetic variants influence development of pediatric B cell acute lymphoblastic leukemia (B-ALL). Genome-wide association studies (GWAS) have identified several pediatric B-ALL susceptibility loci. IKZF1 and PAX5, transcription factors involved in B cell development, have been reported as susceptibility genes for B-ALL development. Therefore, we hypothesized that rare variants of genes involved in B cell development would be candidate susceptibility loci for pediatric B-ALL. Thus, we sequenced TCF3, a key transcription factor gene involving in B cell development. Saliva DNA from 527 pediatric patients with pediatric B-ALL in remission who were registered with the Tokyo Children's Cancer Study Group (TCCSG) were examined. As a TCF3 gene-based evaluation, the numbers of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were compared with those in cancer-free individuals using data in public databases. As a TCF3 single-variant evaluation, the frequencies of rare deleterious germline TCF3 sequence variants in patients with pediatric B-ALL were also compared with those in control data. TCF3 gene-based analysis revealed significant associations between rare deleterious variants and pediatric B-ALL development. In addition, TCF3 variant-based analysis showed particularly strong association between variant rs372168347 (three in 521 TCCSG and three in the 15780 gnomAD whole genome analysis cohort, p = 0.0006) and pediatric B-ALL development. TCF3 variants are known to influence B cell maturation and may increase the risk of preleukemic clone emergence.

Relationship between dietary fiber to carbohydrate ratio and mortality risk in US adults: NHANES 2007-2018.

BACKGROUND AND AIMS: The evidence is inconsistent regarding associations between relative proportions of macronutrient intake and disease risk, potentially due to limitations in accounting for differential effects of simple sugars and dietary fiber, grouped as "carbohydrates." We examined the association between the ratio of dietary fiber to carbohydrate intake (FC-R) measure, the relative proportion of macronutrients, and mortality risk in a nationally representative sample of U.S. adults. METHODS AND RESULTS: We performed a retrospective cohort study, using data from the National Health and Nutrition Examination Survey in 2007-2018 and linked mortality data among 15,789 adults aged ≥40 years. We categorized participants into three groups by tertile cutpoints of FC-R, and by percent calories from carbohydrate (<45 %, 45-65 %, and >65 %). Cox proportional hazards regression was performed to estimate hazard ratios (HR) for all-cause mortality with 95 % confidence intervals (95 % CI), adjusting for demographic, health history, and lifestyle factors. During a median follow-up of 6.5 years, 2044 deaths were observed. Compared to the low FC-R group, higher FC-R groups showed a reduction in mortality risk after adjusting for potential confounders (high vs low: HR = 0.71, 95 % CI = 0.62-0.83). The association persisted in those consuming 45-65 % and >65 % of calories from carbohydrate, while the association was attenuated in those with <45 % of calories from carbohydrate. Percent calories from carbohydrate showed no association with mortality risk. CONCLUSION: Higher FC-R was associated with lower all-cause mortality risk in adults with moderate to high levels of percent calories from carbohydrate. Mechanisms of the association warrant further investigation.

Evaluating the association between caesarean delivery and weight status in early childhood in a Japanese birth cohort study.

To examine whether the prevailing hypothesis of an association between caesarean section (CS) delivery method and increased weight status in early childhood is observed in Japanese. A total of 1277 mother-infant pairs from a prospective hospital-based mother-infant birth cohort that recruited women in their first trimester from May 2010 to November 2013 were included. We assessed the relationship between delivery method and weight status of delivered children at 1, 3 and 6 years of age. In total, 366 children (28.7%) were delivered by CS. Delivery by CS was not associated with body mass index (BMI) z-score (≥ 75 percentile) at age 1 year, (odds ratio (OR) 0.97, 95% confidence interval (CI) 0.69-1.36), 3 years (OR 0.98, 95% CI 0.67-1.42), and 6 years (OR 0.71, 95% CI 0.45-1.12), and also showed no association with low weight status (< 25th percentile). Supplemental evaluations addressing the influence of preterm births, pre-pregnancy BMI, emergency CS, and modification by breastfeeding were consistent with the primary analyses. Our findings do not support the hypothesis that children born by CS are at risk of being overweight in childhood among the Japanese population.

Effect of Medical Fee Schedule Revisions on the Expansion of Nutritional Support Teams in Japan: An Interrupted Time-series Analysis.

