Risk of recurrent stroke and dementia following acute stroke by changes in kidney function: results from the Perindopril Protection Against Recurrent Stroke Study.

BACKGROUND: Limited data exist on the relationship between declining kidney function and cardiovascular events, dementia, and mortality in patients with a history of stroke.Thus the aims of the study were to investigate functional relationships between dynamic kidney function change and cardiovascular outcomes, and clarify whether adding kidney parameters to conventional cardiovascular risk factors improves model discrimination. METHODS: Post hoc analysis of the Perindopril Protection Against Recurrent Stroke Study (PROGRESS) clinical trial of blood pressure lowering for the secondary prevention of stroke. We examined the association between dynamic kidney function defined as percentage change (declines of >30%, and >0 to ≤30%, and increases of ≥0 to <30%, and ≥30%) in estimated glomerular filtration rate (eGFR) over 2 years and recurrent stroke, major cardiovascular events, dementia and all-cause death over the next 2 years using Cox proportional hazard models controlling for eGFR at registration and potential confounders. Restricted cubic splines were used to assess the functional relationships. C-statistics and Net Reclassification Improvement (NRI) at 2 years were used to assess model discrimination. RESULTS: In 4591 patients followed for a mean of approximately 2 years, 254 (5.5%) developed recurrent stroke, 391 (8.5%) had a major cardiovascular event, 221 (4.8%) developed dementia, and 271 (5.9%) died. Reverse J-like or U-like relationships were observed for percent declines in eGFR and outcomes. Using declines in eGFR of >0 to ≤30% as a reference, increased risks were evident for a greater decline (>30%) in relation to recurrent stroke [adjusted hazard ratio 1.85, 95% confidence interval (CI) 1.20-2.85], major cardiovascular event (2.24, 1.62-3.10) and all-cause death (2.09, 1.39-3.15). A larger increase (≥30%) in eGFR was also associated with a greater risk of all-cause death (1.96, 1.14-3.37). Improvements in the C-statistic were found by adding baseline eGFR and percent change compared with a model with conventional cardiovascular risk factors alone, for major cardiovascular events, dementia, and all-cause mortality. CONCLUSION: Declining kidney function following an incident cerebrovascular event is associated with additional risk of a major cardiovascular events, dementia, and 2-year mortality. However, a large increase in kidney function was also found to be associated with a higher risk of mortality.

Impact of renal denervation on quality of life (How does renal denervation contribute to improving hypertension treatment affected by poor medication adherence?).

The US Food and Drug Administration has approved renal denervation (RDN) as a new treatment option for hypertension (HT) because it not only has antihypertensive effects but also improves the quality of blood pressure (BP) reduction. RDN is expected to be increasingly used in clinical practice in the future. This review summarizes the impact of RDN on quality of life (QOL). Although the treatment of HT aims to improve life prognosis, the use of antihypertensive agents can impair QOL because of adverse effects and lifestyle changes associated with long-term medication use. Consequently, poor adherence to antihypertensive agents is a common problem and may be the most important issue affecting patient QOL. In RDN trials in patients taking antihypertensive agents, approximately 40% of patients had poor adherence to the drugs. Poor adherence is often the cause of resistant hypertension. Therefore, RDN should be well suited to treating HT and improving QOL. Studies have shown that approximately 30% of HT patients prefer RDN to drug treatment. Patients who prefer RDN are typically male and younger and have high BP, poor adherence, and a history of adverse effects of antihypertensive agents. We hope that RDN will improve not only life prognosis but also QOL in HT patients because of its benefits for adherence. Furthermore, we expect that in the future, RDN will be used in other sympathetic nervous system-related diseases, such as heart failure, atrial fibrillation, and sleep apnea syndrome.

Safety and Potential Effect of Intrauterine Infusion of Autologous Adipose Tissue-Derived Regenerative Cells in Patients With Implantation Failure: A Pilot Study.

