Japan Cohort Research Articles

Efficacy and Safety of Etrasimod in Patients with Ulcerative Colitis in Japan: Data from the Phase 3 ELEVATE UC 12 and ELEVATE UC 40 JAPAN Trials

Introduction: Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). Here, we report the primary analysis of a phase 3 trial evaluating the efficacy and safety of etrasimod in patients from Japan with moderately to severely active UC. Methods: Patients from Japan who completed the 12-week ELEVATE UC 12 induction trial could enroll in the 40-week ELEVATE UC 40 JAPAN maintenance trial for a combined 52-week treatment period. Patients in this Japan cohort continued their baseline assigned treatment (etrasimod 2 mg QD or placebo) from ELEVATE UC 12. Efficacy was assessed at week 12 and week 52. Treatment-emergent adverse events (TEAEs) pooled from both trials were assessed up to 52 weeks of exposure. Results: The Japan cohort comprised 32 and 16 patients who received etrasimod and placebo, respectively. A numerically greater proportion of patients who received etrasimod versus placebo achieved clinical remission at week 12 (etrasimod: 14.3%; placebo: 7.1%) and week 52 (etrasimod: 25.0%; placebo: 7.1%); a similar trend was observed for all key secondary efficacy endpoints. TEAEs occurred in 84.4% (27/32) and 62.5% (10/16) of patients who received etrasimod and placebo, respectively. No new safety signals were detected. Conclusion: In these induction and maintenance trials evaluating etrasimod in patients from Japan with UC, numerically higher proportions of patients who received etrasimod versus placebo achieved efficacy endpoints. Efficacy and safety findings were consistent with those from the global ELEVATE UC trial populations.

A causal association between esophageal cancer and the oral microbiome: a Mendelian randomization study based on an Asian population.

Previous studies have suggested a crosstalk between the oral microbiome and esophageal cancer (EC), but the exact relationship is unclear. This study aimed to investigate the causal relationship between changes in the oral microbiome and EC by Mendelian randomization (MR). In the study, bidirectional MR analyses were conducted using genome-wide association study data from the oral microbiomes from the 4D-SZ cohort and EC data from the BioBank Japan cohort. Multiple sensitivity tests, including Cochrane's Q statistic, MR-Egger intercept, and MR-PRESSO, were used to assess and validate the relative stability of the resulting data at various levels. Among the 3,117 samples studied, 73 oral microbiomes were found to be statistically causally associated with EC, 38 of which were considered protective factors. According to species analyses, positive results were concentrated in three phyla: Firmicutes (29 species), Patescibacteria (18 species), and Actinobacteria (9 species). It was also determined that Parvimonas micra, Aggregatibacter, and Clostridia had a negative causal relationship, implying that EC caused a decrease in the counts. Following p-value correction, periodonticum_C, unclassified_mgs_3234, and unclassified_mgs_45 were identified as having a strong evidence-grade causal relationship with EC. There was no strong evidence in the results of the inverse MR analyses of EC to the oral microbiome. The sensitivity analysis confirmed the robustness of the findings. This study discovered a bidirectional causal relationship between the oral microbiome and EC, which may provide new insights into the future use of the microbiome for early screening and probiotic therapy.

Predictive value of insulin resistance surrogates for the development of diabetes in individuals with baseline normoglycemia: findings from two independent cohort studies in China and Japan

