A consensus statement from the Japan Diabetes Society (JDS): a proposed algorithm for pharmacotherapy in people with type 2 diabetes-2nd Edition (English version).

The Japan Diabetes Society (JDS) adopted a sweeping decision to release consensus statements on relevant issues in diabetes management that require updating from time to time and launched a "JDS Committee on Consensus Statement Development." In March 2020, the committee's first consensus statement on "Medical Nutrition Therapy and Dietary Counseling for People with Diabetes" was published. In September 2022, a second consensus "algorithm for pharmacotherapy in people with type 2 diabetes" was proposed. In developing an algorithm for diabetes pharmacotherapy in people with type 2 diabetes, the working concept was that priority should be given to selecting such medications as would appropriately address the diabetes pathology in each patient while simultaneously weighing the available evidence for these medications and the prescribing patterns in clinical practice in Japan. These consensus statements are intended to present the committee's take on diabetes management in Japan, based on the evidence currently available for each of the issues addressed. It is thus hoped that practicing diabetologists will not fail to consult these statements to provide the best available practice in their respective clinical settings. Given that the persistent dual GIP/GLP-1 receptor agonist tirzepatide was approved in April 2023, these consensus statements have been revised1). In this revision, specifically, tirzepatide was added to the end of [likely involving insulin resistance] of "Obese patients" in Step 1: "Select medications to address the diabetes pathology involved" in Fig. 2. While the sentence, "Insulin insufficiency and resistance can be assessed by referring to the various indices listed in the JDS 'Guide to Diabetes Management.' was mentioned in the previous edition as well, "While insulin resistance is analogized based on BMI, abdominal obesity, and visceral fat accumulation, an assessment of indicators (e.g., HOMA-IR) is desirable" was added as information in order to more accurately recognize the pathology. Regarding Step 2: "Give due consideration to safety," "For renal excretion" was added to the "Rule of thumb 2: Avoid glinides in patients with renal impairment." The order of the medications in "rule of thumb 3: Avoid thiazolidinediones and biguanides in patients with heart failure (in whom they are contraindicated)." to thiazolidinediones then biguanides. In the description of the lowest part of Fig. 2, for each patient failing to achieve his/her HbA1c control goal, "while reverting to step 1" was changed to "while reverting to the opening" and "including reassessment if the patient is indicated for insulin therapy" was added. In the separate table, the column for tirzepatides was added, while the two items, "Characteristic side effects" and "Persistence of effect" were added to the area of interest. The revision also carried additional descriptions of the figure and table such as tirzepatides and "Characteristic side effects" in the statement, and while not mentioned in the proposed algorithm figure, nonalcoholic fatty liver disease (NAFLD) is covered from this revision for patients with comorbidities calling for medical attention. Moreover, detailed information was added to the relative/absolute indication for insulin therapy, the Kumamoto Declaration 2013 for glycemic targets, and glycemic targets for older people with diabetes. Again, in this revision, it is hoped that the algorithm presented here will not only contribute to improved diabetes management in Japan, but will continue to evolve into a better algorithm over time, reflecting new evidence as it becomes available.

Primary Aldosteronism and Risk of Cardiovascular Outcomes: Genome-Wide Association and Mendelian Randomization Study.

BACKGROUND: Observational studies have reported associations between primary aldosteronism (PA) and cardiovascular outcomes, including coronary artery diseases (CAD), congestive heart failure (CHF), and stroke. However, establishing causality remains a challenge due to the lack of randomized controlled trial data on this topic. We thus aimed to investigate the causal relationship between PA and the risk of developing CAD, CHF, and stroke. METHODS AND RESULTS: Cross-ancestry meta-analysis of genome-wide association studies combining East Asian and European ancestry (1560 PA cases and 742 139 controls) was conducted to identify single-nucleotide variants that are associated with PA. Then, using the identified genetic variants as instrumental variables, we conducted the 2-sample Mendelian randomization analysis to investigate the causal relationship between PA and incident CAD, CHF, and stroke among both East Asian and European ancestry. Summary association results were extracted from large genome-wide association studies consortia. Our cross-ancestry meta-analysis of East Asian and European populations identified 7 genetic loci significantly associated with the risk of PA, for which the genes nearest to the lead variants were CASZ1, WNT2B, HOTTIP, LSP1, TBX3, RXFP2, and NDP. Among the East Asian population, the pooled odds ratio estimates using these 7 genetic instruments of PA were 1.07 (95% CI, 1.03-1.11) for CAD, 1.10 (95% CI, 1.01-1.20) for CHF, and 1.13 (95% CI, 1.09-1.18) for stroke. The results were consistent among the European population. CONCLUSIONS: Our 2-sample Mendelian randomization study revealed that PA had increased risks of CAD, CHF, and stroke. These findings highlight that early and active screening of PA is critical to prevent future cardiovascular events.

