Obesity-induced metabolic imbalance allosterically modulates CtBP2 to inhibit PPAR-alpha transcriptional activity.

Maintenance of metabolic homeostasis is secured by metabolite-sensing systems, which can be overwhelmed by constant macronutrient surplus in obesity. Not only the uptake processes but also the consumption of energy substrates determine the cellular metabolic burden. We herein describe a novel transcriptional system in this context comprised of peroxisome proliferator-activated receptor alpha (PPARα), a master regulator for fatty acid oxidation, and C-terminal binding protein 2 (CtBP2), a metabolite-sensing transcriptional corepressor. CtBP2 interacts with PPARα to repress its activity, and the interaction is enhanced upon binding to malonyl-CoA, a metabolic intermediate increased in tissues in obesity and reported to suppress fatty acid oxidation through inhibition of carnitine palmitoyltransferase 1. In line with our preceding observations that CtBP2 adopts a monomeric configuration upon binding to acyl-CoAs, we determined that mutations in CtBP2 that shift the conformational equilibrium toward monomers increase the interaction between CtBP2 and PPARα. In contrast, metabolic manipulations that reduce malonyl-CoA decreased the formation of the CtBP2-PPARα complex. Consistent with these in vitro findings, we found that the CtBP2-PPARα interaction is accelerated in obese livers while genetic deletion of CtBP2 in the liver causes derepression of PPARα target genes. These findings support our model where CtBP2 exists primarily as a monomer in the metabolic milieu of obesity to repress PPARα, representing a liability in metabolic diseases that can be exploited to develop therapeutic approaches.

Estimation of the causal effects of time-varying treatments in nested case-control studies using marginal structural Cox models.

When estimating the causal effects of time-varying treatments on survival in nested case-control (NCC) studies, marginal structural Cox models (Cox-MSMs) with inverse probability weights (IPWs) are a natural approach. However, calculating IPWs from the cases and controls is difficult because they are not random samples from the full cohort, and the number of subjects may be insufficient for calculation. To overcome these difficulties, we propose a method for calculating IPWs to fit Cox-MSMs to NCC sampling data. We estimate the IPWs using a pseudo-likelihood estimation method with an inverse probability of sampling weight using NCC samples, and additional samples of subjects who experience treatment changes and subjects whose follow-up is censored are required to calculate the weights. Our method only requires covariate histories for the samples. The confidence intervals are calculated from the robust variance estimator for the NCC sampling data. We also derive the asymptotic properties of the estimator of Cox-MSM under NCC sampling. The proposed methods will allow researchers to apply several case-control matching methods to improve statistical efficiency. A simulation study was conducted to evaluate the finite sample performance of the proposed method. We also applied our method to a motivating pharmacoepidemiological study examining the effect of statins on the incidence of coronary heart disease. The proposed method may be useful for estimating the causal effects of time-varying treatments in NCC studies.

Ocular Adverse Events after Coronavirus Disease 2019 mRNA Vaccination: Matched Cohort and Self-Controlled Case Series Studies Using a Large Database.

PURPOSE: To investigate the risk of ocular adverse events after Coronavirus Disease 2019 (COVID-19) mRNA vaccination. DESIGN: Matched cohort and self-controlled case series (SCCS) studies. PARTICIPANTS: We used a population-based database of medical claims and vaccination records in a large Japanese city. In the matched cohort study, we identified individuals who received COVID-19 vaccination (BNT162b2) from February 2021 to September 2021. One control was selected from nonvaccinated individuals by matching time, date of birth, sex, Charlson comorbidity index, and the enrollment period for health insurance. In the SCCS study, we analyzed individuals who developed ocular adverse events. METHODS: In the matched cohort study, we applied the Kaplan-Meier estimator to estimate the cumulative incidence of ocular adverse events over 21 days after the first dose and 84 days after the second dose. In the SCCS method, we used conditional Poisson regression to estimate the incidence rate ratio (IRR) of ocular adverse events during the risk periods (0-21 days after the first dose and 0-84 days after the second dose) compared with the remaining periods. MAIN OUTCOME MEASURES: Composite outcome of uveitis, scleritis, retinal vein occlusion (RVO), and optic neuritis. RESULTS: There were 99 718 pairs eligible for the matched cohort study after the first dose (mean age, 69.3 years; male, 44%). The vaccinated and control groups developed 29 and 21 events, respectively, over 21 days after the first dose, and 79 and 28 events, respectively, over 84 days after the second dose. The differences in cumulative incidence (reference, the control group) were 2.9 (95% confidence interval, -14.5 to 19.1) events/100 000 persons and 51.3 (16.2-84.3) events/100 000 persons, respectively, for the first and second doses. The SCCS study showed the IRRs of 0.89 (0.62-1.28) and 0.89 (0.71-1.11) for the first and second doses, respectively. CONCLUSIONS: The matched cohort analysis found an increased risk for the composite outcome after the second dose; however, the SCCS analysis showed no increased risk. Considering that the SCCS can cancel out time-invariant confounders, the current results suggest that COVID-19 vaccination is unlikely to causally increase the risk of ocular adverse events. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