BackgroundInsulin resistance (IR) plays a crucial role in the occurrence and progression of diabetes. This study aimed to evaluate and compare the predictive value of four IR surrogates, including the triglycerides glucose (TyG) index, TyG and body mass index (TyG-BMI), triglycerides/high-density lipoprotein cholesterol (TG/HDL-C) ratio, and the metabolic score for IR (MetS-IR) for diabetes in two large cohorts.MethodsA total of 116,661 adult participants from the China Rich Healthcare Group and 15,464 adult participants from the Japanese NAGALA cohort were included in the study. Multivariable Cox proportional hazards models were used to assess the standardized hazard ratio (HR) of the TyG index, TyG-BMI, TG/HDL-C ratio, and MetS-IR directly associated with diabetes. Receiver operating characteristic (ROC) curve and time-dependent ROC curve analysis were performed to evaluate and compare the predictive value of the four IR surrogates for diabetes.ResultsIn the two independent cohorts, the average follow-up time was 3.1 years in the China cohort, with 2681(2.30%) incident cases of diabetes recorded, and 6.13 years in the Japan cohort, with 373 incident cases (2.41%) of diabetes recorded. After adjusting for potential confounding factors, we found that among the four IR surrogates, TyG-BMI and MetS-IR showed stronger associations with diabetes. The stronger associations persisted even after further stratification by age, sex, hypertension, and obese subgroups. In terms of diabetes prediction, based on ROC analysis, TyG-BMI demonstrated the highest predictive accuracy for diabetes in the Chinese population, while both TyG-BMI and MetS-IR showed the highest predictive accuracy in the Japanese population. The results of further subgroup ROC analysis confirmed the robustness of these findings. Furthermore, the time-dependent ROC results indicated that among the four IR surrogates, MetS-IR exhibited the highest accuracy in predicting future diabetes at various time intervals in the Japanese population.ConclusionOur findings suggest that evaluating TyG-BMI and MetS-IR as IR surrogates may be the most useful for predicting diabetes events and assessing the risk of developing diabetes in East Asian populations.

P283 Efficacy and safety of etrasimod in patients with moderately to severely active UC in Japan: Integrated analysis of the phase 3 ELEVATE UC 12 and ELEVATE UC 40 JAPAN trials

Abstract Background Etrasimod is an oral, once-daily (QD), selective sphingosine 1-phosphate (S1P)1,4,5 receptor modulator for the treatment of moderately to severely active ulcerative colitis (UC). We evaluated efficacy and safety among Japanese patients with moderately to severely active UC with contextualisation to the global population. Methods ELEVATE UC 40 JAPAN (NCT04706793) was a multicentre, double-blind, 40-week trial of patients from Japan who completed the 12-week phase 3 ELEVATE UC 12 induction trial (NCT03996369; study design described elsewhere1), resulting in a combined 52-week treatment period. Eligible patients were aged 16–80 years with documented history of inadequate/loss of response or intolerance to ≥1 approved UC therapies. Patients (hereafter the ‘Japan cohort’) continued baseline-assigned treatments from ELEVATE UC 12 (etrasimod 2 mg QD or placebo QD). Efficacy was assessed at Weeks 12 and 52 in patients with a Modified Mayo score (MMS) 5–9; the primary endpoint was clinical remission at Weeks 12 and 52. Pooled treatment-emergent adverse events (TEAEs) from ELEVATE UC 12 and ELEVATE UC 40 JAPAN were assessed up to Week 52. Results The Japan cohort comprised 32 and 16 patients receiving etrasimod and placebo, respectively; 28 and 14 patients with an MMS of 5–9, respectively, were included in the analysis. Baseline demographics were similar between treatment groups. A numerically higher proportion of patients receiving etrasimod vs placebo achieved the primary efficacy endpoint (Figure). Similar patterns were observed for all key secondary endpoints (Table). TEAEs occurred in 84.4% (27/32) and 62.5% (10/16) of patients receiving etrasimod vs placebo, respectively. The safety of etrasimod was similar between Japanese and global UC populations. Conclusion In this Japanese population, numerically higher proportions of patients achieved all efficacy endpoints with etrasimod vs placebo. Efficacy and safety findings were consistent with the global ELEVATE UC population.1 Reference 1. Sandborn WJ et al. Lancet 2023; 401: 1159–1171.

HIV RNA and HCV RNA Levels, and Mortality: The Japan Cohort Study of HIV Patients Infected through Blood Products

Background: Most hemophiliacs living with HIV are co-infected with HCV. In their clinical practice, the long-term effects of anti-HIV and anti-HCV therapies have not been sufficiently investigated. Objective: This study aimed to evaluate changes in HIV RNA and HCV RNA levels and the prognosis in hemophiliacs living with HIV over 24 years in Japan. Methods: We used cohort study data of 578 hemophiliacs living with HIV. We analyzed trends in HIV RNA levels between the fiscal years 1997 and 2008 (first follow-up), and trends in HIV RNA and HCV RNA levels between the fiscal years 2009 and 2020 (second follow-up). Mortality rates by HIV RNA and HCV RNA levels were calculated from 11,207 observed person-years and 194 deaths. Results: The percentage of HIV RNA levels <400 copies/mL rose in the first period of follow-up, and the percentage of HCV RNA-negative rose in the second period of follow-up. The participants with HIV RNA levels <400 copies/mL had a significantly lower mortality rate than the others, with a ratio of 0.46 in the first period. HCV antibody-positive participants who were HCV RNA-negative had a significantly lower mortality rate than those who were HCV RNA-positive, with a ratio of 0.47 in the second period. Conclusion: After the introduction of combination anti-HIV therapy over 24 years in hemophiliacs living with HIV, HIV RNA levels decreased in the first half of this period, resulting in decreased mortality. Additionally, HCV RNA levels decreased in the second half of this study period, resulting in even further decreased mortality.