A novel index combining fecal immunochemical test, DNA test, and age improves detection of advanced colorectal adenoma.

Although the fecal immunochemical test for hemoglobin (FIT) is a widely used screening test for colorectal cancer, it is not sensitive enough to detect advanced colorectal adenoma. To address this issue, we performed this study to investigate whether combining the FIT and fecal DNA testing of methylated somatostatin (SST) could improve diagnostic performance for advanced colorectal adenoma. We collected feces from 79 healthy subjects with negative results on colonoscopy, 43 patients with non-advanced colorectal adenoma, 117 patients with advanced colorectal adenoma, and 126 patients with colorectal cancer. After fecal DNA was incubated with methylation-sensitive restriction enzymes, SST methylation levels were measured by droplet digital PCR. Using logistic multivariate analysis, we established a prediction formula for detecting colorectal neoplasia and named it the FAMS (FIT, age, methylated SST) index. The diagnostic performance of a single use of FIT for advanced colorectal adenoma showed a sensitivity of 29.1% (34/117) and specificity of 89.3% (109/122). In contrast, the FAMS index showed a sensitivity of 56.4% (66/117) at a similar specificity point of 91.0% (111/122). Furthermore, even at the higher specificity point of 94.3% (115/122), the sensitivity was still higher than that of FIT, reaching 42.7% (50/117). As the FAMS index showed better diagnostic performance for advanced colorectal adenoma than a single use of FIT, the FAMS index could be a promising tool for detecting advanced colorectal adenoma.

Comparison of machine-learning and logistic regression models for prediction of 30-day unplanned readmission in electronic health records: A development and validation study.

It is expected but unknown whether machine-learning models can outperform regression models, such as a logistic regression (LR) model, especially when the number and types of predictor variables increase in electronic health records (EHRs). We aimed to compare the predictive performance of gradient-boosted decision tree (GBDT), random forest (RF), deep neural network (DNN), and LR with the least absolute shrinkage and selection operator (LR-LASSO) for unplanned readmission. We used EHRs of patients discharged alive from 38 hospitals in 2015-2017 for derivation and in 2018 for validation, including basic characteristics, diagnosis, surgery, procedure, and drug codes, and blood-test results. The outcome was 30-day unplanned readmission. We created six patterns of data tables having different numbers of binary variables (that ≥5% or ≥1% of patients or ≥10 patients had) with and without blood-test results. For each pattern of data tables, we used the derivation data to establish the machine-learning and LR models, and used the validation data to evaluate the performance of each model. The incidence of outcome was 6.8% (23,108/339,513 discharges) and 6.4% (7,507/118,074 discharges) in the derivation and validation datasets, respectively. For the first data table with the smallest number of variables (102 variables that ≥5% of patients had, without blood-test results), the c-statistic was highest for GBDT (0.740), followed by RF (0.734), LR-LASSO (0.720), and DNN (0.664). For the last data table with the largest number of variables (1543 variables that ≥10 patients had, including blood-test results), the c-statistic was highest for GBDT (0.764), followed by LR-LASSO (0.755), RF (0.751), and DNN (0.720), suggesting that the difference between GBDT and LR-LASSO was small and their 95% confidence intervals overlapped. In conclusion, GBDT generally outperformed LR-LASSO to predict unplanned readmission, but the difference of c-statistic became smaller as the number of variables was increased and blood-test results were used.