The utility of the self-controlled study design for pharmacoepidemiological studies without an active comparator medication using a medical information database: An application to assess the risk of varenicline on cardiovascular outcomes.

PURPOSE: To illustrate the utility of the self-controlled study design for studies without an active comparator, we compared the results of a cohort design study with a non-user comparator with those of a self-controlled design study in evaluating the risk of varenicline on cardiovascular outcomes, using a Japanese medical claims database. METHODS: The participating smokers were identified from health-screening results collected between May 2008 and April 2017. Using a non-user-comparator cohort study design, we estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) of varenicline on initial hospitalization with cardiovascular outcomes using Cox's model adjusted for patients' sex, age, medical history, medication history, and health-screening results. Using a self-controlled study design, the within-subject HR was estimated using a stratified Cox's model adjusted for medical history, medication history, and health-screening results. The estimate from a recent meta-analysis was considered the gold standard (risk ratio: 1.03). RESULTS: We identified 460 464 smokers (398 694 males [86.6%]; mean (standard deviation) age: 42.9 [10.8] years) in the database. Of these, 11 561 had been dispensed varenicline at least once, and 4511 had experienced cardiovascular outcomes. The estimate of the non-user-comparator cohort study design exceeded the gold standard (HR [95% CI]: 2.04 [1.22-3.42]), whereas that of the self-controlled study design was close to the gold standard (within-subject HR [95% CI]: 1.12 [0.27-4.70]). CONCLUSIONS: The self-controlled study design is useful alternative to a non-user-comparator cohort design when evaluating the risk of medications relative to their non-use, based on a medical information database.

New balance capability index as a screening tool for mild cognitive impairment.

BACKGROUND: Mild cognitive impairment (MCI) is not just a prodrome to dementia, but a very important intervention point to prevent dementia caused by Alzheimer's disease (AD). It has long been known that people with AD have a higher frequency of falls with some gait instability. Recent evidence suggests that vestibular impairment is disproportionately prevalent among individuals with MCI and dementia due to AD. Therefore, we hypothesized that the measurement of balance capability is helpful to identify individuals with MCI. METHODS: First, we developed a useful method to evaluate balance capability as well as vestibular function using Nintendo Wii balance board as a stabilometer and foam rubber on it. Then, 49 healthy volunteers aged from 56 to 75 with no clinically apparent cognitive impairment were recruited and the association between their balance capability and cognitive function was examined. Cognitive functions were assessed by MoCA, MMSE, CDR, and TMT-A and -B tests. RESULTS: The new balance capability indicator, termed visual dependency index of postural stability (VPS), was highly associated with cognitive impairment assessed by MoCA, and the area under the receiver operating characteristic (ROC) curve was more than 0.8, demonstrating high sensitivity and specificity (app. 80% and 60%, respectively). CONCLUSIONS: Early evidence suggests that VPS measured using Nintendo Wii balance board as a stabilometer helps identify individuals with MCI at an early and preclinical stage with high sensitivity, establishing a useful method to screen MCI.

Prognosis and effectiveness of chemotherapy for medullary breast carcinoma.