Medication overload: A closer look at polypharmacy and potentially inappropriate medications among older people in Taiwan and Japan

BackgroundPolypharmacy and potentially inappropriate medications (PIM) are widely recognized as vital quality indicators of pharmacotherapy in older adults. As Taiwan and Japan grapple with the ongoing challenges of population aging, obtaining an accurate understanding of the prevalence of these indicators is crucial for developing effective strategies to optimize pharmacotherapy in older populations. The present study aims to comprehensively evaluate the prevalence of polypharmacy and PIMs in Taiwan and two Japanese cohorts, shedding light on the similarities and differences in prescribing practices across these populations. MethodsThis study employed a cross-sectional design to investigate individuals aged ≥65 years in Taiwan, as well as two Japanese cohorts: Japan Cohort 1 (dispensing data from chain pharmacies; year 2014 and 2019) and Japan Cohort 2 (claims data; year 2017 and 2019). The prescription records of these participants were collected from the national claims database in Taiwan for the years 2014, 2017, and 2019. To identify polypharmacy and hyper-polypharmacy, the study defined the use of 5–9 and 10+ drugs, respectively. Furthermore, the study identified PIMs based on the STOPP-J criteria. Notably, the study further explored the most frequently used PIMs (by categories) in Taiwan. ResultsIn the year 2019, the prevalence of polypharmacy exhibited similar rates in Taiwan (35.4%) and Japan Cohort 2 (33.1%), while surpassing that of Japan Cohort 1 (25.6%). Nonetheless, the incidence of PIMs in Taiwan was the highest (66.5%), exceeding those of the two Japanese cohorts (Cohort 1: 43.7% and Cohort 2: 40.2%) in the same year. Notably, the top three categories of commonly used PIMs in Taiwan comprised non-steroidal anti-inflammatory drugs (NSAIDs), antithrombotic drugs, and benzodiazepines. ConclusionsThis study highlights the varying prevalence of polypharmacy and PIMs between Taiwan and Japan, but emphasizes the need for collaborative efforts towards optimizing pharmacotherapy in older adults.

Patient access to precision medicine: Identifying barriers to biomarker testing in non-small cell lung cancer.

3131 Background: The growing number of targeted therapies approved to treat non-small cell lung cancer (NSCLC) has anchored biomarker testing in clinical practice. Despite general concordance across international guidelines recommending advanced NSCLC patients be tested for oncogenic alterations and immune biomarkers, this is not always the case. This study uses real-world data to explore the barriers to testing across US, Japan, Germany and China. Methods: Ipsos’ Biomarker Testing Rate Monitor is a multi-stakeholder, physician-reported syndicated patient record database. 206 cancer-treating physicians (US=69, Japan=37, Germany=41, China=59) were screened for seniority and caseload and submitted data on 990 NSCLC patients (aggregate) in which biomarker testing had not taken place. Data were collected online January – December 2022. Results: Analyzing physician cited barriers why patients were not tested, choosing not to test at patient’s current stage was highest in the reported US patient cohort, guidelines not calling for testing at this point was more frequently cited in the Japan (27%) and Germany (25%) patient cohort and patient’s co-pay was more frequently cited in the China cohort (34%). The Japan cohort had higher mentions of tissue not being available. Country disparities in the reported metastatic (IIIB-IV) cohort included lack of tissue in Japan (48%) and Germany (25%), deferring testing to a later point in the US (21%) and high co-pay in China (50%). The top cited reasons are shown. Conclusions: Results from this study indicate that, despite guidelines, not all oncology patients receive biomarker testing. While reimbursement structures are difficult to overcome, a concerted effort is needed to raise awareness of the clinical utility of biomarker testing and of the importance of collecting sufficient tissue during the biopsy to allow patients the chance of benefiting from precision medicines. Similarly, calls for earlier testing would support efforts that ensure the best available treatment options are available to patients throughout their journey. Further investigation using comparator cohort is warranted. [Table: see text]

Association between serum iron markers, iron supplementation and cardiovascular morbidity in pre-dialysis chronic kidney disease.

