AbstractRecently, patients with out-of-hospital cardiac arrest (OHCA) refractory to conventional resuscitation have started undergoing extracorporeal cardiopulmonary resuscitation (ECPR). However, the mortality rate of these patients remains high. This study aimed to clarify whether a center ECPR volume was associated with the survival rates of adult patients with OHCA resuscitated using ECPR. This was a secondary analysis of a retrospective multicenter registry study, the SAVE-J II study, involving 36 participating institutions in Japan. Centers were divided into three groups according to the tertiles of the annual average number of patients undergoing ECPR: high-volume (≥ 21 sessions per year), medium-volume (11–20 sessions per year), or low-volume (< 11 sessions per year). The primary outcome was survival rate at the time of discharge. Patient characteristics and outcomes were compared among the three groups. Moreover, a multivariable-adjusted logistic regression model was applied to study the impact of center ECPR volume. A total of 1740 patients were included in this study. The center ECPR volume was strongly associated with survival rate at the time of discharge; furthermore, survival rate was best in high-volume compared with medium- and low-volume centers (33.4%, 24.1%, and 26.8%, respectively; P = 0.001). After adjusting for patient characteristics, undergoing ECPR at high-volume centers was associated with an increased likelihood of survival compared to middle- (adjusted odds ratio 0.657; P = 0.003) and low-volume centers (adjusted odds ratio 0.983; P = 0.006). The annual number of ECPR sessions was associated with favorable survival rates and lower complication rates of the ECPR procedure.Clinical trial registration: https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000041577 (unique identifier: UMIN000036490).

AIM:Familial hypercholesterolemia (FH) is an underdiagnosed autosomal dominant genetic disorder characterized by high levels of plasma low-density lipoprotein cholesterol (LDL-C) from birth. This study aimed to assess the genetic identification of FH in children with high LDL-C levels who are identified in a universal pediatric FH screening in Kagawa, Japan.METHOD:In 2018 and 2019, 15,665 children aged 9 or 10 years underwent the universal lipid screening as part of the annual health checkups for the prevention of lifestyle-related diseases in the Kagawa prefecture. After excluding secondary hyper-LDL cholesterolemia at the local medical institutions, 67 children with LDL-C levels of ≥ 140 mg/dL underwent genetic testing to detect FH causative mutations at four designated hospitals.RESULTS:The LDL-C levels of 140 and 180 mg/dL in 15,665 children corresponded to the 96.3 and 99.7 percentile values, respectively. Among 67 children who underwent genetic testing, 41 had FH causative mutations (36 in the LDL-receptor, 4 in proprotein convertase subtilisin/kexin type 9, and 1 in apolipoprotein B). The area under the curve of receiver operating characteristic curve predicting the presence of FH causative mutation by LDL-C level was 0.705, and FH causative mutations were found in all children with LDL-C levels of ≥ 250 mg/dL.CONCLUSION:FH causative mutations were confirmed in almost 60% of the referred children, who were identified through the combination of the lipid universal screening as a part of the health checkup system and the exclusion of secondary hyper-LDL cholesterolemia at the local medical institutions.

Objective: In recent years, natural language processing (NLP) techniques have progressed, and their application in the medical field has been tested. However, the use of NLP to detect symptoms from medical progress notes written in Japanese, remains limited. We aimed to detect 2 gastrointestinal symptoms that interfere with the continuation of chemotherapy—nausea/vomiting and diarrhea—from progress notes using NLP, and then to analyze factors affecting NLP. Materials and methods: In this study, 200 patients were randomly selected from 5277 patients who received intravenous injections of cytotoxic anticancer drugs at Kagawa University Hospital, Japan, between January 2011 and December 2018. We aimed to detect the first occurrence of nausea/vomiting (Group A) and diarrhea (Group B) using NLP. The NLP performance was evaluated by the concordance with a review of the physicians’ progress notes used as the gold standard. Results: Both groups showed high concordance: 83.5% (95% confidence interval [CI] 74.1-90.1) in Group A and 97.7% (95% CI 91.3-99.9) in Group B. However, the concordance was significantly better in Group B ( P = .0027). There were significantly more misdetection cases in Group A than in Group B (15.3% in Group A; 1.2% in Group B, P = .0012) due to negative findings or past history. Conclusion: We detected occurrences of nausea/vomiting and diarrhea accurately using NLP. However, there were more misdetection cases in Group A due to negative findings or past history, which may have been influenced by the physicians’ more frequent documentation of nausea/vomiting.