PURPOSE: We aimed to determine the prognosis and potential benefit of postoperative chemotherapy according to subtype of medullary breast carcinoma (MedBC), a very rare invasive breast cancer. METHODS: A cohort of 1518 female patients with unilateral MedBC and 284,544 invasive ductal carcinoma (IDC) cases were enrolled from the Japanese Breast Cancer Registry. Prognosis of MedBC was compared to IDC among patients with estrogen receptor (ER)-negative and HER2-negative subtype (553 exact-matched patients) and ER-positive and HER2-negative subtype (163 MedBC and 489 IDC patients via Cox regression). Disease free-survival (DFS) and overall survival (OS) were compared between propensity score-matched adjuvant chemotherapy users and non-users with ER-negative and HER2-negative MedBC. RESULTS: Among ER-negative and HER2-negative subtype patients, DFS (hazard ratio (HR) 0.45; 95% confidence interval (95% CI), 0.30-0.68; log-rank P < 0.001) and OS (HR 0.51; 95% CI 0.32-0.83; log-rank P = 0.004) were significantly better in MedBC than IDC. Patients treated with postoperative chemotherapy showed better DFS (HR 0.27; 95% CI 0.09-0.80; log-rank P = 0.02) and OS (HR 0.27; 95% CI 0.09-0.80; log-rank P = 0.02) compared to those without. For the ER-positive and HER2-negative subtype, the point estimate for HR for DFS was 0.60 (95% CI 0.24-1.22) while that for OS was 0.98 (95% CI 0.46-1.84) for MedBC. CONCLUSION: In ER-negative and HER2-negative MedBC, the risk of recurrence and death was significantly lower than that of IDC, about half. Postoperative chemotherapy reduced recurrence and mortality. ER-positive and HER2-negative MedBC may have a lower risk of recurrence compared to IDC.

Long-term outcomes after endoscopic resection for late-elderly patients with early gastric cancer.

BACKGROUND AND AIMS: With the population aging, the incidence of early gastric cancer (EGC) is increasing. We aimed to clarify the indications for endoscopic resection (ER) in late-elderly patients with EGC in terms of life expectancy. METHODS: Patients aged ≥75 years who underwent ER for EGC at our institution from January 2007 to December 2012 were enrolled. Clinical data, including Eastern Cooperative Oncology Group performance status (ECOG-PS), Charlson comorbidity index, and Prognostic Nutritional Index (PNI), were collected at the time of ER. Overall survival (OS) was the main outcome measure. RESULTS: Four hundred consecutive patients were enrolled. Mean patient age was 79.3 years (range, 75-93). The 5-year follow-up rate was 89.0% (median follow-up period, 5.6 years). Five-year OS was 80.8% (95% confidence interval [CI], 76.4-84.4), and 5-year net survival standardized for age, sex, and calendar year was 1.09 (95% CI, 1.03-1.15). With a multivariate analysis, ECOG-PS 2 to 4 (hazard ratio, 8.84; 95% CI, 3.07-25.4), PNI <49.1 (hazard ratio, 2.49; 95% CI, 1.53-4.06), and eCura C-2 (hazard ratio, 1.79; 95% CI, 1.11-2.88) were independent prognostic factors. When none of these factors was met, the 5-year OS rate was 90.4% (95% CI, 84.0-94.3). CONCLUSIONS: ER for EGC in late-elderly patients may improve life expectancy. ER is recommended in patients with a good ECOG-PS and PNI and in whom ER is expected to be non-eCura C-2.

Nationwide time-series surveys of pressure ulcer prevalence in Japan.