BACKGROUND: Implantation failure due to thin endometrium has emerged as a major cause of infertility. In this study, we aimed to assess the safety and preliminary efficacy of adipose tissue-derived regenerative cells (ADRCs), a source of adipose-derived stem cells, in infertility patients with implantation failure. METHODS: Five infertile women with implantation failure despite artificial reproductive technology were enrolled in this study and treated with ADRCs via the intrauterine route. The primary outcome was the incidence of adverse events. Additional outcomes were endometrial thickness after ADRC treatment and pregnancy success after embryo transfer. RESULTS: There were no adverse events in any patient. There was no elevation of white blood cell count, C-reactive protein, or D-dimer levels. There was a significant difference in endometrial thickness in the secretory phase before versus after intrauterine transplantation of ADRCs (3.8 ± 1.3 mm versus 8.8 ± 2.8 mm, respectively; p<0.05). A gestational sac and fetal heartbeat were detected on transvaginal ultrasound in two of five patients. CONCLUSION: Intrauterine infusion of autologous ADRCs is a simple and safe procedure that may ameliorate the endometrial microenvironment in infertile women with implantation failure.

Sleep-related breathing disorder in a Japanese occupational population and its association with hypertension-stratified analysis by obesity status.

Sleep-related breathing disorder (SRBD) causes hypertension, and obesity has been highly associated with SRBD, which has become a serious health problem in young and middle-aged Japanese males. However, the relation between SRBD and hypertension considering the effects of obesity remains unknown. In this cross-sectional study, we examined the relationship between SRBD and hypertension, with consideration for the effects of obesity, in Japanese occupational population. Using 3% oxygen desaturation index (3%ODI) obtained by simplified polysomnography (PSG), participants were classified into low (0 ≤ 3%ODI < 5), medium (5 ≤ 3%ODI < 15), and high (15 ≤ 3%ODI) 3%ODI groups. We excluded employees who had not undergone medical examination with simplified PSG in the same year from 2012 to 2018. Logistic regression analysis was performed to calculate odds ratios for having hypertension according to 3%ODI levels. In total, 2532 employees were included. Among them, 25% and 4% were categorized into the medium and high 3%ODI groups, respectively. The odds ratio for hypertension increased significantly with higher 3%ODI levels after adjustment for age, sex, alcohol drinking status and smoking status (p for trend < 0.0001). However, further adjustment for obesity status (body mass index ≥ 25 kg/m2) attenuated the associations. When we performed the stratified analysis by obesity status, the odds ratio for hypertension increased significantly with higher 3%ODI only for non-obese individuals, with significant interaction (p for interaction = 0.014). Higher 3%ODI was significantly associated with higher prevalence of hypertension especially in non-obese participants, suggesting the importance of vigilance for the presence of SRBD even in non-obese individuals. We investigated the association between SRBD and hypertension considering the effects of obesity, which would suggest the need to keep in mind the presence of SRBD even in non-obese individuals.

Influence of Time to Achieve Target Systolic Blood Pressure on Outcome After Intracerebral Hemorrhage: The Blood Pressure in Acute Stroke Collaboration.

OBJECTIVE: To investigate whether an earlier time to achieving and maintaining systolic blood pressure (SBP) at 120 to 140 mm Hg is associated with favorable outcomes in a cohort of patients with acute intracerebral hemorrhage. METHODS: We pooled individual patient data from randomized controlled trials registered in the Blood Pressure in Acute Stroke Collaboration. Time was defined as time form symptom onset plus the time (hour) to first achieve and subsequently maintain SBP at 120 to 140 mm Hg over 24 hours. The primary outcome was functional status measured by the modified Rankin Scale at 90 to 180 days. A generalized linear mixed models was used, with adjustment for covariables and trial as a random effect. RESULTS: A total of 5761 patients (mean age, 64.0 [SD, 13.0], 2120 [36.8%] females) were included in analyses. Earlier SBP control was associated with better functional outcomes (modified Rankin Scale score, 3-6; odds ratio, 0.98 [95% CI, 0.97-0.99]) and a significant lower risk of hematoma expansion (0.98, 0.96-1.00). This association was stronger in patients with bigger baseline hematoma volume (>10 mL) compared with those with baseline hematoma volume ≤10 mL (0.006 for interaction). Earlier SBP control was not associated with cardiac or renal adverse events. CONCLUSIONS: Our study confirms a clear time relation between early versus later SBP control (120-140 mm Hg) and outcomes in the one-third of patients with intracerebral hemorrhage who attained sustained SBP levels within this range. These data provide further support for the value of early recognition, rapid transport, and prompt initiation of treatment of patients with intracerebral hemorrhage.

Relationship between abdominal circumference and the incidence of hyperuricemia in the general Japanese population.