Abstract Background The prevalence of extracorporeal cardiopulmonary resuscitation (ECPR) in patients with out-of-hospital cardiac arrest (OHCA) has been increasing rapidly worldwide. However, guidelines or clinical studies do not provide sufficient data on ECPR practice. The aim of this study was to provide real-world data on ECPR for patients with OHCA, including details of complications. Methods We did a retrospective database analysis of observational multicenter cohort study in Japan. Adult patients with OHCA of presumed cardiac etiology who received ECPR between 2013 and 2018 were included. The primary outcome was favorable neurological outcome at hospital discharge, defined as a cerebral performance category of 1 or 2. Results A total of 1644 patients with OHCA were included in this study. The patient age was 18–93 years (median: 60 years). Shockable rhythm in the initial cardiac rhythm at the scene was 69.4%. The median estimated low flow time was 55 min (interquartile range: 45–66 min). Favorable neurological outcome at hospital discharge was observed in 14.1% of patients, and the rate of survival to hospital discharge was 27.2%. The proportions of favorable neurological outcome at hospital discharge in terms of shockable rhythm, pulseless electrical activity, and asystole were 16.7%, 9.2%, and 3.9%, respectively. Complications were observed during ECPR in 32.7% of patients, and the most common complication was bleeding, with the rates of cannulation site bleeding and other types of hemorrhage at 16.4% and 8.5%, respectively. Conclusions In this large cohort, data on the ECPR of 1644 patients with OHCA show that the proportion of favorable neurological outcomes at hospital discharge was 14.1%, survival rate at hospital discharge was 27.2%, and complications were observed during ECPR in 32.7%.

Aim: This study aimed to investigate the relationship between transient return of spontaneous circulation (ROSC) before extracorporeal membrane oxygenation (ECMO) initiation and outcomes in out-of-hospital cardiac arrest (OHCA) patients, who were resuscitated with extracorporeal cardiopul-monary resuscitation (ECPR).Methods: This study was a secondary analysis of the SAVE-J II study, which was a retrospective multicentre registry study involving 36 participating institutions in Japan. We classified patients into two groups according to the presence or absence of transient ROSC before ECMO initiation. Tran-sient ROSC was defined as any palpable pulse of >= 1 min before ECMO initiation. The primary outcome was favourable neurological outcomes (cerebral performance categories 1-2).Results: Of 2,157 patients registered in the SAVE-J II study, 1,501 met the study inclusion criteria; 328 (22%) experienced transient ROSC before ECMO initiation. Patients with transient ROSC had better outcomes than those without ROSC (favourable neurological outcome, 26% vs 12%, P < 0.001; survival to hospital discharge, 46% vs 24%, respectively; P < 0.001). A Kaplan-Meier plot showed better survival in the transient ROSC group (log-rank test, P < 0.001). In multiple logistic analyses, transient ROSC was significantly associated with favourable neurological outcomes and survival (favourable neurological outcomes, adjusted odds ratio, 3.34 [95% confidence interval, 2.35-4.73]; survival, adjusted odds ratio, 3.99 [95% confidence interval, 2.95-5.40]).Conclusions: In OHCA patients resuscitated with ECPR, transient ROSC before ECMO initiation was associated with favourable outcomes. Hence, transient ROSC is a predictor of improved outcomes after ECPR.