The optimal range of serum iron markers and usefulness of iron supplementation are uncertain in patients with pre-dialysis chronic kidney disease (CKD). We investigated the association between serum iron indices and risk of cardiovascular disease (CVD) events and the effectiveness of iron supplementation using Chronic Kidney Disease Japan Cohort data. We included 1416 patients ages 20-75years with pre-dialysis CKD. The tested exposures were serum transferrin saturation and serum ferritin levels and the outcome measures were any cardiovascular event. Fine-Gray subdistribution hazard models were used to examine the association between serum iron indices and time to events. The multivariable fractional polynomial interaction approach was used to evaluate whether serum iron indices were effect modifiers of the association between iron supplementation and cardiovascular events. The overall incidence rate of CVD events for a median of 4.12years was 26.7 events/1000 person-years. Patients with serum transferrin saturation <20% demonstrated an increased risk of CVD [subdistribution hazard ratio (HR) 2.13] and congestive heart failure (subdistribution HR 2.42). The magnitude of reduction in CVD risk with iron supplementation was greater in patients with lower transferrin saturations (P=.042). Maintaining transferrin saturation >20% and adequate iron supplementation may effectively reduce the risk of CVD events in patients with pre-dialysis CKD.

Processing speed test: Results from a Japanese normative sample of healthy participants compared with a US normative sample

BackgroundThe Processing Speed Test (PST), a validated iPad®-based cognitive screening test for MS, has been applied to the cognitive assessment of Japanese MS patients using US normative data. MethodsTo develop PST normative data from Japanese healthy volunteers and compare the PST score distribution between Japanese and US healthy volunteers, 254 healthy Japanese-speaking volunteers were enrolled and stratified by age (20–65 years). Potential participants with a Mini-Mental State Examination score < 27 were excluded. PST raw scores (total correct) were from the Japan cohort and compared with age-restricted US normative data and propensity score-matched data created by matching sex, age, and educational level from a published study of 428 healthy participants. PST score distributions and standardized z-scores were compared using t-test and Kolmogorov–Smirnov test statistics. ResultsThe mean age of the Japan cohort was 44.1 years. The PST scores of Japanese volunteers were significantly different from those of the age-restricted (mean ± SD 61.8 ± 10.1 vs 53.7 ± 10.8; p < 0.001) and the propensity score-matched US cohort (62.1 ± 10.1 vs 53.3 ± 10.6; p < 0.001). ConclusionRegression analyses centered on US normative data could underestimate disease severity in Japanese MS patients, suggesting that separate normative data should be considered for each population sample.

Excess risk of cardiovascular events in patients in the United States vs. Japan with chronic kidney disease is mediated mainly by left ventricular structure and function

While patients receiving dialysis therapy in the United States are more likely to develop cardiovascular disease (CVD) than those in Japan, direct comparisons of patients with predialysis chronic kidney disease (CKD) are rare. To study this, we compared various outcomes in patients with predialysis CKD using data from the Chronic Renal Insufficiency Cohort (CRIC) and CKD Japan Cohort (CKD-JAC) studies and determined mediators of any differences. Candidate mediators included left ventricular (LV) indices assessed by echocardiography. Among 3125 CRIC and 1097 CKD-JAC participants, the mean LV mass index (LVMI) and ejection fraction (EF) were 55.7 and 46.6 g/m2 and 54% and 65%, respectively (both significant). The difference in body mass index (32 and 24 kg/m2, respectively) largely accounted for the differences in LVMI and C-reactive protein levels across cohorts. Low EF and high LVMI were significantly associated with subsequent CVD in both cohorts. During a median follow-up of five years, CRIC participants were at higher risk for CVD (adjusted hazard ratio [95% confidence interval]: 3.66 [2.74-4.89]) and death (4.69 [3.05-7.19]). A three-fold higher C-reactive protein concentration and higher phosphate levels in the United States cohort were moderately strong mediators of the differences in CVD. However, echocardiographic parameters were stronger mediators than these laboratory measures. LVMI, EF and their combination mediated the observed difference in CVD (27%, 50%, and 57%, respectively) and congestive heart failure (33%, 62%, and 70%, respectively). Thus, higher LV mass and lower EF, even in the normal range, were found to be predictive of CVD in CKD.

Biopsy-proven CKD etiology and outcomes: the Chronic Kidney Disease Japan Cohort (CKD-JAC) study.

The Kidney Disease: Improving Global Outcomes guidelines advocate the cause-glomerular filtration rate (GFR)-albuminuria (CGA) classification for predicting outcomes. However, there is a dearth of data supporting the use of the cause of chronic kidney disease. This study aimed to address how to incorporate a prior biopsy-proven diagnosis in outcome prediction. We examined the association of biopsy-proven kidney disease diagnoses with kidney failure with replacement therapy (KFRT) and all-cause death before KFRT in patients with various biopsy-proven diagnoses (n=778, analysis A) and patients with diabetes mellitus labeled with biopsy-proven diabetic nephropathy (DN), other biopsy-proven diseases and no biopsy (n=1117, analysis B). In analysis A, adding biopsy-proven diagnoses to the GFR-albuminuria (GA) classification improved the prediction of 8-year incidence of KFRT and all-cause death significantly regarding integrated discrimination improvement and net reclassification index. Fine-Gray (FG) models with KFRT as a competing event showed significantly higher subdistribution hazard ratios (SHRs) for all-cause death in nephrosclerosis {4.12 [95% confidence interval (CI) 1.11-15.2)], focal segmental glomerulosclerosis [3.77 (95% CI 1.09-13.1)]} and membranous nephropathy (MN) [2.91 (95% CI 1.02-8.30)] than in immunoglobulin A nephropathy (IgAN), while the Cox model failed to show significant associations. Crescentic glomerulonephritis had the highest risk of all-cause death [SHR 5.90 (95% CI 2.05-17.0)]. MN had a significantly lower risk of KFRT than IgAN [SHR 0.45 (95% CI 0.24-0.84)]. In analysis B, other biopsy-proven diseases had a lower risk of KFRT than biopsy-proven DN in the FG model, with death as a competing event [SHR 0.62 (95% CI 0.39-0.97)]. The CGA classification is of greater value in predicting outcomes than the GA classification.

Conversations and Reactions Around Severe Hypoglycemia (CRASH): Japan Results From a Global Survey of People with T1DM or Insulin-Treated T2DM and Caregivers.

AimsThe CRASH study examined severe hypoglycemia (SH) experiences among people with diabetes (PWD) and caregivers across eight countries. Here we report findings from the Japan cohort, with references to data from the United Kingdom (UK) cohort.Materials and MethodsAdults with type 1 (T1DM) or insulin-treated type 2 diabetes mellitus (T2DM) and caregivers (not necessarily related) were recruited from online patient panels. Participants who had experienced at least one SH event in the past 3 years were eligible for study inclusion. Participants completed an online survey regarding their experience with SH, its treatment, and actions during and after an event.ResultsOf the 9367 PWD and caregivers from the online patient panels, 8475 participants were ineligible and a total of 53 Japanese participants (35 T1DM, 9 T2DM, 9 caregivers) completed the survey. Most SH incidents occurred at home and were unattended by a healthcare provider. For T1DM, 29% of Japan PWD and 13% of the UK PWD called an ambulance during an SH event; of these, 90% (Japan) and 50% (UK) were transported to hospital. Glucagon use was low (3% Japan and 10% UK for T1DM). Japanese respondents reported emotional impacts of SH, including feeling scared (86% T1DM, 56% T2DM), unprepared (63% T1DM, 78% T2DM), and helpless (60% T1DM, 33% T2DM). Despite the emotional burden, most PWD did not immediately discuss their SH event with a healthcare provider, with the majority (75% T1DM, 71% T2DM) waiting until their next doctor’s appointment.ConclusionConversations around SH between healthcare providers and PWD appear to be insufficient in Japan. An emotional burden of SH was reported by PWD and caregivers. Education regarding the prevention of SH and available treatment options may reduce SH events and improve treatment preparation, while alleviating PWD concerns.

The impact of a change in infant BCG vaccination policy on adolescent TB incidence rates: A South African population-level cohort study

ObjectiveSouth Africa’s infant Bacille Calmette Guerin (BCG) vaccine policy changed from percutaneous (PC) BCG Japan to intradermal (ID) BCG Denmark in 2000. This study investigated whether this change in infant BCG vaccination had any durable impact on TB incidence rates (IR) into adolescence. MethodsThe Cape Town electronic TB register provided data (from 2008 to 2018) on HIV-negative TB patients born in 1991–1999 (BCG Japan cohort) and 2001–2008 (BCG Denmark cohort). Statistics South Africa provided population estimates. Annual TB IR per 100,000 population were calculated stratified by age, gender and birth year. Interrupted time series analysis with a segmented Poisson regression and birth cohort analyses were used to compare incidence between the BCG cohorts and trends over time. FindingsTB IR increased throughout adolescence, with 17-year-olds having 7.34 [95% confidence interval (CI), 6.48–8.32] times higher TB IR than 10-year-olds. Females had 1.22 [95% CI 1.17–1.27] higher IR than males. Overall, adolescents who received ID BCG Denmark had a lower TB IR compared to PC BCG Japan (rate ratio 0.86, [95% CI 0.80–0.94]). No interaction between BCG and age, nor BCG and gender were identified. Birth cohort analyses showed the increase in TB IR started around one year earlier in females than in males. ConclusionThe change in infant BCG policy was associated with a modest decrease in TB incidence in 10- to 17-year-old HIV-negative adolescents. However, TB incidence rapidly increased with age in both adolescent cohorts and remained high despite BCG vaccination at birth.

Low-intensity cigarette smoking and mortality risks: a pooled analysis of prospective cohort studies in Japan.

Increasing proportions of smokers in Japan smoke <10 cigarettes per day (CPD). Yet, the health risks of low-intensity smoking in Asia are poorly understood. We performed a pooled analysis of 410 294 adults from nine population-based prospective cohort studies participating in the Japan Cohort Consortium. Cigarette-use data were collected at each study baseline in 1983-1994. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality were calculated using multivariable-adjusted Cox regression by CPD among current smokers and by age at cessation among former smokers, with never smokers as the referent group. Pooled HRs and CIs were computed using a random-effect model. The smoking prevalence was 54.5% in men and 7.4% in women. About 15.5% of male and 50.4% of female current smokers smoked 1-10 CPD (low-intensity). Both male and female low-intensity smokers had higher all-cause mortality risks than never smokers. Risks were further higher with increasing CPD in a dose-response manner. HRs (95% CIs) were 1.27 (0.97-1.66), 1.45 (1.33-1.59) and 1.49 (1.38-1.62) for 1-2, 3-5 and 6-10 CPD, respectively, in men; 1.28 (1.01-1.62), 1.49 (1.34-1.66) and 1.68 (1.55-1.81) for 1-2, 3-5 and 6-10 CPD, respectively, in women. Similar associations were observed for smoking-related causes of death. Among former low-intensity smokers, younger age at cessation was associated with lower mortality risk. Smoking very low amounts was associated with increased mortality risks in Japan. All smokers should quit, even if they smoke very few CPD.

Combined landscape of single-nucleotide variants and copy number alterations in clonal hematopoiesis.

Clonal hematopoiesis (CH) in apparently healthy individuals is implicated in the development of hematological malignancies (HM) and cardiovascular diseases. Previous studies of CH analyzed either single-nucleotide variants and indels (SNVs/indels) or copy number alterations (CNAs), but not both. Here, using a combination of targeted sequencing of 23 CH-related genes and array-based CNA detection of blood-derived DNA, we have delineated the landscape of CH-related SNVs/indels and CNAs in 11,234 individuals without HM from the BioBank Japan cohort, including 672 individuals with subsequent HM development, and studied the effects of these somatic alterations on mortality from HM and cardiovascular disease, as well as on hematological and cardiovascular phenotypes. The total number of both types of CH-related lesions and their clone size positively correlated with blood count abnormalities and mortality from HM. CH-related SNVs/indels and CNAs exhibited statistically significant co-occurrence in the same individuals. In particular, co-occurrence of SNVs/indels and CNAs affecting DNMT3A, TET2, JAK2 and TP53 resulted in biallelic alterations of these genes and was associated with higher HM mortality. Co-occurrence of SNVs/indels and CNAs also modulated risks for cardiovascular mortality. These findings highlight the importance of detecting both SNVs/indels and CNAs in the evaluation of CH.

Cardiovascular disease history and β-blocker prescription patterns among Japanese and American patients with CKD: a cross-sectional study of the CRIC and CKD-JAC studies.

Cardiovascular disease (CVD) is a major complication in individuals with chronic kidney disease (CKD). In Japan, the incidence of CVD among persons with CKD is lower than that in the United States. Although various classes of antihypertensive agents are prescribed to prevent CVD, the proportion varies between the United States and Japan. Until now, few studies have compared clinical practices and CVD prevalence among patients with CKD in the United States vs. Japan. In this study, we performed a cross-sectional comparison of the prevalence of CVD and the prescription of β-blockers at study entry to the Chronic Kidney Disease Japan Cohort (CKD-JAC) Study and the Chronic Renal Insufficiency Cohort (CRIC) Study. The mean patient age was 58.2 and 60.3 years, the mean estimated glomerular filtration rate (eGFR) was 42.8 and 28.9 (mL/min/1.73 m2), and the median urinary albumin:creatinine ratio was 51.9 and 485.9 (mg/g) among 3939 participants in the CRIC Study and 2966 participants in the CKD-JAC Study, respectively. The prevalence of any CVD according to a self-report (CRIC Study) was 33%, while that according to a medical chart review (CKD-JAC Study) was 24%. These findings were consistent across eGFR levels. Prescriptions for β-blockers differed between the CRIC and CKD-JAC Studies (49% and 20%, respectively). The odds ratios for the association of any history of CVD and β-blocker prescription were 3.0 [2.6-3.5] in the CRIC Study and 2.0 [1.6-2.5] in the CKD-JAC Study (P < 0.001 for the interaction). In conclusion, the prevalence of CVD and treatment with β-blockers were higher in the CRIC Study across eGFR levels.

All-cause and cardiovascular disease mortality in underweight patients with diabetic nephropathy: BioBank Japan cohort.

We aimed to determine mortality risk in underweight patients with diabetic nephropathy for microalbuminuria or macroalbuminuria. We analyzed mortality and death‐cause data from BioBank Japan, with baseline years 2003–2007. We analyzed mortality rates from all causes and ischemic heart disease, according to body mass index (<18.5, 18.5–21.9, 22–24.9 and ≥25 kg/m2). The mean (standard deviation) of patient age, body mass index, and glycated hemoglobin at enrollment was 61.6 years (11.7 years), 25.0 kg/m2 (4.4 kg/m2) and 7.7% (1.5%), respectively. Hazard ratios of all‐cause and ischemic heart disease mortality were highest (1.79 [P = 0.0001] and 2.95 [P = 0.027], respectively) in patients with body mass index <18.5 kg/m2, as compared with body mass index 22–24.9 kg/m2. All‐cause mortality risk for body mass index <18.5 kg/m2 was similar to that for current smokers (hazard ratio 1.70, P < 0.0001). Underweight could be a predictor of mortality risk in patients with diabetic nephropathy for microalbuminuria or macroalbuminuria.

Asthma and Chronic Obstructive Pulmonary Disease Overlap According to the Japanese Respiratory Society Diagnostic Criteria: The Prospective, Observational ACO Japan Cohort Study.

IntroductionPatients with asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) present with chronic respiratory symptoms with features of both asthma and COPD. New ACO diagnostic criteria (2018) were suggested by the Japanese Respiratory Society (JRS). This prospective, multicenter, observational cohort study was conducted to investigate the proportion of patients who meet the JRS ACO diagnostic criteria among COPD patients in clinical practice.MethodsThis 2-year ongoing study enrolled consecutive outpatients aged ≥ 40 years with COPD who visited one of 27 Japanese centers at which the medical examinations/tests required for ACO diagnosis were routinely conducted. At registration, the proportion of ACO or non-ACO patients was determined using the JRS diagnostic criteria, and the characteristics of the two groups were compared using analysis of variance and chi-square test.ResultsOf 708 COPD patients analyzed at registration, 396 (55.9%) had the data necessary for ACO diagnosis to be conducted, and 312 (44.1%) were lacking these data. Of the 396 patients who had the data necessary for ACO diagnosis, 101 (25.5%) met the diagnostic criteria for ACO, and 295 (74.5%) did not (non-ACO patients). ACO patients were younger, had a greater rate of asthma based on a physician’s diagnosis, and used more medications, including inhaled corticosteroids (p < 0.05), compared with non-ACO patients.ConclusionsWe have determined the proportion of patients with the data necessary to diagnose ACO using the JRS criteria, and the proportion of these who met the ACO criteria among the COPD population at the time of registration. Patients, including those lacking necessary examination/test data at registration, will continue to undergo follow-up to explore changes in their testing and ACO diagnostic status over time. Analyses of study data over 2 years will provide relevant information on the ACO symptoms, clinical course, and real-world treatment patterns.Trial registrationClinicalTrials.gov identifier, NCT03577795.Electronic supplementary materialThe online version of this article (10.1007/s12325-020-01573-x) contains supplementary material, which is available to authorized users.

Ultra-mutated colorectal cancer patients with POLE driver mutations exhibit distinct clinical patterns.

POLE mutations, which lead to an ultramutated phenotype in colorectal cancer (CRC), have been reported as a promising marker in immunotherapy. We performed sequencing of CRC cases in Zhejiang University (ZJU) and extracted obtainable data from recently published results, including The Cancer Genome Atlas (TCGA), Japanese studies and clinical trials, to present clinical patterns of POLE driver‐mutated CRC and reveal its heterogeneity. The rate of somatic POLE driver mutations has been reported as 2.60% (ZJU cohort), 1.50% (TCGA cohort), 1.00% (Japan cohort), and 1.00% (Lancet cohort). POLE driver mutations show a clearly increased mutation burden (mean TMB: 217.98 mut/Mb in ZJU; 203.13 mut/Mb in TCGA). Based on pooled data, more than 70.00% of patients with POLE driver mutations were diagnosed before they were 55 years old and at an early disease stage (Stage 0–II >70.00%), and more than 70.00% were male. Among Asian patients, 68.40% developed POLE driver mutations in the left‐side colon, whereas 64.00% of non‐Asian patients developed them in the right‐side colon (p < 0.01). The top three amino acid changes due to POLE driver mutations are P286R, V411L, and S459F. Investigators and physicians should ascertain the heterogeneity and clinical patterns of POLE driver mutations to be better equipped to design clinical trials and analyze the data.

Cause-specific mortality rates in patients with diabetes according to comorbid macro- and microvascular complications: BioBank Japan Cohort.

ObjectiveThis study aimed to compare cause‐specific mortality rates in patients with type 2 diabetes with and without various vascular complications.MethodsIn Japanese hospitals, we followed up 30 834 patients with a mean age of 64.4 (standard deviation [SD]: 11.1) years. Patients were followed up from 2003 to 2007 for a median of 7.5 (interquartile range: 6.1‐9.7) years. We calculated cause‐specific mortality rates (number of deaths/1000 person‐years) and confounder‐adjusted hazard ratios in patients with macrovascular disease and in those with diabetic nephropathy, neuropathy and retinopathy, allowing for overlap of complications.ResultsAll‐cause mortality rate was highest (51.4) in the nephropathy group, followed by the macrovascular disease group (45.2), the neuropathy group (39.5), the retinopathy group (38.7) and the nonvascular complication group (18.1). In the nephropathy group, morality rates of ischaemic heart, cerebrovascular, and infectious diseases and cancer were also highest among the groups. However, the cancer mortality rate was similar among the vascular complication groups. Relative to the nonvascular complication group, covariate‐adjusted hazard ratios for ischaemic heart and cerebrovascular disease mortality were triple to quadruple in the macro‐ and microvascular complication groups. All‐cause mortality rates rose exponentially according to age.ConclusionHighest risks of all‐cause, cancer, and ischaemic heart, infectious, and cerebrovascular disease mortality were determined in Japanese patients with diabetic nephropathy. Although cancer is the primary cause of death in Japanese patients with diabetes, cancer mortality rates are similar among those with and without vascular complications.