Meat consumption and incident type 2 diabetes: an individual-participant federated meta-analysis of 1·97 million adults with 100 000 incident cases from 31 cohorts in 20 countries.

BACKGROUND: Meat consumption could increase the risk of type 2 diabetes. However, evidence is largely based on studies of European and North American populations, with heterogeneous analysis strategies and a greater focus on red meat than on poultry. We aimed to investigate the associations of unprocessed red meat, processed meat, and poultry consumption with type 2 diabetes using data from worldwide cohorts and harmonised analytical approaches. METHODS: This individual-participant federated meta-analysis involved data from 31 cohorts participating in the InterConnect project. Cohorts were from the region of the Americas (n=12) and the Eastern Mediterranean (n=2), European (n=9), South-East Asia (n=1), and Western Pacific (n=7) regions. Access to individual-participant data was provided by each cohort; participants were eligible for inclusion if they were aged 18 years or older and had available data on dietary consumption and incident type 2 diabetes and were excluded if they had a diagnosis of any type of diabetes at baseline or missing data. Cohort-specific hazard ratios (HRs) and 95% CIs were estimated for each meat type, adjusted for potential confounders (including BMI), and pooled using a random-effects meta-analysis, with meta-regression to investigate potential sources of heterogeneity. FINDINGS: Among 1 966 444 adults eligible for participation, 107 271 incident cases of type 2 diabetes were identified during a median follow-up of 10 (IQR 7-15) years. Median meat consumption across cohorts was 0-110 g/day for unprocessed red meat, 0-49 g/day for processed meat, and 0-72 g/day for poultry. Greater consumption of each of the three types of meat was associated with increased incidence of type 2 diabetes, with HRs of 1·10 (95% CI 1·06-1·15) per 100 g/day of unprocessed red meat (I2=61%), 1·15 (1·11-1·20) per 50 g/day of processed meat (I2=59%), and 1·08 (1·02-1·14) per 100 g/day of poultry (I2=68%). Positive associations between meat consumption and type 2 diabetes were observed in North America and in the European and Western Pacific regions; the CIs were wide in other regions. We found no evidence that the heterogeneity was explained by age, sex, or BMI. The findings for poultry consumption were weaker under alternative modelling assumptions. Replacing processed meat with unprocessed red meat or poultry was associated with a lower incidence of type 2 diabetes. INTERPRETATION: The consumption of meat, particularly processed meat and unprocessed red meat, is a risk factor for developing type 2 diabetes across populations. These findings highlight the importance of reducing meat consumption for public health and should inform dietary guidelines. FUNDING: The EU, the Medical Research Council, and the National Institute of Health Research Cambridge Biomedical Research Centre.

A consensus statement from the Japan Diabetes Society: A proposed algorithm for pharmacotherapy in people with type 2 diabetes - 2nd edition (English version).

This algorithm was issued for the appropriate use of drugs for the treatment of type 2 diabetes mellitus in Japan. The revisions include safety considerations, fatty liver disease as a comorbidity to be taken into account and the position of tirzepatide.

Height, body mass index, physical activity, and risk of colorectal cancer in relation to expression of insulin receptor: The Japan Public Health Center-based Prospective Study.

To ascertain the involvement of insulin receptors (IRs) in colorectal carcinogenesis, we investigated the association of height, body mass index (BMI), and physical activity with colorectal cancer (CRC) and two subtypes of CRC according to the expression level of IR. We utilized data from a large-scale, population-based prospective cohort study of 18,158 middle-aged and elderly subjects in Akita and Okinawa, Japan. In the statistical analysis, we used the Cox proportional hazards model and estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of CRC and its subtypes as defined by immunohistochemistry of IRß, a transmembrane subunit of IR. In the IRß-defined subtypes, height showed no apparent association with the risk of IRß-positive CRC. In contrast, a multivariable HR of IRß-positive CRC was 1.77 (95% CI = 1.04-3.03) with a BMI of ≥30.0 kg/m2 (i.e., obesity), compared to a BMI of <25.0 kg/m2. Further, an increase in physical activity was significantly associated with decreased risk of IRß-positive CRC (multivariable HR per 5 METs-hour/day = 0.93, 95% CI = 0.88-0.99). Meanwhile, we found no significant association between any exposure and IRß-negative CRC. Likewise, heterogeneity between the two subtypes of CRC was not statistically significant. These findings imply that obesity and physical activity exert promoting and suppressing effects on the development of CRC expressing IRs, respectively.