Abstract Aims Interoception is the sensing function of physiological conditions and is crucial in self-regulation and decision-making. We examined the association of heartbeat tracking task performance, an indicator of interoceptive accuracy, with the degree of improvement in exercise tolerance in patients undergoing home-based cardiac rehabilitation. Methods and results Participants underwent baseline peak oxygen uptake (VO2) measurements and a heartbeat tracking task. The heartbeat tracking task score varies between 0 and 1, with higher scores indicating a better heartbeat perception. After 6 months of home-based exercise training, peak VO2 was measured again, and the percentage change (%Δ peak VO2) relative to the peak VO2 at baseline was calculated. Univariate regression analysis was performed to examine the association between %Δ peak VO2 and the heartbeat tracking task score. Multiple regression analysis was performed to determine the predictors of %Δ peak VO2. Of 120 participants, 100 patients (age 65.9 ± 11.9 years; 86% male) were included. There was a significant positive association between %Δ peak VO2 and the heartbeat tracking task score at baseline (R2 = 0.236, P < 0.001). In multiple regression analysis, the percentage of measured peak VO2 to the predicted value (%predicted peak VO2) (β = −0.248, P = 0.002), exercise adherence (β = 0.364, P < 0.001), and heartbeat tracking task score at baseline (β = 0.372, P < 0.001) were significantly associated with %Δ peak VO2. Conclusions Heartbeat tracking task performance, an indicator of interoceptive accuracy, at baseline is associated with the degree of improvement in exercise tolerance.

When detected early, uterine cervical cancer is one of the most successfully treatable forms of cancer. The diagnostic accuracy of the standard method, the Pap smear test followed by colposcopy, remains unsatisfactory. To improve detection of early-stage cervical cancer, new diagnostic tools for uterine cervical intraepithelial neoplasm (CIN) need to be developed. Magnifying endoscopy with narrow- band imaging (ME-NBI), which allows the visualization of the micro-structure as well as micro-vascularity of the mucosal surface, has excellent diagnostic ability for early gastrointestinal neoplasms. In our previous investigation, ME-NBI was efficacious for diagnosis of CIN. We herein report two notable cases of CIN3 that were diagnosed by ME-NBI that were not detected by colposcopy. These cases illustrate the usefulness of ME-NBI for diagnosis of early-stage uterine cervical neoplasms.

AimSkeletal muscle mass is associated with exercise tolerance in patients with chronic heart failure (CHF). Anthropometric indicators are used to evaluate skeletal muscle mass, as these can be easily assessed in clinical practice. However, the association between anthropometric indicators and exercise tolerance is unclear. This study aimed to investigate the association between anthropometric indicators and exercise tolerance in CHF patients.MethodsWe evaluated 69 patients with CHF. Mid‐arm circumference, mid‐arm muscle circumference (MAMC), calf circumference and body mass index were measured as the anthropometric indicators. Exercise tolerance was evaluated according to the peak oxygen uptake (VO2). Correlation analyses were carried out to determine the association between peak VO2 and anthropometric indicators. Furthermore, univariate and multiple regression analyses were carried out using peak VO2 as the dependent variable, and age, male, left ventricular ejection fraction, angiotensin II receptor blocker or angiotensin converting enzyme inhibitor, diuretics, B‐type natriuretic peptide, estimated glomerular filtration rate, hemoglobin and anthropometric indicators as the independent variables.ResultsThere were significant positive correlations between the peak VO2 and mid‐arm circumference (rs = 0.378, P = 0.001), MAMC (r = 0.634, P < 0.001) and calf circumference (r = 0.292, P = 0.015). In multiple regression analysis, MAMC (β = 0.721, P < 0.001) and estimated glomerular filtration rate (β = 0.279, P = 0.007) were independent factors associated with peak VO2.ConclusionsMAMC is independently associated with peak VO2 in CHF patients. Thus, MAMC could be an indicator of exercise tolerance, which is closely related to the severity and prognosis of CHF. Geriatr Gerontol Int 2021; 21: 411–415.

The current standard for diagnosing cervical intraepithelial neoplasia (CIN) is colposcopy followed by punch biopsy. We have developed flexible magnifying endoscopy with narrow band imaging (ME-NBI) for the diagnosis of CIN. Here, we investigated the feasibility of targeted endoscopic forceps biopsy (E-Bx) under guidance of ME-NBI for the diagnosis of CIN. We prospectively enrolled 32 consecutive patients with confirmed or suspected high-grade CIN undergoing cervical conization. Next to colposcopy, the same patients underwent ME-NBI just before conization. ME-NBI was performed, and 30 E-Bx samples were taken from lesions suspicious for high-grade CIN and 15 from non-suspicious mucosa. We recalled 82 punch biopsy (P-Bx) specimens taken from lesions suspicious for high-grade CIN under colposcopic examination before enrollment. The proportion of sufficient biopsy samples, which had an entire mucosal layer with subepithelial tissue, for the diagnosis of CIN was evaluated by both methods. Performance of targeted E-Bx for the final diagnosis of at least high-grade CIN was calculated. Seventeen P-Bx specimens were unavailable. The proportion of sufficient samples with E-Bx was 84%, which was similar to that with P-Bx (87%) (p = 0.672). The sensitivity, specificity, and accuracy of ME-NBI using E-Bx was 92%, 81%, and 88%, respectively. In conclusion, ME-NBI-guided E-Bx samples were feasible for histological diagnoses of CIN, and further investigation of its diagnostic accuracy is warranted.