OBJECTIVE: The Japanese Society of Pressure Ulcers (JSPU) has two purposes: first, to improve knowledge and skills among health professionals related to preventing and managing pressure ulcers (PUs); and second, to represent those in the field managing PUs, including with government and health authorities. Since 2006, JSPU has conducted fact-finding surveys about every four years to identify PU prevalence in Japan (2006, 2010, 2013 and 2016). Based on the prevalence identified by these surveys, an attempt was made to validate the achievements of JSPU's activities. METHOD: Information from one-day surveys of hospitals, long-term care health facilities, long-term care welfare facilities, and home visit nursing care stations was analysed. We used generalised estimating equations to estimate the proportions of PUs and their 95% confidence intervals (CIs) for each survey. RESULTS: A total of 662,419 patients in 2631 facilities participated in the surveys. The estimated proportions for all facilities (95% CI) in chronological order, from the first to the fourth survey, were: 2.67% (2.52-2.83); 2.61% (2.43-2.80); 1.99% (1.83-2.17); and 1.79% (1.65-1.94), respectively. In all facility types, the proportion of PUs was lower in the fourth survey than the first survey. CONCLUSION: The proportion of PUs showed a decreasing trend and was low according to global standards, demonstrating the efficacy of JSPU's activities.

High protein diet-induced metabolic changes are transcriptionally regulated via KLF15-dependent and independent pathways.

High protein diet (HPD) is an affordable and positive approach in prevention and treatment of many diseases. It is believed that transcriptional regulation is responsible for adaptation after HPD feeding and Kruppel-like factor 15 (KLF15), a zinc finger transcription factor that has been proved to perform transcriptional regulation over amino acid, lipid and glucose metabolism, is known to be involved at least in part in this HPD response. To gain more insight into molecular mechanisms by which HPD controls expressions of genes involved in amino acid metabolism in the liver, we performed RNA-seq analysis of mice fed HPD for a short period (3 days). Compared to a low protein diet, HPD feeding significantly increased hepatic expressions of enzymes involved in the breakdown of all the 20 amino acids. Moreover, using KLF15 knockout mice and in vivo Ad-luc analytical system, we were able to identify Cth (cystathionine gamma-lyase) as a new target gene of KLF15 transcription as well as Ast (aspartate aminotransferase) as an example of KLF15-independent gene despite its remarkable responsiveness to HPD. These findings provide us with a clue to elucidate the entire transcriptional regulatory mechanisms of amino acid metabolic pathways.

CtBP2 confers protection against oxidative stress through interactions with NRF1 and NRF2.

While molecular oxygen is essential for aerobic organisms, its utilization is inseparably connected with generation of oxidative insults. To cope with the detrimental aspects, cells evolved antioxidative defense systems, and insufficient management of the oxidative insults underlies the pathogenesis of a wide range of diseases. A battery of genes for this antioxidative defense are regulated by the transcription factors nuclear factor-erythroid 2-like 1 and 2 (NRF1 and NRF2). While the regulatory steps for the activation of NRFs have been investigated with particular emphasis on nuclear translocation and proteosomal degradation, unknown redundancy may exist considering the indispensable nature of these defense systems. Here we unraveled that C-terminal binding protein 2 (CtBP2), a transcriptional cofactor with redox-sensing capability, is an obligate partner of NRFs. CtBP2 forms transcriptional complexes with NRF1 and NRF2 that is required to promote the expression of antioxidant genes in response to oxidative insults. Our findings illustrate a basis for understanding the transcriptional regulation of antioxidative defense systems that may be exploited therapeutically.

Impact of Body Weight Gain on the Incidence of Nonalcoholic Fatty Liver Disease in Nonobese Japanese Individuals.

INTRODUCTION: We aimed to investigate the effect of recent short-term weight gain on the incidence of nonalcoholic fatty liver disease (NAFLD) in nonobese (body mass index < 25 kg/m) participants. METHODS: This retrospective cohort study included nonobese individuals who participated in an annual health checkup between 2008 and 2018 in Tokyo, Japan. We estimated the multivariable adjusted hazard ratio for the development of NAFLD diagnosed via ultrasound after a 3-kg unit gain in weight measured at a 2-year landmark time point postbaseline. Multivariable adjustments included weight change from the age of 20 and other relevant confounding factors. Sensitivity analyses using additional landmark time points at 1, 3, 4, and 5 years postbaseline and time-dependent Cox proportional hazards regressions were performed. RESULTS: Among the 27,064 nonobese participants (142,699 person years of follow-up), 2,895 were diagnosed with NAFLD. Approximately 90% of the patients with NAFLD maintained their nonobese status before disease diagnosis. The adjusted hazard ratio for the development of NAFLD (for a 3-kg unit of weight gain) at the 2-year landmark time point postbaseline was 1.60 (95% confidence interval, 1.46-1.76) in nonobese men and 1.66 (95% confidence interval, 1.51-1.83) in nonobese women. This association was maintained in the sensitivity analyses. DISCUSSION: Recent short-term weight gain is an independent risk factor for NAFLD development in nonobese men and women. Clinicians should be mindful of the association between weight gain and NAFLD onset, even in the nonobese population.