In this study, we aimed to separately evaluate the relationship between waist circumference and the incidence of hyperuricemia in men and women in the general Japanese population. We performed a population-based longitudinal study using data from the annual health examination of residents of Iki City, Japan. A total of 5567 participants without hyperuricemia at baseline were included in the analysis. The men and women were placed into groups according to the tertile of waist circumference. The outcome was incident hyperuricemia (uric acid > 416 µmol/L [7.0 mg/dL]). The relationship between waist circumference and the incidence of hyperuricemia was investigated using Cox proportional hazards models. During the follow-up period, hyperuricemia developed in 697 people (551 men and 146 women). The incidence (per 1000 person-years) of hyperuricemia increased with increasing waist circumference in the men (34.9 for tertile 1, 49.9 for tertile 2 and 63.3 for tertile 3; Ptrend < 0.001) and women (5.5 for tertile 1, 6.3 for tertile 2 and 11.9 for tertile 3; Ptrend < 0.001). Significant associations were identified after adjustment for potential confounders (men: Ptrend < 0.001; women: Ptrend = 0.014). In conclusion, both men and women with larger waist circumferences were at higher risks of subsequent hyperuricemia.

Association of gut microbiome with COPD in Japanese male residents: the SESSA study.

Background: Altered gut microbiota may contribute to COPD development or progression. Herein, we investigated the association of gut microorganisms with COPD, taking into account the impact of smoking status. Methods: This cross-sectional observational study was a part of the Shiga Epidemiological Study of Subclinical Atherosclerosis, a population-based cohort study of Japanese men aged 46-76 years, conducted from 2010 to 2016. The gut microbiome, determined using 16S rRNA gene sequencing, was compared among 99 never-smokers, 306 non-COPD ever-smokers and 76 patients with COPD while adjusting for age, body mass index, ethanol consumption and treatment for type 2 diabetes mellitus. Results: The abundance of phylum Firmicutes was comparable between patients with COPD and non-COPD ever-smokers but tended to be higher in never-smokers. Similarly, the α- and ß-diversity analysis showed similarity between patients with COPD and non-COPD ever-smokers, which tended to differ from never-smokers. Discriminant analysis identified the genus [Prevotella] to be more prevalent in patients with COPD than in never-smokers or non-COPD ever-smokers. Post hoc analysis confirmed similarity of gut microbiome between COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) I and non-COPD ever-smokers, which was different from GOLD II. Conclusion: Smoking may alter the overall gut microbial composition, but gut microbial composition itself may not play a role in the development of COPD. Rather, specific gut bacteria, such as [Prevotella], could be a risk factor for the development of COPD; this may be a potential therapeutic target.

Association of step counts with cognitive function in apparently healthy middle-aged and older Japanese men.

Background: Increasing physical activity may prevent cognitive decline. Previous studies primarily focused on older adults and used self-reported questionnaires to assess physical activity. We examined the relationship between step count, an objective measure of physical activity, and cognitive function in community-based middle-aged and older Japanese men. Methods: The Shiga Epidemiological Study of Subclinical Atherosclerosis randomly recruited community-dwelling healthy men aged 40-79 years from Shiga, Japan, and measured their step counts over 7 consecutive days using a pedometer at baseline (2006-2008). Among men who returned for follow-up (2009-2014), we assessed their cognitive function using the Cognitive Abilities Screening Instrument (CASI) score. We restricted our analyses to those with valid 7-day average step counts at baseline and those who remained free of stroke at follow-up (n = 676). Using analysis of covariance, we calculated the adjusted means of the CASI score according to the quartiles of the average step counts. Results: The mean (standard deviation) of age and unadjusted CASI score were 63.8 (9.1) years and 90.8 (5.8), respectively. The CASI score was elevated in higher quartiles of step counts (90.2, 90.4, 90.6, and 91.8 from the lowest to the highest quartile, respectively, [p for trend = 0.004]) in a model adjusted for age and education. Further adjustment for smoking, drinking, and other cardiovascular risk factors resulted in a similar pattern of association (p for trend = 0.005). Conclusion: In apparently healthy middle-aged and older Japanese men, a greater 7-day average step count at baseline was associated with significantly higher cognitive function score.

Intensive blood pressure lowering and renal function in ischemic stroke patients: secondary analysis of ENCHANTED trial.

