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Context Although elevated parathyroid hormone (PTH) levels are associated with higher mortality risks, the evidence is limited as to when PTH is expected to be elevated and thus should be measured among the general population. Objective This work aimed to build a machine learning–based prediction model of elevated PTH levels based on demographic, lifestyle, and biochemical data among US adults. Methods This population-based study included adults aged 20 years or older with a measurement of serum intact PTH from the National Health and Nutrition Examination Survey (NHANES) 2003 to 2006. We used the NHANES 2003 to 2004 cohort (n = 4096) to train 6 machine-learning prediction models (logistic regression with and without splines, lasso regression, random forest, gradient-boosting machines [GBMs], and SuperLearner). Then, we used the NHANES 2005 to 2006 cohort (n = 4112) to evaluate the model performance including area under the receiver operating characteristic curve (AUC). Results Of 8208 US adults, 753 (9.2%) showed PTH greater than 74 pg/mL. Across 6 algorithms, the highest AUC was observed among random forest (AUC [95% CI] = 0.79 [0.76-0.81]), GBM (AUC [95% CI] = 0.78 [0.75-0.81]), and SuperLearner (AUC [95% CI] = 0.79 [0.76-0.81]). The AUC improved from 0.69 to 0.77 when we added cubic splines for the estimated glomerular filtration rate (eGFR) in the logistic regression models. Logistic regression models with splines showed the best calibration performance (calibration slope [95% CI] = 0.96 [0.86-1.06]), while other algorithms were less calibrated. Among all covariates included, eGFR was the most important predictor of the random forest model and GBM. Conclusion In this nationally representative data in the United States, we developed a prediction model that potentially helps us to make accurate and early detection of elevated PTH in general clinical practice. Future studies are warranted to assess whether this prediction tool for elevated PTH would improve adverse health outcomes.

Background Many countries have been increasing their state pension age (SPA); nonetheless, there is little consensus on whether retirement affects the risk of cardiovascular disease (CVD). This study examined the associations of retirement with CVD and risk factors. Methods We used harmonized longitudinal datasets from the Health and Retirement Study and its sister surveys in 35 countries. Data comprised 396 904 observations from 106 927 unique individuals aged 50–70 years, with a mean follow-up period of 6.7 years. Fixed-effects instrumental variable regressions were performed using the SPA as an instrument. Results We found a 2.2%-point decrease in the risk of heart disease [coefficient = -0.022 (95% confidence interval: -0.031 to -0.012)] and a 3.0%-point decrease in physical inactivity [-0.030 (-0.049 to -0.010)] among retirees, compared with workers. In both sexes, retirement was associated with a decreased heart disease risk, whereas decreased smoking was observed only among women. People with high educational levels showed associations between retirement and decreased risks of stroke, obesity and physical inactivity. People who retired from non-physical labour exhibited reduced risks of heart disease, obesity and physical inactivity, whereas those who retired from physical labour indicated an increased risk of obesity. Conclusions Retirement was associated with a reduced risk of heart disease on average. Some associations of retirement with CVD and risk factors appeared heterogeneous by individual characteristics.

Background Iodine-induced hyperthyroidism is a potential consequence of iodinated radiologic contrast, for which its association with long-term cardiovascular outcomes has not been previously studied. Objective To investigate the relationships between hyperthyroidism observed after iodine exposure and incident atrial fibrillation/flutter. Design, Setting, and Participants Retrospective cohort study of the U.S. Veterans Health Administration (1998-2021) of patients age ≥18 years with a normal baseline serum thyrotropin (TSH) concentration and subsequent TSH Measurements Cox proportional hazards regression was employed to ascertain the adjusted hazard ratio (HR) with 95% confidence interval (CI) of incident atrial fibrillation/flutter following iodine-induced hyperthyroidism, compared to iodine-induced euthyroidism. Results Iodine-induced hyperthyroidism was observed in 2,500 (5.6%) of 44,607 Veterans (mean ± SD age, 60.9 ± 14.1 years; 88% men), and atrial fibrillation/flutter in 10.4% over a median follow-up of 3.7 years (IQR, 1.9-7.4). Adjusted for sociodemographic and cardiovascular risk factors, iodine-induced hyperthyroidism was associated with an increased risk of atrial fibrillation/flutter, compared to those who remained euthyroid after iodine exposure (adjusted HR = 1.19 [95% CI 1.06-1.33]). Females were at greater risk for incident atrial fibrillation/flutter than males (females, HR = 1.81 [95% CI 1.12-2.92]; males, HR = 1.15 [95% CI 1.03-1.30]; p-for-interaction, 0.04). Conclusion Hyperthyroidism following a high iodine load was associated with an increased risk of incident atrial fibrillation/flutter, particularly among females. The observed sex-based differences should be confirmed in a more sex-diverse study sample, and the cost-benefit analysis of long-term monitoring for cardiac arrhythmias following iodine-induced hyperthyroidism should be evaluated.