Hepatocyte ELOVL Fatty Acid Elongase 6 Determines Ceramide Acyl-Chain Length and Hepatic Insulin Sensitivity in Mice.

BACKGROUND AND AIMS: Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. ELOVL fatty acid elongase 6 (Elovl6) is responsible for converting C16 saturated and monounsaturated fatty acids (FAs) into C18 species. We have previously shown that Elovl6 contributes to obesity-induced insulin resistance by modifying hepatic C16/C18-related FA composition. APPROACH AND RESULTS: To define the precise molecular mechanism by which hepatic Elovl6 affects energy homeostasis and metabolic disease, we generated liver-specific Elovl6 knockout (LKO) mice. Unexpectedly, LKO mice were not protected from high-fat diet-induced insulin resistance. Instead, LKO mice exhibited higher insulin sensitivity than controls when consuming a high-sucrose diet (HSD), which induces lipogenesis. Hepatic patatin-like phospholipase domain-containing protein 3 (Pnpla3) expression was down-regulated in LKO mice, and adenoviral Pnpla3 restoration reversed the enhancement in insulin sensitivity in HSD-fed LKO mice. Lipidomic analyses showed that the hepatic ceramide(d18:1/18:0) content was lower in LKO mice, which may explain the effect on insulin sensitivity. Ceramide(d18:1/18:0) enhances protein phosphatase 2A (PP2A) activity by interfering with the binding of PP2A to inhibitor 2 of PP2A, leading to Akt dephosphorylation. Its production involves the formation of an Elovl6-ceramide synthase 4 (CerS4) complex in the endoplasmic reticulum and a Pnpla3-CerS4 complex on lipid droplets. Consistent with this, liver-specific Elovl6 deletion in ob/ob mice reduced both hepatic ceramide(d18:1/18:0) and PP2A activity and ameliorated insulin resistance. CONCLUSIONS: Our study demonstrates the key role of hepatic Elovl6 in the regulation of the acyl-chain composition of ceramide and that C18:0-ceramide is a potent regulator of hepatic insulin signaling linked to Pnpla3-mediated NAFLD.

Sodium-glucose cotransporter-2 inhibitors and the risk of urinary tract infection among diabetic patients in Japan: Target trial emulation using a nationwide administrative claims database.

AIM: To assess the risk of urinary tract infection (UTI) occurrence associated with sodium-glucose cotransporter-2 (SGLT2) inhibitor use relative to biguanide use in diabetes in a population-based cohort study using a target trial emulation framework. METHODS: Using a Japanese nationwide administrative claims database, we constructed a cohort of patients aged ≥40 years who were dispensed SGLT2 inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors or biguanides between April 2014 and March 2015. For computational ease, we randomly sampled 100% of SGLT2 inhibitor users, 3% of DPP-4 inhibitor users, and 20% of biguanide users; new antidiabetic drug initiators were analysed. We estimated the intention-to-treat (ITT) hazard ratios (HRs) of UTI with inverse probability of treatment (IPT)-weighted Cox's proportional hazards models that ignored subsequent treatment changes. Treatment weights were computed using patient sex, age, medications, medical history and hospitalization history. We also estimated per-protocol (PP) HRs using IPT- and inverse probability of censoring-weighted Cox's models that adjusted for nonrandom treatment changes. RESULTS: We analysed 11 364 SGLT2 inhibitor initiators, 9035 DPP-4 inhibitor initiators, and 10 359 biguanide initiators. When compared with biguanide initiators, SGLT2 inhibitor initiators had a crude HR of 1.14 (95% confidence interval [CI] 1.05-1.24), an ITT HR of 0.94 (95% CI 0.86-1.03), and a PP HR of 0.90 (95% CI 0.78-1.03); and DPP-4 inhibitor initiators had a crude HR of 1.13 (95% CI 1.04-1.23), an ITT HR of 0.85 (95% CI 0.77-0.94), and a PP HR of 0.83 (95% CI 0.71-0.95). CONCLUSION: Use of SGLT2 inhibitors or DPP-4 inhibitors did not increase the risk of UTI compared with biguanide use. Accounting for treatment changes did not substantially influence the estimated effects.