Confounder Selection and Sensitivity Analyses to Unmeasured Confounding from Epidemiological and Statistical Perspectives.

In observational studies, identifying and adjusting for a sufficient set of confounders is crucial for accurately estimating the causal effect of the exposure on the outcome. Even in studies with large sample sizes, which typically benefit from small variances in estimates, there is a risk of producing estimates that are precisely inaccurate if the study suffers from systematic errors or biases, including confounding bias. To date, several approaches have been developed for selecting confounders. In this article, we first summarize the epidemiological and statistical approaches to identify a sufficient set of confounders. Particularly, we introduce the modified disjunctive cause criterion as one of the most useful approaches, which involves controlling for any pre-exposure covariate that affects the exposure, outcome, or both. It then excludes instrumental variables but includes proxies for the shared common cause of exposure and outcome. Statistical confounder selection is also useful when dealing with a large number of covariates, even in studies with small sample sizes. After introducing several approaches, we discuss some pitfalls and considerations in confounder selection, such as the adjustment for instrumental variables, intermediate variables, and baseline outcome variables. Lastly, as it is often difficult to comprehensively measure key confounders, we introduce two statistics, E-value and Robustness value, for assessing sensitivity to unmeasured confounders. Illustrated examples are provided using the National Health and Nutritional Examination Survey Epidemiologic Follow-up Study. Integrating these principles and approaches will enhance our understanding of confounder selection and facilitate better reporting and interpretation of future epidemiological studies.

Evaluation of a program designed to prevent diabetic nephropathy aggravation: A retrospective cohort study using health checkups and claims data in Japanese municipalities.

AIMS: Japan started the Diabetic Nephropathy Aggravation Prevention Program. Its early impact was assessed in this study. METHODS: This study used the Kokuho Database of patients with type 2 diabetes from program-implementing and non-implementing municipalities (fiscal years [FYs] 2015-2021). Implementing municipalities facilitated clinic visits and provided education to eligible patients. Average treatment effects on the treated in FYs 2016 and 2018 were evaluated using the inverse probability of treatment weighting. Comparison included intervened vs. non-intervened patients in program-implementing municipalities (Comparison A), intervened patients in program-implementing vs. eligible patients in non-implementing municipalities (Comparison B), and eligible patients in implementing and non-implementing municipalities (Comparison C). RESULTS: Overall, 89,611/89,685 patients from FY 2016/2018 were eligible. Among 68,125/68,170 patients in program-implementing municipalities, 1,470/1,819 were intervened. In Comparison A, the estimated effect of the program on ΔeGFR at 3 years were -0.4 (95 % confidence interval; -1.0, 0.2)/-0.4 (-0.9, 0.1) mL/min/1.73 m2 in FY 2016/2018. Comparisons B and C demonstrated similar tendency; distribution of %change in eGFR varied between municipalities. CONCLUSIONS: Early in the program, renal function did not improve in the intervened patients or program-implementing municipalities. Diverse eGFR changes across municipalities highlighted diverse intervention outcomes, emphasizing the need of program refinement.

Rare-Earth-Metal-Free Solid-State Fluorescent Carbonized-Polymer Microspheres for Unclonable Anti-Counterfeit Whispering-Gallery Emissions from Red to Near-Infrared Wavelengths.