BACKGROUND: Renal failure is a major safety concern of intensive systolic blood pressure (SBP) lowering. We aimed to determine the effect of this treatment on early change in renal function in participants of the international Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED). METHODS: Post-hoc analysis of the ENCHANTED BP-arm in which thrombolyzed patients with acute ischemic stroke (AIS) were randomized to intensive (target 130-140 mm Hg within 1 h) or guideline-recommended (target <180 mm Hg) management within 6 h of symptom onset. Primary outcome is early change in renal function, defined by a difference in estimated glomerular filtration rate (∆eGFR = 24 h - baseline eGFR), analyzed using linear regression with adjustment for clinical variables. Key SBP parameters were attained (mean), variability (standard deviation [SD]) and magnitude of reduction within 24 h. RESULTS: Of 2151 participants (mean age 66.9 years; 38% female) included with available baseline eGFR, there were significant differences in attained 144.3±10.2 vs 149.8±12.0 [5.5 mm Hg]; P<0.0001), variation (15.1±5.4 vs 14.0±5.6 mm Hg; P<0.0001) and magnitude of reduction (44.6±16.2 vs 38.7±17.6 mm Hg; P<0.0001) in SBP within 24 hours. 1718 (79.9%) participants with complete follow-up eGFR were included in the primary analysis, and there was no significant difference in ∆eGFR (adjusted mean difference -1.10, 95% confidence interval [CI] -3.14 to -0.94; P=0.29) between the intensive and guideline groups, respectively. The neutral effect on ∆eGFR was consistent in patients with different baseline eGFR stages and in sensitivity analysis after multiple imputation for missing follow-up eGFR. SBP variability was significantly associated with decreasing ∆eGFR (per 5 mm Hg increase by category: adjusted mean difference -1.35, 95%CI -2.43 to -0.28; P for trend=0.01). CONCLUSIONS: Intensive SBP lowering with a target of 130-140 mm Hg had no impact on early renal function in thrombolyzed AIS patients. Wide SBP variability was associated with a larger decline in eGFR. CLINICAL TRIAL REGISTRATION: ENCHANTED is registered at ClinicalTrials.gov (NCT01422616).

Association between occurrence of multiple white and flat elevated gastric lesions and oral proton pump inhibitor intake.

BACKGROUND/AIMS: Multiple white and flat elevated lesions (MWFL) that develop from the gastric corpus to the fornix may be strongly associated with oral antacid intake. Therefore, this study aimed to determine the association between the occurrence of MWFL and oral proton pump inhibitor (PPI) intake and clarify the endoscopic and clinicopathological characteristics of MWFL. METHODS: The study included 163 patients. The history of oral drug intake was collected, and serum gastrin levels and anti-Helicobacter pylori immunoglobulin G antibody titers were measured. Upper gastrointestinal endoscopy was performed. The primary study endpoint was the association between MWFL and oral PPI intake. RESULTS: In the univariate analyses, MWFL were observed in 35 (49.3%) of 71 patients who received oral PPIs and 10 (10.9%) of 92 patients who did not receive oral PPIs. The occurrence of MWFL was significantly higher among patients who received PPIs than in those who did not (p<0.001). Moreover, the occurrence of MWFL was significantly higher in patients with hypergastrinemia (p=0.005). In the multivariate analyses, oral PPI intake was the only significant independent factor associated with the presence of MWFL (p=0.001; odds ratio, 5.78; 95% confidence interval, 2.06-16.2). CONCLUSION: Our findings suggest that oral PPI intake is associated with the presence of MWFL (UMINCTR 000030144).

Dysbiosis of Gut Microbiota in Patients with Chronic Kidney Disease.

Objective The gut bacterial microbiota is altered in patients with chronic kidney disease (CKD). However, the bacterial composition at each stage of CKD is unclear in these patients, including those receiving renal replacement therapy. We herein report the changes in the gut microbiota among patients with CKD. Methods A total of 93 individuals were recruited for the study. Seventy-three patients had stage 3-5 CKD, including those receiving renal replacement therapy (CKD group), and 20 were age- and sex-matched controls (CKD stage 1-2). The gut microbiome composition was analyzed using a 16S ribosomal RNA gene-based sequencing protocol. Results At the genus level, the butyrate-producing bacteria Lachnospira, Blautia, Coprococcus, Anaerostipes, and Roseburia were more abundant in the control group (linear discriminant analysis score of >3) than in the CKD group. Lachnospira was more abundant in the control group than in patients with CKD stage 3a. Compared to the control group, multiplex butyrate-producing bacteria were deficient in patients with CKD stage 3b-5D, including in patients receiving renal replacement therapy. Conclusion Our findings highlight the fact that the gut bacterial composition, including butyrate-producing bacteria, deteriorates from CKD stage 3b. Even after renal replacement therapy, the bacterial composition did not change.