Detecting early gastric cancer: Comparison between the diagnostic ability of convolutional neural networks and endoscopists.

OBJECTIVES: Detecting early gastric cancer is difficult, and it may even be overlooked by experienced endoscopists. Recently, artificial intelligence based on deep learning through convolutional neural networks (CNNs) has enabled significant advancements in the field of gastroenterology. However, it remains unclear whether a CNN can outperform endoscopists. In this study, we evaluated whether the performance of a CNN in detecting early gastric cancer is better than that of endoscopists. METHODS: The CNN was constructed using 13,584 endoscopic images from 2639 lesions of gastric cancer. Subsequently, its diagnostic ability was compared to that of 67 endoscopists using an independent test dataset (2940 images from 140 cases). RESULTS: The average diagnostic time for analyzing 2940 test endoscopic images by the CNN and endoscopists were 45.5 ± 1.8 s and 173.0 ± 66.0 min, respectively. The sensitivity, specificity, and positive and negative predictive values for the CNN were 58.4%, 87.3%, 26.0%, and 96.5%, respectively. These values for the 67 endoscopists were 31.9%, 97.2%, 46.2%, and 94.9%, respectively. The CNN had a significantly higher sensitivity than the endoscopists (by 26.5%; 95% confidence interval, 14.9-32.5%). CONCLUSION: The CNN detected more early gastric cancer cases in a shorter time than the endoscopists. The CNN needs further training to achieve higher diagnostic accuracy. However, a diagnostic support tool for gastric cancer using a CNN will be realized in the near future.

Transcriptional co-repressor CtBP2 orchestrates epithelial-mesenchymal transition through a novel transcriptional holocomplex with OCT1.

The epithelial to mesenchymal transition (EMT) is a cell intrinsic program controlling cellular morphological and phenotypic remodeling in a wide range of biological processes. Despite the accumulating evidence, the transcriptional networks regulating EMT still remain to be elucidated. In this study, we demonstrate that C-terminal binding protein 2 (CtBP2), a critical transcriptional co-repressor harboring pyridine nucleotide sensing capability, orchestrates the EMT program at least in part through a novel transcriptional interaction with an octamer transcription factor, OCT1 (POU2F1, POU class 2 homeobox 1). We identified novel interactions of CtBP2 with several octamer transcription factors, and CtBP2 exhibits a direct interaction with OCT1 in particular. OCT1 accelerates the EMT program as reported, which is diminished by the mutation of the CtBP-binding motif in OCT1, suggesting OCT1 represses epithelial gene expression through recruiting the co-repressor CtBP2. In accordance with these findings, a canonical EMT activator transforming growth factor-ß (TGF-ß) promotes the formation of the CtBP2/OCT1 complex. Our observations illustrate the role of CtBP2 to orchestrate the EMT program through the interaction with OCT1 and highlight the potential of therapeutic exploitation of this new transcriptional system for a wide range of diseases.

Breast cancer survival among Japanese individuals and US residents of Japanese and other origins: a comparative registry-based study.