Colloidal carbon dots (CDs) have garnered much attention as metal-free photoluminescent nanomaterials, yet creation of solid-state fluorescent (SSF) materials emitting in the deep red (DR) to near-infrared (NIR) range poses a significant challenge with practical implications. To address this challenge and to engineer photonic functionalities, a micro-resonator architecture is developed using carbonized polymer microspheres (CPMs), evolved from conventional colloidal nanodots. Gram-scale production of CPMs utilizes controlled microscopic phase separation facilitated by natural peptide cross-linking during hydrothermal processing. The resulting microstructure effectively suppresses aggregation-induced quenching (AIQ), enabling strong solid-state light emission. Both experimental and theoretical analysis support a role for extended π-conjugated polycyclic aromatic hydrocarbons (PAHs) trapped within these microstructures, which exhibit a progressive red shift in light absorption/emission toward the NIR range. Moreover, the highly spherical shape of CPMs endows them with innate photonic functionalities in combination with their intrinsic CD-based attributes. Harnessing their excitation wavelength-dependent photoluminescent (PL) property, a single CPM exhibits whispering-gallery modes (WGMs) that are emission-tunable from the DR to the NIR. This type of newly developed microresonator can serve as, for example, unclonable anti-counterfeiting labels. This innovative cross-cutting approach, combining photonics and chemistry, offers robust, bottom-up, built-in photonic functionality with diverse NIR applications.

Impact of COVID-19 pandemic on physical health amongst children: Difference-in-differences analyses of nationwide school health checkup database.

INTRODUCTION: The COVID-19 pandemic posed tremendous challenges for children. However, the long-term effects of the pandemic on various aspects of physical health at a national level remain unclear. METHODS: In this retrospective cohort study, we analysed data from nationwide health checkup records amongst children aged 7-15 years. The dataset comprised 3 544 146 records from 393 794 individuals who graduated from junior high school during fiscal years 2007 to 2022. Difference-in-differences (DID) analyses with multiple time periods were used to examine the impact of COVID-19 on physical health outcomes. RESULTS: Compared with the pre-pandemic period, the COVID-19 pandemic was associated with excess increases in obesity for boys and girls, persisting over the 3 years (+0.42%; [95% CI, 0.23-0.61]). Also, it was associated with excess increases in underweight (+0.28% [0.25-0.32]) and poor visual acuity amongst boys in the 3rd year (+1.80% [1.30-2.30]). There were excess reductions in dental caries (-1.48% [-2.01 to -0.95]), glucosuria (-0.55 [-0.88 to -0.23]) and hematuria (-0.43% [-0.73 to -0.13]) during the 3rd year of the pandemic. CONCLUSIONS: These findings underscore the multifaceted impact of the pandemic on various health indicators for school-aged children. This information could be valuable for public health policy and paediatric healthcare planning in the post-pandemic era.

Hyperfine couplings between the paramagnetic moment and nuclei in the metallic phase of low silica X zeolite loaded with potassium.

Temperature dependences of NMR spectra have been observed for 23Na and 27Al in the metallic phase of Na-K form low silica X (LSX) zeolite loaded with potassium, where the condition of saturation is achieved with a loading level of 9.0 atoms per supercage and the paramagnetic moment contributes to the magnetism of the system beyond simple isolated spin. Two separated peaks have been recognized for 23Na, where the shift values show a quite linear relationship with susceptibility, and the so-called K-χ plot works quite well to give values of 0.32 kOe µB-1 and 0.40 kOe µB-1 for hyperfine coupling constants. Although no separated peak is seen in the 27Al NMR spectrum, the spectral centroid deviates to the positive side. The shoulder of the spectrum scales to susceptibility and the K-χ plot also works well to give a value of 0.15 kOe µB-1 for the hyperfine coupling constant. The orbital of potassium-originated electrons confined in the cage of LSX is understood as seeping out over the framework of zeolite, which is wider than that of the sodium-originated case.

Valid instrumental variable selection method using negative control outcomes and constructing efficient estimator.