Cerebral haemodynamics during the immediate transition period in neonates may differ depending on whether delivery is vaginal or by caesarean section. However, these differences have never been confirmed by near-infrared time-resolved spectroscopy (TRS). Therefore, the purpose of this study was to compare cerebral blood volume (CBV) and cerebral haemoglobin oxygen saturation (ScO2) between healthy term neonates by mode of delivery. Subjects were 31 healthy term neonates who did not require resuscitation. Thirteen neonates were delivered vaginally (VD group) and 18 were delivered by elective caesarean section (CS group). Absolute oxyhaemoglobin, deoxyhaemoglobin, and total haemoglobin concentrations were measured continuously by TRS; oxyHb × 100/totalHb (ScO2) (%) and CBV (mL/100 g brain tissue) were also calculated. Measurements were started as soon as possible after birth, obtained from 1 to 2 min after birth, and continued until 15 min after birth. CBV was significantly higher in the VD group than in the CS group in the 4 min after birth but not thereafter. There were no significant between-group differences in ScO2 and SpO2. These findings indicate that there is a difference in cerebral haemodynamic patterns in the first 4 min after delivery between term neonates by mode of delivery when CBV is monitored by TRS.

Objective To investigate the detection ability of flexible magnifying endoscopy with narrow band imaging (ME-NBI) for cervical intraepithelial neoplasia grade two or worse (CIN2+) compared with colposcopy. Design Multicenter, prospective, non-randomized, paired comparison study. Setting Three Japanese medical centers. Population Japanese women. Methods Eligible patients had positive PAP smear test results, suspicious high-grade CIN in previous colposcopy, or definitive CIN3 diagnosed previously. A gastrointestinal endoscopist examined the cervix using ME-NBI in an endoscopy room and, subsequently, a gynecologist blinded to the ME-NBI findings performed colposcopy in a different room. CIN2+ locations were documented in a scheme immediately after each examination. Punch biopsy samples were obtained from all areas diagnosed as CIN2+ with both methods and from one normal area. The reference standard was the presence of at least one histological diagnosis of CIN2+ among all biopsy specimens. Main outcome measures The primary outcome was the detection sensitivity of patients with CIN2+, comparing ME-NBI and colposcopy. Results We enrolled 88 patients. The detection sensitivity for patients with CIN2+ was not statistically different between the two methods (both: 79%, 95% CI: 66%–88%). For diagnosing CIN2+, ME-NBI tended to show a higher sensitivity than colposcopy (69% vs. 58%, respectively), while its specificity tended to be lower vs. colposcopy (55% vs. 70%, respectively). Patients reported significantly less discomfort and embarrassment with ME-NBI vs. colposcopy. Conclusion ME-NBI showed comparable sensitivity to colposcopy for detecting CIN2+ lesions, and ME-NBI was more patient-acceptable.