BACKGROUND: Breast cancer survival outcomes vary across different ethnic groups. We clarified the differences in clinicopathological and survival characteristics of breast cancer among Japanese, US residents with Japanese origin (USJ), and US residents with other origins (USO). METHOD: Using Surveillance, Epidemiology, and End Results (SEER) 18 dataset and Japanese Breast Cancer Society (JBCS) registry, we included patients first diagnosed with breast cancer between 2004 and 2015. We categorized the patients into three groups based on the database and the recorded ethnicity: Japanese (all those from the JBCS registry), USJ (those from SEER with ethnicity: Japanese), and USO (those from SEER with ethnicity other than Japanese). Excluding patients diagnosed after 2012, stage 0, and 4 patients, we examined the overall survival (OS) and breast cancer-specific survival (BCSS) using the Kaplan-Meier method and Cox proportional hazards models, adjusting for age, sex, cancer stage, and hormone receptor (HR) status. RESULTS: We identified 7362 USJ, 701,751 USO, and 503,013 Japanese breast cancer patients. The proportion of HR-positive breast cancer was the highest among USJ (71%). OS was significantly longer among Japanese and USJ than USO (Hazard ratio 0.46; 95% Confidence Interval [CI] 0.45-0.47 for Japanese and 0.66 [95% CI 0.59-0.74] for USJ) after adjusting for baseline covariates. BCSS was also significantly higher in the two groups (HR 0.53 [95% CI 0.51-0.55] for Japanese and 0.53 [95% CI 0.52-0.74] for USJ). CONCLUSIONS: In stage I-III breast cancer, Japanese and US residents with Japanese origin experienced significantly longer survival than US residents with non-Japanese origins.

Longitudinal effects of a nationwide lifestyle intervention program on cardiometabolic outcomes in Japan: An observational cohort study.

The Japanese government launched a nationwide health screening and lifestyle intervention program in 2008 to prevent and reduce metabolic syndrome in at-risk individuals. This study examined the longitudinal effects of the program's lifestyle interventions on metabolic outcomes using health insurance data from one prefecture. The study population comprised 16,317 individuals aged 40-74 years who met the recommendation criteria for the interventions between 2009 and 2015. Participants were categorized into an overall intervention group (comprising a single-session motivational intervention group and a multi-session intensive intervention group) and a non-intervention group. We evaluated the interventions' effects on the initiation of medications for metabolic disorders (hyperlipidemia, hypertension, and hyperglycemia) and metabolic syndrome incidence for 6 years using discrete hazard models that adjusted for sex, age, health screening measurements, and smoking habit. The longitudinal effects on health screening measurements were also evaluated using regression models for repeated measures. The adjusted hazard ratios (aHRs) (95% confidence interval [CI]) for initiation of medications were 0.83 (0.77-0.90), 0.77 (0.71-0.84), and 0.66 (0.57-0.77) for overall, motivational, and intensive interventions, respectively. The aHRs (95%CI) for metabolic syndrome incidence were 0.84 (0.75-0.94), 0.80 (0.71-0.91), and 0.67 (0.51-0.89) for overall, motivational, and intensive interventions, respectively. The interventions reduced body mass index and waist circumference, but had modest effects on blood lipids, blood glucose, and hemoglobin A1c levels; blood pressure was unaffected. These interventions represent an effective strategy to prevent the progression of preclinical metabolic syndrome, but further studies are needed to evaluate their long-term preventive effects on cardiovascular disease and diabetes.

Presence or absence of adjacent vertebral fractures has no effect on long-term global alignment and quality of life in patients with osteoporotic vertebral fractures treated with balloon kyphoplasty.