In observational studies, instrumental variable (IV) methods are commonly applied when there are unmeasured covariates. In Mendelian randomization, constructing an allele score using many single nucleotide polymorphisms is often implemented; however, estimating biased causal effects by including some invalid IVs poses some risks. Invalid IVs are those IV candidates that are associated with unobserved variables. To solve this problem, we developed a novel strategy using negative control outcomes (NCOs) as auxiliary variables. Using NCOs, we are able to select only valid IVs and exclude invalid IVs without knowing which of the instruments are invalid. We also developed a new two-step estimation procedure and proved the semiparametric efficiency of our estimator. The performance of our proposed method was superior to some previous methods through simulations. Subsequently, we applied the proposed method to the UK Biobank dataset. Our results demonstrate that the use of an auxiliary variable, such as an NCO, enables the selection of valid IVs with assumptions different from those used in previous methods.

GWAS meta-analysis of kidney function traits in Japanese populations.

BACKGROUND: Genetic epidemiological evidence for the kidney function traits in East Asian population including Japanese remain still relatively unclarified. Especially, the number of GWASs for kidney traits reported still remains limited, and the sample size of each independent study is relatively small. Given the genetic variability between ancestries/ethnicities, implementation of GWAS with sufficiently large sample sizes in specific population of Japanese is considered meaningful. METHODS: We conducted the GWAS meta-analyses of kidney traits by leveraging the GWAS summary data of the representative large genome cohort studies with about 200,000 Japanese participants (n = 202,406 for estimated glomerular filtration rate [eGFR] and n = 200,845 for serum creatinine [SCr]). RESULTS: In the present GWAS meta-analysis, we identified 110 loci with 169 variants significantly associated with eGFR (on chromosomes 1-13 and 15-22; p < 5×10-8), whereas we also identified 112 loci with 176 variants significantly associated with SCr (on chromosomes 1-22; p < 5×10-8), of which one locus (more than 1Mb distant from known loci) with one variant (CD36 rs146148222 on chromosome 7) for SCr was considered as the truly novel finding. CONCLUSIONS: The present GWAS meta-analysis of largest genome cohort studies in Japanese provided some original genomic loci associated with kidney function in Japanese, which may contribute to the possible development of personalized prevention of kidney diseases based on genomic information in the near future.

Bioinspired Carbonized Polymer Microspheres for Full-Color Whispering Gallery Mode Emission for White Light Emission, Unclonable Anticounterfeiting, and Chemical Sensing Applications.

Light-element-based fluorescent materials, colloidal graphene quantum dots, and carbon dots (CDs) have sparked an immense amount of scientific interest in the past decade. However, a significant challenge in practical applications has emerged concerning the development of solid-state fluorescence (SSF) materials. This study addresses this knowledge gap by exploring the unexplored photonic facets of C-based solid-state microphotonic emitters. The proposed synthesis approach focuses on carbonized polymer microspheres (CPMs) instead of conventional nanodots. These microspheres exhibit remarkable SSF spanning the entire visible spectrum from blue to red. The highly spherical shape of CPMs imparts built-in photonic properties in addition to its intrinsic CD-based attributes. Leveraging their excitation-dependent photoluminescence property, these microspheres exhibit amplified spontaneous emission, assisted by the whispering gallery mode resonance across the visible spectral region. Remarkably, unlike conventional semiconductor quantum dots or dye-doped microresonators, this single microstructure showcases adaptable resonant emission without structural/chemical modifications. This distinctive attribute enables a plethora of applications, including microcavity-assisted energy transfer for white light emission, highly sensitive chemical sensing, and secure encrypted anticounterfeiting measures. This interdisciplinary approach, integrating photonics and chemistry, provides a robust solution for light-element-based SSF with inherent photonic functionality and wide-ranging applications.

Comparison of instrumental variable methods with continuous exposure and binary outcome: A simulation study.