Introduction: In 2018, the fee schedule for nutrition support teams (NSTs) in Japanese hospitals was changed. The change was intended to encourage more hospitals to establish NSTs, and this study aims to investigate whether this change had the desired effect. Specifically, we will look at the proportion of hospitals with NSTs before and after the 2018 revision to see if there was a significant increase in the number of hospitals with NSTs. Methods: The study analyzed administrative data from 10 Japanese prefectures dating from June 2015 to September 2021 using an interrupted time-series design. The analysis focused on all acute care hospitals within these prefectures and measured the percentage of hospitals with NSTs. Subgroup analyses were conducted based on hospital size and functions. In April 2018, the intervention, a fee schedule revision, was implemented. Results: We analyzed 1,471 acute care hospitals. Immediately after the intervention, the percentage of hospitals with NSTs increased by 4.59% (95% CI = 3.92%, 5.26%) and by 0.66% (95% CI = 0.57%, 0.75%) quarterly thereafter. We observed a marked increase in NST formation among large-sized (20.9%), medium-sized (28.0%), and highly acute care hospitals (hospitals with emergency medical care centers and intensive care units, 22.3% and 23.6%, respectively). We also noted a moderate increase among hospitals with convalescent rehabilitation units (10.1%) and a modest increase among small-sized hospitals (6.9%). Conclusions: Relaxation of the NST fee requirement increased the proportion of hospitals with NSTs in Japan, especially among larger and highly acute care hospitals.

Epidemiology of adverse events attributed to airway management in paediatric anaesthesia: protocol for the prospective, multicentre, registry-based, cross-sectional Japan Pediatric Difficult Airway in Anesthesia study (J-PEDIA).

INTRODUCTION: Failure to secure an airway during general anaesthesia is a major cause of adverse events (AEs) in children. The safety of paediatric anaesthesia may be improved by identifying the incidence of AEs and their attributed risk factors. The aim of the current study is to obtain real-world data on the incidence of adverse peri-intubation events and assess their association with patient characteristics (including the prevalence of difficult airway features) and choice of anaesthesia management. These data can be used to develop a targeted education programme for anaesthesia providers towards quality improvement activities. METHODS AND ANALYSIS: This prospective, multicentre, registry-based, cross-sectional study will be conducted in four tertiary care hospitals in Japan from June 2022 to May 2025. Children <18 years of age undergoing surgical and/or diagnostic test procedures under general anaesthesia or sedation by anaesthesiologists will be enrolled in this study. Data on patient characteristics, discipline of anaesthesia providers and methodology of airway management will be collected through a standardised verification system. The exposure of interest is the presence of difficult airway features defined based on the craniofacial appearance. The primary and secondary endpoints are all AEs associated with airway management and reduced peripheral capillary oxygen saturation values. Potential confounders are related to the failure to secure the airway and variations in the anaesthesia providers' levels, adjusted using hierarchical multivariable regression models with mixed effects. The sample size was calculated to be approximately 16 000 assuming a 99% probability of obtaining a 95% Wilson CI with±0.3% of the half-width for the 2.0% of the incidence of critical AEs. ETHICS AND DISSEMINATION: The study protocol was approved by the Institutional Review Board at Aichi Children's Health and Medical Center (2021051). The results will be reported in a peer-reviewed journal and a relevant academic conference. TRIAL REGISTRATION NUMBER: UMIN000047351.

Age at surgery and native liver survival in biliary atresia: a systematic review and meta-analysis.

Biliary atresia (BA) is a childhood rare disease of the liver and bile ducts that requires prompt surgical intervention. Age at surgery is an important prognostic factor; however, controversy exists with regard to the benefit of early Kasai procedure (KP). We aimed to conduct a systematic review and meta-analysis to examine the relationship between the age at KP and native liver survival (NLS) of BA patients. We performed the electronic database search using Pubmed, EMBASE, Cochrane, and Ichushi Web and included all relevant studies published from 1968 up to May 3, 2022. Studies that examined the timing of KP at ages 30, 45, 60, 75, 90, 120, and/or 150 days were included. The outcome measures of interest were NLS rates at 5, 10, 15, 20, and 30 years post-KP and the hazard ratio or risk ratio for NLS. The quality assessment was used using the ROBINS-I tool. Among 1653 potentially eligible studies, nine articles met the inclusion criteria for the meta-analysis. Meta-analysis for hazard ratios revealed that there was a significantly faster time to liver transplantation in the group of patients who had KP at later timing as compared with earlier KP (HR = 2.12, 95% CI 1.51-2.97). The risk ratio comparing KP ≤ 30 days and KP ≥ 31 days on native liver survival was 1.22 (95% CI 1.13-1.31). The sensitivity analysis showed that comparing KP ≤ 30 days and KP 31-60 days, the risk ratio was 1.13, 95% CI 1.04-1.22.  Conclusion: Our meta-analysis showed the importance of early diagnosis and surgical interventions ideally before 30 days of life in infants with BA on native liver survival on 5, 10, and 20 years. Therefore, effective newborn screening of BA targeting KP ≤ 30 days is needed to ensure prompt diagnosis of affected infants. What is Known: • Age at surgery is an important prognostic factor. What is New: • Our study performed an updated systematic review and meta-analysis to examine the relationship between age at Kasai procedure and native liver survival in patients with BA.