Optimum Baseline Clinical Severity Scale Cut Points for Prognosticating Intracerebral Hemorrhage: INTERACT Studies.

BACKGROUND: The optimal cut point of baseline National Institutes of Health Stroke Scale (NIHSS) and Glasgow Coma Scale scores for prognosticating acute intracerebral hemorrhage (ICH) is unknown. METHODS: Secondary analyses of participant data are from the INTERACT (Intensive Blood Pressure Reduction in Acute Intracerebral Hemorrhage Trials) 1 and 2 studies. Receiver operating characteristic analyses were used to compare the predictive performance of baseline NIHSS and Glasgow Coma Scale scores, ICH score, and max-ICH score. Optimal cut points for predicting 90-day clinical outcomes (death or major disability [defined as modified Rankin Scale scores 3-6], major disability [defined as modified Rankin Scale scores 3-5], and death alone) were determined using the Youden index. Logistic regression models were adjusted for age, sex, hematoma volume, and other known risk factors for poor prognosis. We validated our findings in the INTERACT1 database. RESULTS: There were 2829 INTERACT2 patients (age, 63.5±12.9 years; male, 62.9%; ICH volume, 10.96 [5.77-19.49] mL) included in the main analyses. The baseline NIHSS score (area under the curve, 0.796) had better prognostic utility for predicting death or major disability than the Glasgow Coma Scale score (area under the curve, 0.650) and ICH score (area under the curve, 0.674) and was comparable to max-ICH score (area under the curve, 0.789). Similar findings were observed when assessing the outcome of major disability. A cut point of 10 on baseline NIHSS optimally (sensitivity, 77.5%; specificity, 69.2%) predicted death or major disability (adjusted odds ratio, 4.50 [95% CI, 3.60-5.63]). The baseline NIHSS cut points that optimally predicted major disability and death alone were 10 and 12, respectively. The predictive effect of NIHSS≥10 for poor functional outcomes was consistent in all subgroups including age and baseline hematoma volume. Results were consistent when analyzed in the independent INTERACT1 validation database. CONCLUSIONS: In patients with mild-to-moderate ICH, a baseline NIHSS score of ≥10 was optimal for predicting poor outcomes at 90 days. Prediction based on baseline NIHSS is better than baseline Glasgow Coma Scale score. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT00226096 and NCT00716079.

The gut microbiota and coronary artery calcification in Japanese men.

BACKGROUND: The gut microbiota differs between patients with coronary artery disease (CAD) and healthy controls; however, it currently remains unclear whether these differences exist prior to the onset of CAD. We herein investigated the gut microbiota associated with subclinical coronary artery calcification (CAC) in a Japanese population. METHODS: A total of 663 Japanese men were enrolled in this cross-sectional study. Computed tomography and gut microbiology tests were performed, and CAC scores were calculated using the Agatston method. Participants were categorized into 4 groups based on their CAC scores: CAC = 0, 0

Update on the INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4): progress and baseline features in 2053 participants.

BACKGROUND AND AIMS: Uncertainty persists over the effects of blood pressure (BP) lowering in acute stroke. The INTEnsive ambulance-delivered blood pressure Reduction in hyper-Acute stroke Trial (INTERACT4) aims to determine efficacy and safety of hyperacute intensive BP lowering in patients with suspected acute stroke. Given concerns over the safety of this treatment in the pre-hospital setting, particularly in relation to patients with intracerebral hemorrhage, we provide an update on progress of the study and profile of participants to date. METHODS: INTERACT4 is an ongoing multicentre, ambulance-delivered, randomized, open-label, blinded endpoint trial of pre-hospital BP lowering in patients with suspected acute stroke and elevated BP in China. Patients are randomized via a mobile phone digital system to intensive (target systolic BP [SBP] <140mmHg within 30 min) or guideline-recommended BP management. Primary outcome is an ordinal analysis of the full range of scores on the modified Rankin scale scores at 90 days. RESULTS: Between March 2020 and April 2023, 2053 patients (mean age 70 years, female 39%) were recruited with a mean BP 178/98 mmHg in whom 45% have a diagnosis of primary intracerebral hemorrhage upon arrival at hospital. At the time of presentation to hospital, the mean SBP was 160 and 170mmHg in the intensive and control groups (Δ10 mmHg), respectively. The independent data and safety monitoring board has not identified any safety concerns and recommended continuation of the trial. The sample size was reduced from 3116 to 2320 after meetings in August 2022 as the stroke mimic rate was persistently lower than initially estimated (6% vs 30%). The study is expected to be completed in late 2023 and the results announced in May 2024. CONCLUSIONS: INTERACT4 is on track to provide reliable evidence of the effectiveness of ambulance-delivered intensive BP lowering in patients with suspected acute stroke. TRIAL REGISTRATION: ClinicalTrials.gov NCT03790800 ; registered on 2 January 2019. Chinese Trial Registry ChCTR1900020534 , registered on 7 January 2019.