BACKGROUND: Instrumental variable (IV) methods are widely employed to estimate causal effects when concerns regarding unmeasured confounders. Although comparisons among several IV methods for binary outcomes exist, comprehensive evaluations are insufficient. Therefore, in this study, we aimed to conduct a simulation with some settings for a detailed comparison of these methods, focusing on scenarios where IVs are valid and under effect homogeneity with different instrument strengths. METHODS: We compared six IV methods under 32 simulation scenarios: two-stage least squares (2SLS), two-stage predictor substitutions (2SPS), two-stage residual inclusions (2SRI), limited information maximum likelihood (LIML), inverse-variance weighted methods with a linear outcome model (IVWLI), and inverse-variance weighted methods with a non-linear model (IVWLL). By comparing these methods, we examined three key estimates: the parameter estimates of the exposure variable, the causal risk ratio, and the causal risk differences. RESULTS: Based on the results, six IV methods could be classified into three groups: 2SLS and IVWLI, 2SRI and 2SPS, and LIML and IVWLL. The first pair showed a clear bias owing to outcome model misspecification. The second pair showed a relatively good performance when strong IVs are available; however, the estimates suffered from a significant bias when only weak IVs are used. The third pair produced relatively conservative results, although they were less affected by weak IV issues. CONCLUSIONS: The findings indicate that no panacea is available for the bias associated with IV methods. We suggest using multiple IV methods: one for primary analysis and another for sensitivity analysis.

Importance of circulating leptin and adiponectin in the causal pathways between obesity and the development of colorectal cancer in Japanese men.

BACKGROUND: The mechanistic associations between obesity and risk of colorectal cancer (CRC) remain unclear. Here, using body mass index (BMI) as an obesity indicator, we decomposed the total effects of obesity on the risk of CRC into: (1) direct effects, which are possibly mediated by unmeasured or currently unknown factors; (2) indirect effects mediated by circulating leptin and adiponectin; and (3) indirect effects that are not mediated by circulating leptin and adiponectin but by hyperinsulinemia and chronic inflammation (assessed via circulating connecting peptide and C-reactive protein, respectively). METHODS: We adopted a causal mediation framework, using data from a large prospective cohort study of 44,271 Japanese men. RESULTS: BMI was not associated with the risk of CRC due to direct and indirect effects that were not mediated by circulating leptin and adiponectin. By contrast, individuals with BMIs of 25.0-27.4 kg/m2 (risk ratio, 1.29; 95% confidence interval, 0.98-1.69) and ≥27.5 kg/m2 (risk ratio, 1.28; 95% confidence interval, 0.98-1.68) had a higher risk of CRC due to indirect effects of circulating leptin and adiponectin. CONCLUSIONS: Our mediation analyses suggest that the association between BMI and CRC risk may be largely mediated by a pathway involving circulating leptin and adiponectin.

Validity of self-reported Helicobacter pylori eradication treatment from questionnaire and interview surveys of the JPHC-NEXT study: comparison with prescription history from insurance claims data.

BACKGROUND: We aimed to evaluate the validity of self-administered questionnaire surveys and face-to-face interview surveys for the detection of Helicobacter pylori eradication therapy. METHODS: Participants were a cohort, aged 40-74 years, living in three different locations of Japan, who took part in the baseline survey (2011-2012) of the Japan Public Health Center-based Prospective Study for the Next Generation (JPHC-NEXT). Five years after the baseline survey, a questionnaire and interview survey were independently conducted to determine the history of Helicobacter pylori eradication treatment over the 5-year period. Prescription of Helicobacter pylori eradication medications in national insurance claims data from the baseline survey to the 5-year survey was used as a reference standard. RESULTS: In total, 15,760 questionnaire surveys and 8,006 interview surveys were included in the analysis. There were 3,471 respondents to the questionnaire and 2,398 respondents to the interview who reported having received Helicobacter pylori eradication treatment within the past five years. Comparison of the questionnaire survey to national insurance claims data showed a sensitivity of 95.1% (2213/2328), specificity of 90.6% (12174/13432), positive predictive value of 63.8% (2213/3471), negative predictive value of 99.1% (12174/12289), and Cohen's Kappa value of 0.71. Respective values of the interview survey were 94.4% (1694/1795), 88.7% (5507/6211), 70.6% (1694/2398), 98.2% (5507/5608), and 0.74. CONCLUSION: Both the questionnaire and the interview showed high sensitivity, high specificity, and good agreement with the insurance claim prescriptions data. Some participants may have received eradication treatment without going through the public insurance claim database, resulting in a low positive predictive value.