Understanding the Psychological Well-being of Patients With Locked-in Syndrome: A Scoping Review.

Locked-in syndrome (LiS) is a neurological disorder caused by lesions affecting the ventral pons and midbrain and is characterized by loss of physical function, but with perceived consciousness intact. Despite severely limited function, previous studies have shown the quality of life (QoL) in patients to be more positive than naturally assumed by caregivers and relatives. The present review aims to synthesize the broad scientific literature focused on the psychological well-being of LiS patients. A scoping review was performed to synthesize the available evidence on the psychological well-being of LiS patients. Eligible studies included those that target individuals with LiS as the study population, evaluated psychological well-being, and explored the factors related to it. We extracted study population details, type of QoL methods, method of communication, and primary findings from the studies. We summarized the findings categorized into health-related QoL (HRQoL), global QoL, and other tools for assessing psychological status. Across the 13 eligible studies, we observed that patients with LiS had reasonable or similar psychological well-being as the standard based on HRQoL and global QoL assessment. Caregivers and healthcare professionals seem to rate the psychological QoL of LiS patients lower than patients themselves. Studies showed evidence that the longer duration of LiS is a factor that positively affects QoL, and augmentative and alternative communication tools and recovery of speech production showed positive effects as well. Studies reported a range of 27% to 68% of patients experiencing thoughts of suicide and euthanasia. The evidence shows that LiS patients had reasonable psychological well-being. There appear to be differences between patients' assessed well-being and the negative perceptions by caregivers. Response shift and adaptation to disease by patients are considered potential reasons. A sufficient moratorium period and provision of information to support patients' QoL and appropriate decision-making seems necessary.

Utility of a modified Controlling Nutritional Status score in mortality risk assessment of patients on hemodialysis.

PURPOSE: Malnutrition is common among hemodialysis patients. A nutritional index may be important for their prognosis prediction. We examined the use of a modified version of the Controlling Nutritional Status (CONUT) score as a predictor of mortality in hemodialysis patients and investigated whether statin use modified the association. METHODS: We conducted a retrospective cohort study in 1130 adults (mean age 67.7 years, 35.0% women) on maintenance hemodialysis at four outpatient dialysis clinics in Japan. The exposure of interest was modified CONUT scores calculated by one-time data of serum albumin and total cholesterol at baseline, or mean data of these measures using multiple blood test results. The primary outcome was all-cause mortality. We examined the association between modified CONUT groups (low-risk, middle-risk, and high-risk) and mortality using multivariate Cox proportional hazard regression and logistic regression models in overall patients and by statin use. RESULTS: During a median follow-up of 6.6 years, 525 (46.5%) patients died. Analysis using both one-time and mean data showed increased mortality risk in the high-risk modified CONUT score group as compared to the low-risk group (mean data: HR 2.52, 95% CI 1.96, 3.24); when stratified by statin use, the effect appeared stronger among users (mean data: HR 5.84, 95% CI 2.98, 11.44). Strong predictive ability was observed, particularly for mortality risk at 5 year follow-up using mean data (AUC = 0.842). CONCLUSION: Our results suggest that the modified CONUT score may be useful in helping clinicians quickly identify hemodialysis patients with poorer prognosis who may benefit from close monitoring and interventions.

Association between fetal sex and pregnancy outcomes among women with twin pregnancies: a multicenter cross-sectional study.