BACKGROUND: Global sagittal malalignment after osteoporotic vertebral fracture is correlated with decreased quality of life. Balloon kyphoplasty promotes short-term global alignment, but long-term correction is difficult in patients with such fractures. Adjacent vertebral fracture is one of the major complications of balloon kyphoplasty. We investigated the correlation of the incidence of adjacent vertebral fracture with the loss of global alignment correction after balloon kyphoplasty. METHODS: Forty patients were enrolled in this retrospective study. Adjacent vertebral fracture occurred in 17 patients. Sagittal vertical axis, the angle between the two vertebrae above and below the balloon kyphoplasty site (local alignment angle), and the vertebral kyphotic angle at the kyphoplasty site were measured pre- and post-operatively. Clinical results were assessed. RESULTS: There were no significant differences between the sagittal vertical axis before and after balloon kyphoplasty in groups with (+) or without (-) adjacent vertebral fracture. Local alignment angles decreased soon after balloon kyphoplasty, but increased during follow-up in both groups. Vertebral kyphotic angles decreased significantly soon after balloon kyphoplasty in both groups; although this increased significantly in the adjacent vertebral fracture (-) group, but not in the adjacent vertebral fracture (+) group, during follow-up. Correction loss of alignment was found in both adjacent vertebral fracture (+) and (-) groups, attributed to adjacent vertebral fracture in the former and re-collapse of the balloon kyphoplasty site in the latter. No significant differences in clinical results were observed between the groups, although these were strongly correlated with sagittal vertical axis before balloon kyphoplasty. CONCLUSIONS: The adjacent vertebral fracture (+) and (-) groups exhibited similar correction loss of alignment and improved quality of life. The presence or absence of adjacent vertebral fractures had no effect on long-term global alignment and patient quality of life.

Influence of Intermittent Cold Stimulations on CREB and Its Targeting Genes in Muscle: Investigations into Molecular Mechanisms of Local Cryotherapy.

Local cryotherapy is widely used as a treatment for sports-related skeletal muscle injuries. The molecular mechanisms are unknown. To clarify these mechanisms, we applied one to three 15-min cold stimulations at 4 °C to various cell lines (in vitro), the tibialis anterior (TA) muscle (ex vivo), and mouse limbs (in vivo). In the in vitro assay, cyclic AMP (cAMP) response element binding protein 1 (CREB1) was markedly phosphorylated (p-CREB1), and the CREB-binding protein (CBP) was recruited to p-CREB-1 in response to two or three cold stimulations. In a reporter assay with the cAMP-responsive element, the signals significantly increased after two to three cold stimulations at 4 °C. In the ex vivo study, CREB-targeting genes were significantly upregulated following two or three cold stimulations. The in vivo experiment disclosed that cold stimulation of a mouse limb for 9 days significantly increased mitochondrial DNA copy number and upregulated genes involved in mitochondrial biogenesis. The results suggest that local cryotherapy increases CREB transcription and upregulates CREB-targeting genes, in a manner dependent on cold stimulation frequency and duration. This information will inform further investigations into local cryotherapy as a treatment for sports-related skeletal muscle trauma.

Application of convolutional neural networks for evaluating Helicobacter pylori infection status on the basis of endoscopic images.

BACKGROUND AND AIM: We recently reported the role of artificial intelligence in the diagnosis of Helicobacter pylori (H. pylori) gastritis on the basis of endoscopic images. However, that study included only H. pylori-positive and -negative patients, excluding patients after H. pylori-eradication. In this study, we constructed a convolutional neural network (CNN) and evaluated its ability to ascertain all H. pylori infection statuses. METHODS: A deep CNN was pre-trained and fine-tuned on a dataset of 98,564 endoscopic images from 5236 patients (742 H. pylori-positive, 3649 -negative, and 845 -eradicated). A separate test data set (23,699 images from 847 patients; 70 positive, 493 negative, and 284 eradicated) was evaluated by the CNN. RESULTS: The trained CNN outputs a continuous number between 0 and 1 as the probability index for H. pylori infection status per image (Pp, H. pylori-positive; Pn, negative; Pe, eradicated). The most probable (largest number) of the three infectious statuses was selected as the 'CNN diagnosis'. Among 23,699 images, the CNN diagnosed 418 images as positive, 23,034 as negative, and 247 as eradicated. Because of the large number of H. pylori negative findings, the probability of H. pylori-negative was artificially re-defined as Pn -0.9, after which 80% (465/582) of negative diagnoses were accurate, 84% (147/174) eradicated, and 48% (44/91) positive. The time needed to diagnose 23,699 images was 261 seconds. CONCLUSION: We used a novel algorithm to construct a CNN for diagnosing H. pylori infection status on the basis of endoscopic images very quickly. ABBREVIATIONS: H. pylori: Helicobacter pylori; CNN: convolutional neural network; AI: artificial intelligence; EGD: esophagogastroduodenoscopies.