Introduction: Familial hypercholesterolemia (FH) is an autosomal hereditary disease found in patients who have elevated low-density lipoprotein cholesterol (LDL-C) from birth. Early detection and treatment of FH during childhood potentially reduces the risk of premature cardiovascular events. In Kagawa prefecture, a unique community health system, involving three steps, has been conducted to prevent lifestyle-related diseases for 10-year-old children. This system includes universal lipid screening, selection by pediatricians, and next-generation sequencing (NGS) of FH-related genes in hospitals. The aim of this study is to compare 3 international guidelines to detect pediatric FH with this unique community health system in Kagawa. Methods: In Kagawa prefecture, the universal lipid screening of approximately 8,000 children at 10 years of age is performed annually, covering over 90% of the target group. After excluding secondary hypercholesterolemia, pediatric clinics introduced children with LDL-C >140mg/dL to 4 designated hospitals to perform NGS. We applied the guidelines of the Dutch Lipid Clinic Network (DLCN), Simon Broome (SB), and the Japanese Atherosclerosis Society (JAS) to children who received NGS in the unique community health system in Kagawa. Results: We performed NGS for 46 children from January 2018 to February 2020 (LDL-C 186.0±50.3 mg/dL; Male/F 27/19) and 26 (57%) had FH genetic mutations (23 LDL-R and 3 PCSK9 mutations). Seventeen children met FH criteria for DLCN (35%), 10 for Simon Broome (22%), and 11 for JAS (24%), respectively. The combination of NGS and either of the 3 guidelines increased the number of children diagnosed as FH up to 31 (67%). Conclusion: International guidelines detected only half of pediatric FH who were diagnosed by the unique community health system in Kagawa. Further investigation will be required to build an effective universal screening system for pediatric FH.

Introduction: Familial hypercholesterolemia (FH) is an autosomal hereditary disease found in patients who have elevated low-density lipoprotein cholesterol (LDL-C) levels from birth. Early detection and treatment of FH during childhood potentially reduces the risk of premature cardiovascular events. In Kagawa prefecture, a unique community health system, involving three steps, has been conducted to prevent lifestyle-related diseases for 10-year-old children. This system includes universal lipid screening, selection by pediatricians, and next-generation sequencing (NGS) of FH-related genes in the hospitals. The aim of this study is to investigate whether this system can be effective in detection of FH. Methods: In Kagawa prefecture, the universal lipid screening of children at 10 years of age is performed annually at school, covering over 90% of the target group. After excluding secondary hypercholesterolemia, pediatric clinics introduced children with LDL-C levels >140 mg/dL to four hospitals to perform NGS to detect FH. Results: In 2017, 279 children (3.7%) showed elevated LDL-C >140mg/dL among 7,647 ones who received the screening. We performed NGS for 46 children after excluding secondary hypercholesterolemia by pediatricians (LDL-C 186.0±50.3 mg/dL; M/F 27/19) and 26 children (57%) had FH genetic mutations (23 LDL-R, 3 PCSK9). The children with LDL-C >180mg/dL are recommended to receive statin therapy according to the guideline from the Japanese Atherosclerosis Society (JAS). Children with LDL-C levels ≥180 mg/dL have 74% of positive genetic mutations, and even those with 140-180 mg/dl LDL-C levels have as much as 44%, respectively (Table). Conclusions: The unique community health system in Kagawa can efficiently detect FH of children. Further investigation will be required for the effective prevention of future atherosclerotic cardiovascular diseases.

Purpose: To examine the potential role of Medical Information Database Network (MID-NET (R)), a newly established Japanese medical information database network, in postmarketing drug safety assessments through the characterization of its advantages and limitations in five pilot studies. Methods: The pilot studies were designed to address three major objectives in postmarketing drug safety assessments, ie, the examination of actual drug utilization, the impact of safety-related regulatory actions, and drug-associated risks. The five studies were conducted on the following topics: (a) utilization of codeine-containing products and its relationship with respiratory depression, (b) impact of a Dear Healthcare Professional letter on hypocalcemia incidence associated with denosumab (Ranmark (R)) use, (c) risk of acute myocardial infarction associated with antidiabetic drug use, (d) risk of glucose metabolism disorders associated with atypical antipsychotic drug use, and (e) prospective monitoring of abnormal laboratory test results during new drug prescriptions. Results: The pilot studies were successfully conducted and demonstrated the value of MID-NET (R) in postmarketing drug safety assessments. In particular, the ability to utilize laboratory test results as objective clinical indicators is a major advantage of this database. Potential limitations include a relatively small sample size and a lack of patient-level data linkages among hospitals. Conclusions: MID-NET (R) was confirmed to be a valuable database for postmarketing drug safety assessments. The use of laboratory test results to define clinical outcomes may allow more objective and accurate analyses to be conducted. These studies furthered our understanding of the characteristics of MID-NET (R), including its advantages and limitations.