PURPOSE: To examine the frequency and to what extent fetal sex is associated with pregnancy outcomes among twin pregnancies, stratified by chorionicity. METHODS: This registry-based multicenter cross-sectional study was conducted using the Japan Society of Obstetrics and Gynecology perinatal database between 2007 and 2016. The sample population was restricted to women with twin pregnancies. The main pregnancy-related outcomes included preterm birth, very preterm birth, extremely preterm birth, preeclampsia, twin-to-twin transfusion syndrome (TTTS), and selective intrauterine growth restriction (s-IUGR). Birth weight, small for gestational age (SGA), and fetal death were also investigated. RESULTS: The primary analysis was performed based on 37,953 women, including 23,804 women with dichorionic diamniotic (DD) twins and 14,149 women with monochorionic diamniotic (MD) twins. Women with male/male DD twins had a significantly higher risk of preterm birth (adjusted risk ratio [aRR]: 1.07, 95% confidence interval [CI]: 1.03-1.10) and a lower risk of preeclampsia (aRR: 0.74, 95% CI: 0.62-0.88) than women with female/female DD twins. Women with male/male MD twins also had a significantly higher risk of preterm birth (aRR: 1.06, 95% CI: 1.04-1.09) than women with female/female MD twins. Risks of preeclampsia, TTTS, and s-IUGR did not differ by sex among MD pregnancies. Male SGA risk was significantly higher among male/male twins than among male/female DD twins. Among MD twins, risks of SGA and fetal death were significantly higher in male/male fetuses. CONCLUSIONS: This study demonstrated significant associations between fetal sex and several pregnancy outcomes in twin pregnancies, some of which differed by chorionicity.

Cost-Effectiveness Analysis of Universal Screening for Biliary Atresia in Japan.

OBJECTIVE: To evaluate the cost-effectiveness of universal newborn screening using stool color card or direct bilirubin (DB) testing when comparing with no screening for biliary atresia in Japanese setting. STUDY DESIGN: A decision analytic Markov microsimulation model was developed to evaluate the universal screening for biliary atresia. Our screening strategies included stool color card, DB, or no screening. The outcomes of all newborns undergoing 3 strategies were simulated to analyze event-free life-years defined as liver transplant-free survival, costs, and incremental cost-effectiveness ratio (ICER) over a 25-year period with an annual discount rate of 2% applied for both costs and outcomes. A 1-way sensitivity analysis was performed to assess the uncertainty. RESULTS: There were 941 000 newborn infants in our cohort and 114 cases of biliary atresia. The base case analysis showed that the stool color card strategy was $14 927 337 higher than no screening with an increase in 44 more event-free life-years gained, resulting in an ICER of $339 258 per event-free life-year gained. The DB screening strategy compared with stool color card was $138 994 060 higher with an increase in 271 more event-free life-years gained and an ICER of $512 893 per event-free life-year gained. The DB screening strategy compared with no screening resulted in an ICER of $488 639 per event-free life-year gained. The DB screening resulted in 16 fewer liver transplants than stool color card and stool color card had 2 fewer liver transplants than no screening. CONCLUSIONS: Universal screening for biliary atresia could be cost-effective depending on the willingness to pay thresholds for health benefits.

Prominence of NUDT15 genetic variation associated with 6-mercaptopurine tolerance in a genome-wide association study of Japanese children with acute lymphoblastic leukaemia.

Inherited genetic variation is associated with 6-mercaptopurine (6-MP) dose reduction and frequent toxicities induced by 6-MP. However, the tolerable dose for 6-MP is not fully predicted by the known variation in NUDT15 and TPMT among Asian children with acute lymphoblastic leukaemia (ALL). We performed a genome-wide association study (GWAS) related to 6-MP dose among Japanese children with ALL. This GWAS comprised 224 patients previously enrolled in Tokyo Children's Cancer Study Group clinical studies with replication attempted in 55 patients. Genome-wide single nucleotide polymorphism (SNP) genotypes were evaluated for association with average 6-MP dose during the initial 168 days of maintenance therapy. Possible associations were observed across five gene-coding regions, among which only variants at 13q14.2 were significant and replicated genome-wide (rs116855232, NUDT15, ß = -10.99, p = 3.7 × 10-13 ). Notable findings were observed for variants in AFF3 (rs75364948, p = 2.05 × 10-6 ) and CHST11 (rs1148407, p = 2.09 × 10-6 ), but were not replicated possibly due to small numbers. A previously reported candidate SNP in MTHFR was associated with higher average 6-MP dose (rs1801133, p = 0.045), and FOLH1 (rs12574928) was associated in an evaluation of candidate regions (padjust  = 0.013). This study provides strong evidence that rs116855232 in NUDT15 is the genetic factor predominantly associated with 6-MP tolerable dose in children in Japan.

Public attitudes in the clinical application of genome editing on human embryos in Japan: a cross-sectional survey across multiple stakeholders.