Among colorectal cancer (CRC) patients, pre-existing diabetes is suggested to influence poor prognosis, but the impact on adjuvant chemotherapy implementation is largely unknown. We aimed to compare the implementation rate of adjuvant chemotherapy between CRC patients with and without pre-existing diabetes in a retrospective cohort study.Colorectal cancer diagnosis information was obtained from the hospital-based cancer registry of patients with stage III CRC who underwent curative surgery in 2013 in Japan (n = 6,344). Health claims data were used to identify diabetes and chemotherapy. We examined the association between diabetes and the implementation rate of adjuvant chemotherapy using a generalized linear model adjusted for age, sex, updated Charlson Comorbidity Index, hospital type and prefecture. Furthermore, we applied a mediation analysis to examine the extent to which postoperative complications mediated the association.Of the 6,344 patients, 1,266 (20.0%) had diabetes. The mean ages were 68.2 and 71.3 years for patients without and with diabetes, respectively. Compared with those without diabetes, patients with diabetes were less likely to receive adjuvant chemotherapy (crude rate 58.9 and 49.8%; adjusted percentage point difference 4.6; 95% confidence interval 1.7-7.5). The difference was evident for patients aged80 years, and larger for platinum-containing regimens than others. Mediation analysis showed that postoperative complications explained 9.1% of the inverse association between diabetes and adjuvant chemotherapy implementation.We observed that patients with stage III CRC and diabetes are less likely to receive adjuvant chemotherapy than those without diabetes, and postoperative complications might partially account for the association.

Background In medicine, clinicians treat individuals under an implicit assumption that high-risk patients would benefit most from the treatment (‘high-risk approach’). However, treating individuals with the highest estimated benefit using a novel machine-learning method (‘high-benefit approach’) may improve population health outcomes. Methods This study included 10 672 participants who were randomized to systolic blood pressure (SBP) target of either 0) versus the high-risk approach (treating individuals with SBP ≥130 mmHg). Using transportability formula, we also estimated the effect of these approaches among 14 575 US adults from National Health and Nutrition Examination Surveys (NHANES) 1999–2018. Results We found that 78.9% of individuals with SBP ≥130 mmHg benefited from the intensive SBP control. The high-benefit approach outperformed the high-risk approach [average treatment effect (95% CI), +9.36 (8.33–10.44) vs +1.65 (0.36–2.84) percentage point; difference between these two approaches, +7.71 (6.79–8.67) percentage points, P-value Conclusions The machine-learning-based high-benefit approach outperformed the high-risk approach with a larger treatment effect. These findings indicate that the high-benefit approach has the potential to maximize the effectiveness of treatment rather than the conventional high-risk approach, which needs to be validated in future research.