Colposcopy, which is a standard modality for diagnosing cervical intraepithelial neoplasia (CIN), can have limited accuracy owing to poor visibility. Flexible magnifying endoscopy with narrow band imaging (ME-NBI) has excellent diagnostic accuracy for early gastrointestinal neoplasms and is expected to be highly useful for CIN diagnosis. This study aimed to determine the characteristic findings and evaluate the diagnostic ability of ME-NBI for lesions ≥ CIN 3.

The aim of this study was to to estimate the sample size for the assumed feasibility study of the computer-assisted input support on a clinica trial. More than 1,500 observations were required for the feasibility study with assumed settings. Further study was required for more efficient research design.

The ratio of urinary coproporphyrin (UCP) I to total urinary coproporphyrin I and III [UCP {I/(I + III)]] serves as a biomarker of the ATP‐binding cassette, sub‐family C, member 2 (ABCC2) function. The aim of this study was to clarify the characteristics of the developmental pattern of UCP [I/(I + III)] in order to estimate ABCC2 function in children, especially in the neonatal period, by measuring it throughout the entirety of childhood.

Dubin-Johnson syndrome (DJS) is an autosomal recessive inherited disorder characterized by conjugated hyperbilirubinemia. Neonatal-onset DJS is rare. It is caused by dysfunction of adenosine triphosphate-binding cassette, sub-family C, member 2 (ABCC2). We found a novel compound heterozygous mutation of DJS-related gene: W709R (T2145C): a missense mutation in exon 17, and R768W (C2302T), a missense mutation in exon 18. Serum diglucuronosyl bilirubin/monoglucuronosyl bilirubin ratio was high. ABCC2 may excrete diglucuronosyl bilirubin preferentially over monoglucuronosyl bilirubin.

Low-frequency oscillations in cerebral blood flow that are suggestive of resting-state brain activity have recently been reported, but no study on the development of resting-state brain activity in preterm infants has been performed. The objective of this study was to measure the cerebral blood flow oscillations, which are assumed to represent brain function in the resting state, in preterm and term infants of the same postconceptional age. The subjects were 9 preterm infants who had reached full term (gestational age (GA): 23-34 weeks, postconceptional age: 37-46 weeks) and 10 term infants (GA: 37-40 weeks, postconceptional age: 37-41 weeks). Their changes in concentration of oxyhemoglobin ([oxyHb]) and deoxyhemoglobin ([deoxyHb]) were measured in the parieto-temporal region during quiet sleep using multi-channel near-infrared spectroscopy, and the power spectral densities (PSD) of the oscillations in the concentrations of these molecules were analyzed and compared. The preterm infants displayed a higher proportion of 0.06-0.10 Hz low frequency oscillations of [oxyHb] and [deoxyHb] than the term infants, and the gestational age and the proportion of low frequency oscillations were inversely correlated. These findings suggest that resting-state cerebral blood flow oscillations differ between preterm and term infants, and that the development of circulatory regulation and nerve activity in preterm infants are influenced by the extrauterine environment.

Background Measured unbound bilirubin concentration is influenced by bilirubin photoisomers. Bilirubin photoisomers are produced even with only a slight light exposure, and clinical samples are inevitably exposed to light. The objective of the study was to evaluate the influence of bilirubin photoisomers on the measurement of unbound bilirubin using serum of jaundiced neonates during blue light phototherapy. Methods Five neonates treated with phototherapy for hyperbilirubinaemia were enrolled. The samples were taken 12 h after initiation of phototherapy. Samples were processed by irradiation with blue light, by indoor ceiling light, by both blue light and indoor ceiling light or shaded. Bilirubin subfractions, total bilirubin and unbound bilirubin were measured. Results Compared with the non-irradiated samples, the (EZ)-cyclobilirubin concentration and (ZE)-bilirubin/(ZZ)-bilirubin ratio significantly increased in the blue light-irradiated samples, the (ZE)-bilirubin/(ZZ)-bilirubin ratio significantly increased in the indoor ceiling light-irradiated samples, and the (EZ)-cyclobilirubin, (EZ)-bilirubin and (ZE)-bilirubin/(ZZ)-bilirubin ratio significantly increased in the samples irradiated with both lights. No change was noted in unbound bilirubin in any group. Conclusions We consider that changes in bilirubin photoisomers induced by light exposure during clinical practice do not influence the measured unbound bilirubin concentration.