Two-year evolution of quality of life following radiotherapy and/or chemotherapy in patients with head and neck cancer.

Objective: This study aims to elucidate the trajectory of quality of life (QoL) over a two-year period after radiotherapy and/or chemotherapy for head and neck cancer (HNC), addressing the gap in long-term QoL information. Methods: Employing a prospective longitudinal observational design, we tracked 58 HNC patients who underwent radiotherapy and/or chemotherapy, analyzing their QoL using Short-Form 36-Item Health Survey version 2 (SF36v2), the European Organization for Research and Treatment of Cancer quality of life (EORTC-QLQ-C30), and the European Organization for Research and Treatment of Cancer quality of life head and neck-35 (EORTC-QLQ-H&N35) questionnaires for two years post-discharge. The data underwent repeated measures analysis of variance. Results: Over the two-year follow-up, 10 patients (17.2%) succumbed, and 8 (13.8%) dropped out. SF36v2 physical and role-social component summary scores declined during treatment, requiring 1-2 years for recovery. The mental component summary score remained stable. EORTC-QLQ-30 revealed global health status recovery within one year post-discharge. EORTC-QLQ-H&N35 items like "swallowing," "senses problems," "trouble with social eating," "dry mouth," "sticky saliva," "coughing," and "felt ill" worsened pre-discharge. "Trouble with social contact" improved within a year, while "pain," "swallowing," "senses problems," "trouble with social eating," and "coughing" improved within two years. "Dry mouth" and "sticky saliva" persisted throughout the two-year follow-up, common symptoms of HNC and treatment side effects. Conclusions: Recovery of specific QoL aspects in HNC patients treated with radiotherapy and/or chemotherapy may require up to two years. Prolonged monitoring and management of oral symptoms could enhance QoL. Future research should extend follow-up beyond two years for comprehensive interventions enhancing patient QoL.

Association between serum ALT levels and incidence of new-onset diabetes in general population of Japanese: a longitudinal observational study (ISSA-CKD).

OBJECTIVE: We aimed to clarify the relationship between serum alanine transaminase (ALT) levels and incidence of new-onset diabetes in a Japanese general population. SETTING: Population-based retrospective cohort study using annual health check-up data for residents of Iki City, Nagasaki Prefecture, Japan. PARTICIPANTS: A total of 5330 Japanese individuals (≥30 years old) without diabetes at baseline were analysed. PRIMARY AND SECONDARY OUTCOME MEASURES: Serum ALT levels were determined using an enzymatic method and were classified into gender-specific quartile groups as follows: group 1 (3-16 U/L in men and 3-13 U/L in women), group 2 (17-21 U/L in men and 14-16 U/L in women), group 3 (22-29 U/L in men and 17-22 U/L in women) and group 4 (30-428 U/L in men and 23-268 U/L in women). The study outcome was the incidence of diabetes (fasting glucose ≥7.0 mmol/L, non-fasting glucose ≥11.1 mmol/L, glycated haemoglobin ≥6.5% or use of glucose-lowering therapies). RESULTS: After an average follow-up period of 5.0 years, 279 individuals developed diabetes. The incidence rate of diabetes increased with elevation of serum ALT levels (0.7% per 100 person-years in group 1, 0.9% in group 2, 0.9% in group 3 and 1.7% in group 4) (p<0.001 for trend). This association was significant after adjustment for other risk factors including age, sex, obesity, hypertension, dyslipidaemia, smoking, current daily alcohol intake and regular exercise (p<0.001 for trend). Comparable associations were observed between men and women (p=0.459 for interaction). CONCLUSION: Serum ALT levels were associated with future development of diabetes in the general Japanese population.