Identifying unequivocal signs of life on Mars is one of the most important objectives for sending missions to the red planet. Here we report Red Stone, a 163-100 My alluvial fan–fan delta that formed under arid conditions in the Atacama Desert, rich in hematite and mudstones containing clays such as vermiculite and smectites, and therefore geologically analogous to Mars. We show that Red Stone samples display an important number of microorganisms with an unusual high rate of phylogenetic indeterminacy, what we refer to as “dark microbiome”, and a mix of biosignatures from extant and ancient microorganisms that can be barely detected with state-of-the-art laboratory equipment. Our analyses by testbed instruments that are on or will be sent to Mars unveil that although the mineralogy of Red Stone matches that detected by ground-based instruments on the red planet, similarly low levels of organics will be hard, if not impossible to detect in Martian rocks depending on the instrument and technique used. Our results stress the importance in returning samples to Earth for conclusively addressing whether life ever existed on Mars., The research leading to these results is a contribution from the Project “MarsFirstWater”, funded by the European Research Council, Consolidator Grant no 818602 to AGF, and by the Human Frontiers Science Program grant n° RGY0066/2018 to A.A.-B. Additional funding provided was provided by MINECO grant PID2019-107442RB-C32 (O.P.-B. and A.M.), Grants-in-Aid for Scientific Research from the Japan Society for Promotion of Science grant numbers 17H06458 and 21H04515 (K.F.), grant numbers 17H06456, 17H06458, 20H00195, and 21H04515 (K.F. and Y.S.), Consejería de Educación e Investigación, Comunidad Autónoma de Madrid/European Social Fund program (MAFM), grant n° ESP2017-87690-C3-3-R (DC), Ramón y Cajal grant n° RYC2018-023943-I (L.S.-G.), AEI grant MDM-2017-0737 and MCIN/AEI grant PID2019-107442RB-C32 (V.M.-I.), MCIU/AEI (Spain) and FEDER (UE) grant n° PGC2018-094076-B-I00 (J.W. and C.A.), Italian Space Agency agreement 2017-48-H.0 (T.F., J.R.B. and G.P.), the Ministry of Science of Spain grant PID2019-107442RB-C31 (J.A.M., M.V., G.L.R., A.A. and F.R.), María Zambrano’ excellence grant program (CA3/RSUE/2021-00405), funded by the Spanish Ministry of Universities (MFM), NASA Mars Exploration Program contracts NNH13ZDA018O, NNH15AZ24I, NNH13ZDA018O and LANL Laboratory Directed Research and Development (LDRD) funding XX5V (A.M.O, R.C.W., A.R. and S.M.C.), NASA-GSFC grant NNX17AJ68G (M.M. and S.S.J.), NES focused on Sample Analysis at Mars of the Mars Science Laboratory mission, and Mars Organic Molecules Analyzer of the Exomars 2022 mission (O.M., C.S., and C.F.), and grants RTI2018-094368-B-I00 and MDM-2017-0737 Unidad de Excelencia “Maria de Maeztu”- Centro de Astrobiología (INTA-CSIC) by the Spanish Ministry of Science and Innovation/State Agency of Research MCIN/AEI/ 10.13039/501100011033 and by “ERDF A way of making Europe” (C.E., M.G.V., M.M.-P., and V.P.). R.C.W. thanks Dot Delapp for performing pre-processing of the LIBS data., With funding from the Spanish government through the "Severo Ochoa Center of Excellence" accreditation MDM-2017-0737.

Objective To examine whether parathyroid hormone (PTH) is associated with mortality among U.S. adults. Methods This study included 8286 U.S. adults aged ≥20 years with a measurement of serum intact PTH from the National Health and Nutrition Examination Survey 2003-2006 linked to national mortality data through 2015. Multivariable Cox proportional hazard regression models were employed to estimate the adjusted hazard ratio (aHR) of all-cause and cause-specific (cardiovascular and cancer) mortality according to intact PTH levels (low or low-normal, 74 pg/mL). We also stratified the analyses by serum albumin-adjusted calcium and 25-hydroxy vitamin D (25OHD) levels. Results During a median follow-up of 10.1 years, the mean age was 49 years, and 48% were men. After adjusting for potential confounders, both the high-normal and high PTH groups showed higher risks of all-cause mortality than the low or low-normal PTH group (high-normal PTH, aHR, 1.28; 95% confidence interval [CI], 1.10-1.48; high PTH, aHR, 1.42; 95% CI, 1.19-1.69]. When stratified by calcium and 25OHD levels, the association between high PTH and mortality was also found among participants with albumin-adjusted calcium levels of ≥9.6 mg/dL (aHR, 1.53; 95% CI, 1.17-2.01) and those with 25OHD levels of ≥20 ng/mL (aHR, 1.46, 95% CI, 1.17-1.82). We found no evidence of the increased cause-specific mortality risks in the high PTH group. Conclusion Higher PTH levels were associated with an increased risk of all-cause mortality, particularly among participants with albumin-adjusted calcium levels of ≥9.6 mg/dL or 25OHD levels of ≥20 ng/mL.

Although untreated Graves' disease (GD) is associated with a higher risk of cardiac complications and mortality, there is no well-established way to predict the onset of thyrotoxicosis in clinical practice. The aim of this study was to identify important variables that will make it possible to predict GD and thyrotoxicosis (GD + painless thyroiditis (PT)) by using a machine-learning-based model based on complete blood count and standard biochemistry profile data. We identified 19,335 newly diagnosed GD patients, 3,267 PT patients, and 4,159 subjects without any thyroid disease. We built a GD prediction model based on information obtained from subjects regarding sex, age, a complete blood count, and a standard biochemistry profile. We built the model in the training set and evaluated the performance of the model in the test set by using the artificial intelligence software Prediction One. Our machine learning-based model showed high discriminative ability to predict GD in the test set (area under the curve [AUC] 0.99). The main contributing factors to predict GD included age and serum creatinine, total cholesterol, alkaline phosphatase, and total protein levels. We still found high discriminative ability even when we restricted the variables to these five most contributory factors in our prediction model (AUC 0.97) built by using artificial intelligence software showed high GD prediction ability based on information regarding only five factors.

Introduction: This study aimed to clarify the diagnostic structural features in cytology specimens that are useful in subtyping non-small cell lung carcinoma (NSCLC) into adenocarcinoma (ADC) and squamous cell carcinoma (SQCC). Methods: Cytology specimens (n = 233) of NSCLCs, which included ADCs (n = 149) and SQCCs (n = 84), were analyzed. The following cytological features were evaluated: isolated cell, flat sheet, three-dimensional cluster with irregular arrangement, papillary-like structure, micropapillary-like structure, acinar-like structure, palisading pattern, protrusion of nuclei at the periphery of the cluster, honeycomb pattern, streaming arrangement, three-dimensional sheets with regular arrangement, flattening at the periphery of the cluster, fuzzy pattern at the periphery of the cluster, and mutual inclusion. Results: ADCs exhibited significantly higher frequencies of flat sheet (p < 0.001), papillary-like structure (p < 0.001), micropapillary-like structure (p = 0.028), acinar-like structure (p < 0.001) and protrusion of nuclei at the periphery of the cluster (p < 0.001) than SQCCs. The latter exhibited significantly higher frequencies of streaming arrangement (p < 0.001), three-dimensional sheets with regular arrangement (p < 0.001), flattening at the periphery of the cluster (p < 0.001), fuzzy pattern at the periphery of the cluster (p < 0.001), and mutual inclusion (p < 0.001) than ADCs. Discussion/Conclusion: Cytological structural features, such as flat sheet, papillary-like structure, micropapillary-like structure, acinar-like structure, and protrusion of nuclei at the periphery of the cluster, indicated ADC, whereas streaming arrangement, three-dimensional sheets with regular arrangement, flattening at the periphery of the cluster, fuzzy pattern at the periphery of the cluster, and mutual inclusion indicated SQCC. Paying attention to these cytological structural features can enable the accurate subtyping of NSCLC into ADC and SQCC.

Background: Coronary artery calcium (CAC) has been widely recognized as an important predictor of cardiovascular disease (CVD). Given the finite resources, it is important to identify individuals who would receive the most benefit from detecting positive CAC by screening. However, the evidence is limited as to whether the burden of positive CAC on CVD differs by multidimensional individual characteristics. We sought to investigate the heterogeneity in the association between positive CAC and incident CVD. Methods: This cohort study included adults from MESA (Multi-Ethnic Study of Atherosclerosis) ages ≥45 years and free of cardiovascular disease. After propensity score matching in a 1:1 ratio, we applied a machine learning causal forest model to (1) evaluate the heterogeneity in the association between positive CAC and incident CVD, and (2) predict the increase in CVD risk at 10-years when CAC>0 (versus CAC=0) at the individual level. We then compared the estimated increase in CVD risk when CAC>0 to the absolute 10-year atherosclerotic CVD (ASCVD) risk calculated by the 2013 American College of Cardiology/American Heart Association pooled cohort equations. Results: Across 3328 adults in our propensity score–matched analysis, our causal forest model showed the heterogeneity in the association between CAC>0 and incident CVD. We found a dose–response relationship of the estimated increase in CVD risk when CAC>0 with higher 10-year ASCVD risk. Almost all individuals (2293 of 2428 [94.4%]) with borderline risk of ASCVD or higher showed ≥2.5% increase in CVD risk when CAC>0. Even among 900 adults with low ASCVD risk, 689 (69.2%) showed ≥2.5% increase in CVD risk when CAC>0; these individuals were more likely to be male, Hispanic, and have unfavorable CVD risk factors than others. Conclusions: The expected increases in CVD risk when CAC>0 were heterogeneous across individuals. Moreover, nearly 70% of people with low ASCVD risk showed a large increase in CVD risk when CAC>0, highlighting the need for CAC screening among such low-risk individuals. Future studies are needed to assess whether targeting individuals for CAC measurements based on not only the absolute ASCVD risk but also the expected increase in CVD risk when CAC>0 improves cardiovascular outcomes.

Psychosocial stress is a key contributing factor to the pathogenesis of hypertension and cardiovascular disease. We examined the association of urinary stress hormone levels with incident hypertension and cardiovascular events. This prospective cohort study included 412 adults (age 48–87 years) free of hypertension from the Multi-Ethnic Study of Atherosclerosis with measurements of urinary stress hormones (norepinephrine, epinephrine, dopamine, and cortisol). Multivariable Cox proportional hazard models were used to estimate the adjusted hazard ratio (aHR) of incident hypertension and cardiovascular events according to urinary stress hormone levels. The average age (SD) was 61.2 (9.1) years, and 50% were female. Over a median follow-up of 6.5 years, there was an increased risk of incident hypertension per doubling of norepinephrine (aHR, 1.31 [95% CI, 1.06–1.61]), epinephrine (aHR, 1.21 [95% CI, 1.03–1.41]), dopamine (aHR, 1.28 [95% CI, 1.00–1.64]), and cortisol (aHR, 1.23 [95% CI, 1.04–1.44]). The associations were generally stronger among participants P -for-interaction, 0.04) and cortisol ( P -for-interaction, 0.04). Over a median follow-up of 11.2 years, there was an increased risk of incident cardiovascular events per doubling of cortisol (aHR, 1.90 [95% CI, 1.16–3.09]), but not for catecholamines. In this multiethnic population study, higher urinary stress hormone levels were associated with an increased risk of incident hypertension. Urinary cortisol levels were also associated with an increased risk of incident cardiovascular events. Our findings highlight a potentially important role of stress hormones in the prevention and treatment of hypertension and cardiovascular diseases.

An inappropriately low frequency of healthcare utilization has been reported to be associated with poor control of chronic diseases, accelerating healthcare disparities. However, the evidence is limited regarding the association between no healthcare utilization and mortality.To examine whether individuals without healthcare utilization have the increased risks of mortality among the US general population.Prospective cohort study PARTICIPANTS: Adults aged ≥ 20 years (n = 39,067) in the National Health and Nutrition Examination Survey (NHANES)1999-2014 linked to national mortality data through December 2015.The exposure was the number of visits to healthcare providers during the past year (healthcare utilization): none, 1-3 times (referent), 4-9 times, or ≥ 10 times. Cox hazard regression models were employed to estimate the adjusted hazard ratios (aHR) of all-cause, cardiovascular, and cancer mortality adjusting for socio-demographic characteristics and comorbidities.During a median follow-up of 7.4 years, participants without visit over the past year showed higher risks of all-cause mortality (aHR [95% CI] = 1.16 [1.04-1.30]) and cardiovascular mortality (aHR [95% CI] = 1.62 [1.28-2.05]) than those who visited the office 1-3 times. We found no evidence of the association between no visit and cancer mortality. The association between no providers' office visit and all-cause mortality was stronger among males (aHR [95% CI] = 1.22 [1.06-1.40]) than females (aHR [95% CI] = 0.97 [0.79-1.19]; p-for-interaction = 0.01) and among uninsured individuals (aHR [95% CI] = 1.22 [0.98-1.51]) than insured individuals (aHR [95% CI] = 1.09 [0.95-1.25]; p-for-interaction = 0.04).No providers' office visit over a year was associated with increased risks of all-cause and cardiovascular mortality. Further investigations are warranted to identify the underlying reasons for the elevated mortality risks due to no healthcare utilization.

Background A study has shown that industry payments to physicians for drugs are associated not only with higher drug prescriptions but also with higher non-drug costs due to additional utilization of healthcare services. However, the association between industry payments to cardiologists for antiplatelet drugs and the costs and number of percutaneous coronary interventions they perform has not been investigated. Objective To examine the association between industry payments to cardiologists for antiplatelet drugs and the costs and number of percutaneous coronary interventions they perform. Design Using the 2016 Open Payments Database linked to the 2017 Medicare Provider Utilization and Payment Data, we examined the association between the value of industry payments related to the antiplatelet drugs prasugrel and ticagrelor and healthcare spending and volume for cardiovascular procedures, adjusted for potential cofounders. Subjects A total of 7456 cardiologists who performed diagnostic cardiac catheterizations on Medicare beneficiaries in 2017. