DNA Damage in Rheumatoid Arthritis: An Age-Dependent Increase in the Lipid Peroxidation-Derived DNA Adduct, Heptanone-Etheno-2′-Deoxycytidine

Objective. To evaluate what types of DNA damages are detected in rheumatoid arthritis (RA). Methods. The DNA adducts such as 8-oxo-hydroxy-7,8-dihydro-2′-deoxyguanosine (8-oxo-dG), 1,N6-etheno-2′-deoxyadenosine (εdA), and heptanone-etheno-2′-deoxycytidine (HεdC) in genomic DNAs, derived from whole blood cells from 46 RA patients and 31 healthy controls, were analyzed by high-performance liquid chromatography tandem mass spectrometry, and their levels in RA patients and controls were compared. In addition, correlation between DNA adducts and clinical parameters of RA was analyzed. Results. Compared with controls, the levels of HεdC in RA were significantly higher (P<0.0001) and age dependent (r = 0.43, P < 0.01), while there was no significant difference in 8-oxo-dG and εdA accumulation between RA patients and controls. HεdC levels correlated well with the number of swollen joints (r = 0.57, P < 0.0001) and weakly with the number of tender joints (r = 0.26, P = 0.08) of RA patients, while they did not show a significant association with serological markers such as C-reactive protein and matrix metalloproteinase 3. Conclusion. These findings indicate that HεdC may have some influence on the development of RA and/or its complications

Clinical impact of acute hyperglycemia on development of diabetes mellitus in non-diabetic patients with acute myocardial infarction

AbstractBackgroundAcute hyperglycemia (AH) after the onset of acute myocardial infarction (AMI) is a manifestation of transient abnormal glucose metabolism that may reflect AMI severity, and thus be a predictor of poor prognosis. However, it remains unknown whether AH may predict development of de novo diabetes mellitus (dn-DM) in non-diabetic AMI patients.Methods and resultsAmong AMI patients registered in the Osaka Acute Coronary Insufficiency Study between 1998 and 2007, we investigated hospital records of 1493 patients who had an admission glycated hemoglobin A1c (HbA1c) level of ≤6.0% and were subjected to glycometabolic profiling after survival discharge. dn-DM was defined as initiation of diabetic medication or documentation of an HbA1c level of ≥6.5% during the 5-year follow-up period. AH, defined as an admission serum glucose level of ≥200mg/dl, was observed in 133 (8.9%) patients. dn-DM development was more frequent in post-AMI patients with AH than those without [24.8% vs 12.0%, adjusted hazard ratio (HR) 1.776, p=0.021], particularly among patients with an HbA1c of <5.6% on admission. Treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers was associated with a reduced incidence of dn-DM in patients with AH (adjusted HR 0.397, p=0.031).ConclusionAdmission AH was a predictor of dn-DM in non-diabetic post-AMI patients. Renin–angiotensin system inhibitors were associated with reduced incidence of dn-DM in post-AMI patients with AH

Reduced risk of recurrent myocardial infarction in homozygous carriers of the chromosome 9p21 rs1333049 c risk allele in the contemporary percutaneous coronary intervention era: A prospective observational study

Hara M, Sakata Y, Nakatani D on behalf of the OACIS Investigators, et al. Reduced risk of recurrent myocardial infarction in homozygous carriers of the chromosome 9p21 rs1333049 C risk allele in the contemporary percutaneous coronary intervention era: a prospective observational study. BMJ Open 2014;4:e005438. doi: 10.1136/bmjopen-2014-00543

Association of lifestyle-related factors with circadian onset patterns of acute myocardial infarction: A prospective observational study in Japan

Objective: The onset of acute myocardial infarction (AMI) shows characteristic circadian variations involving a definite morning peak and a less-defined night-time peak. However, the factors influencing the circadian patterns of AMI onset and their influence on morning and night-time peaks have not been fully elucidated. Design, setting and participants: An analysis of patients registered between 1998 and 2008 in the Osaka Acute Coronary Insufficiency Study, which is a prospective, multicentre observational study of patients with AMI in the Osaka region of Japan. The present study included 7755 consecutive patients with a known time of AMI onset. Main outcomes and measures: A mixture of two von Mises distributions was used to examine whether a circadian pattern of AMI had uniform, unimodal or bimodal distribution, and the likelihood ratio test was then used to select the best circadian pattern among them. The hierarchical likelihood ratio test was used to identify factors affecting the circadian patterns of AMI onset. The Kaplan-Meier method was used to estimate survival curves of 1-year mortality according to AMI onset time. Results: The overall population had a bimodal circadian pattern of AMI onset characterised by a high and sharp morning peak and a lower and less-defined night-time peak (bimodal p<0.001). Although several lifestyle-related factors had a statistically significant association with the circadian patterns of AMI onset, serum triglyceride levels had the most prominent association with the circadian patterns of AMI onset. Patients with triglyceride ?150 mg/dL on admission had only one morning peak in the circadian pattern of AMI onset during weekdays, with no peaks detected on weekends, whereas all other subgroups had two peaks throughout the week. Conclusions: The circadian pattern of AMI onset was characterised by bimodality. Notably, several lifestyle-related factors, particularly serum triglyceride levels, had a strong relation with the circadian pattern of AMI onset.Edahiro R, Sakata Y, Nakatani D, et al. Association of lifestyle-related factors with circadian onset patterns of acute myocardial infarction: a prospective observational study in Japan. BMJ Open 2014;4:e005067. doi: 10.1136/bmjopen-2014-00506

臨床統計家育成の諸問題

要旨あり統計教育の新展開総合報

Antenatal antiarrhythmic treatment for fetal tachyarrhythmias: a study protocol for a prospective multicentre trial

Introduction Several retrospective or single-centrestudies demonstrated the efficacy of transplacentaltreatment of fetal tachyarrhythmias. Our retrospectivenationwide survey showed that the fetal therapy willbe successful at an overall rate of 90%. For fetuseswith hydrops, the treatment success rate will be 80%.However, standard protocol has not been established.The objective of this study is to evaluate the efficacy andsafety of the protocol-defined transplacental treatment offetal tachyarrhythmias. Participant recruitment began inOctober 2010.Methods and analysis The current study is a multicentre,single-arm interventional study. A total of 50 fetuseswill be enrolled from 15 Japanese institutions. Theprotocol-defined transplacental treatment is performed forsingletons with sustained fetal tachyarrhythmia ≥180 bpm,with a diagnosis of supraventricular tachycardia or atrialflutter. Digoxin, sotalol, flecainide or a combination is usedfor transplacental treatment. The primary endpoint isdisappearance of fetal tachyarrhythmias. The secondaryendpoints are fetal death related to tachyarrhythmia,proportion of preterm birth, rate of caesarean sectionattributable to fetal arrhythmia, improvement in fetalhydrops, neonatal arrhythmia, neonatal central nervoussystem disorders and neonatal survival. Maternal, fetal andneonatal adverse events are evaluated at 1 month afterbirth. Growth and development are also evaluated at 18and 36 months of corrected age.Ethics and dissemination The Institutional Review Boardof the National Cerebral and Cardiovascular Center ofJapan has approved this study. Our findings will be widelydisseminated through conference presentations and peerreviewedpublications

Assessment of risk factors related to healthcare-associated methicillin-resistant Staphylococcus aureus infection at patient admission to an intensive care unit in Japan

<p>Abstract</p> <p>Background</p> <p>Healthcare-associated methicillin-resistant <it>Staphylococcus aureus </it>(HA-MRSA) infection in intensive care unit (ICU) patients prolongs ICU stay and causes high mortality. Predicting HA-MRSA infection on admission can strengthen precautions against MRSA transmission. This study aimed to clarify the risk factors for HA-MRSA infection in an ICU from data obtained within 24 hours of patient ICU admission.</p> <p>Methods</p> <p>We prospectively studied HA-MRSA infection in 474 consecutive patients admitted for more than 2 days to our medical, surgical, and trauma ICU in a tertiary referral hospital in Japan. Data obtained from patients within 24 hours of ICU admission on 11 prognostic variables possibly related to outcome were evaluated to predict infection risk in the early phase of ICU stay. Stepwise multivariate logistic regression analysis was used to identify independent risk factors for HA-MRSA infection.</p> <p>Results</p> <p>Thirty patients (6.3%) had MRSA infection, and 444 patients (93.7%) were infection-free. Intubation, existence of open wound, treatment with antibiotics, and steroid administration, all occurring within 24 hours of ICU admission, were detected as independent prognostic indicators. Patients with intubation or open wound comprised 96.7% of MRSA-infected patients but only 57.4% of all patients admitted.</p> <p>Conclusions</p> <p>Four prognostic variables were found to be risk factors for HA-MRSA infection in ICU: intubation, open wound, treatment with antibiotics, and steroid administration, all occurring within 24 hours of ICU admission. Preemptive infection control in patients with these risk factors might effectively decrease HA-MRSA infection.</p

Practical application of cure mixture model for long-term censored survivor data from a withdrawal clinical trial of patients with major depressive disorder

<p>Abstract</p> <p>Background</p> <p>Survival analysis methods such as the Kaplan-Meier method, log-rank test, and Cox proportional hazards regression (Cox regression) are commonly used to analyze data from randomized withdrawal studies in patients with major depressive disorder. However, unfortunately, such common methods may be inappropriate when a long-term censored relapse-free time appears in data as the methods assume that if complete follow-up were possible for all individuals, each would eventually experience the event of interest.</p> <p>Methods</p> <p>In this paper, to analyse data including such a long-term censored relapse-free time, we discuss a semi-parametric cure regression (Cox cure regression), which combines a logistic formulation for the probability of occurrence of an event with a Cox proportional hazards specification for the time of occurrence of the event. In specifying the treatment's effect on disease-free survival, we consider the fraction of long-term survivors and the risks associated with a relapse of the disease. In addition, we develop a tree-based method for the time to event data to identify groups of patients with differing prognoses (cure survival CART). Although analysis methods typically adapt the log-rank statistic for recursive partitioning procedures, the method applied here used a likelihood ratio (LR) test statistic from a fitting of cure survival regression assuming exponential and Weibull distributions for the latency time of relapse.</p> <p>Results</p> <p>The method is illustrated using data from a sertraline randomized withdrawal study in patients with major depressive disorder.</p> <p>Conclusions</p> <p>We concluded that Cox cure regression reveals facts on who may be cured, and how the treatment and other factors effect on the cured incidence and on the relapse time of uncured patients, and that cure survival CART output provides easily understandable and interpretable information, useful both in identifying groups of patients with differing prognoses and in utilizing Cox cure regression models leading to meaningful interpretations.</p