Recent advances in genome editing technology are accompanied by increasing public expectations on its potential clinical application, but there are still scientific, ethical, and social considerations that require resolution. In Japan, discussions pertaining to the clinical use of genome editing in human embryos are underway. However, understanding of the public's sentiment and attitude towards this technology is limited which is important to help guide the debate for prioritizing policies and regulatory necessities. Thus, we conducted a cross-sectional study and administered an online questionnaire across three stakeholder groups: the general public, patients and their families, and health care providers. We received responses from a total of 3,511 individuals, and the attitudes were summarized and compared among the stakeholders. Based on the distribution of responses, health care providers tended to be cautious and reluctant about the clinical use of genome editing, while patients and families appeared supportive and positive. The majority of the participants were against the use of genome editing for enhancement purposes. Participants expressed the view that clinical use may be acceptable when genome editing is the fundamental treatment, the risks are negligible, and the safety of the technology is demonstrated in human embryos. Our findings suggest differences in attitudes toward the clinical use of genome editing across stakeholder groups. Taking into account the diversity of the public's awareness and incorporating the opinion of the population is important. Further information dissemination and educational efforts are needed to support the formation of the public's opinion.

A phase I/IIa trial of atorvastatin in Japanese patients with acute Kawasaki disease with coronary artery aneurysm: Study protocol of a multicenter, single-arm, open-label trial.

BACKGROUND: Kawasaki disease (KD) is a systemic vasculitis complicated with coronary artery abnormalities (CAAs). Intravenous immunoglobulin reduces the occurrence of CAAs, but significant number of KD patients with CAAs still exists. Thus, new approaches to prevent and attenuate CAAs are warranted. Atorvastatin has been shown to promote endothelial cell homeostasis and suppress vascular inflammation and has received enthusiasm as a potentially new candidate treatment for KD. In the United States, a phase I/IIa dose-escalation study of atorvastatin in KD patients with CAAs demonstrated the safety and pharmacokinetic data of atorvastatin. However, due to the uncertainty in the application of these results to other populations, we aim to examine the tolerability and generate pharmacokinetics data in Japanese KD patients. METHODS: This is a multicenter, single-arm, open-label, phase I/IIa study of atorvastatin in acute KD patients with CAAs in Japan. A minimum of 9 and a maximum of 18 KD patients (2 years-17 years old) will be recruited for a 3 + 3 dose-escalation study of a 6-week course of atorvastatin (0.125-0.5 mg/kg/day). The primary outcome will be safety of atorvastatin. The secondary outcomes will be pharmacokinetics of atorvastatin, activity of atorvastatin and echocardiographic assessment of CAAs. The activity of atorvastatin will include assessment of C-reactive protein or high sensitivity C-reactive protein and white blood cell levels. DISCUSSION: This study will provide evidence of the safety, tolerability, and pharmacokinetics of atorvastatin in Japanese KD patients and may lead new standard therapy for acute-phase KD associated with CAA complications. TRIAL REGISTRATION: Japan Registry of Clinical Trials (JRCTs031180057). Registered December 19, 2018, https://jrct.niph.go.jp/en-latest-detail/jRCTs031180057.

Direct health care cost of treatment and medication of biliary atresia patients using the National Database of Health Insurance Claims and Specific Health Checkups.

BACKGROUND: Treatment of biliary atresia (BA), which typically requires an initial surgical intervention called the Kasai procedure (KP) and possible liver transplant (LT) afterwards, is quite resource-intensive and would affect patients and families for a lifetime; yet a comprehensive view of the economic burden has not been reported. We estimated direct health care costs from the public payer perspective using the National Database of Health Insurance Claims and Specific Health Checkups of Japan. METHODS: Children newly diagnosed at ages 0 days to 4 years between April 2010 and September 2019 were identified. Costs of treatment were estimated for six phases of care: prediagnosis, KP and inpatient hospitalization, follow-up after KP, pre-transplant checkup, LT and inpatient hospitalization, and follow-up after LT. RESULTS: Mean total prediagnosis medical cost was $6847 (USD) and KP and inpatient hospitalization was $42,157 per year. Follow-up after KP was $15,499, and pre-transplant checkup after KP was $36,015 per year. Mean cost for LT and inpatient hospitalization was $105,334, and follow-up after liver transplant was $25,459 per year. CONCLUSIONS: Treatment of BA requires extensive medical resource consumption. The use of the comprehensive national database allowed us to estimate the costs which will be useful for health service planning and cost-effectiveness analysis.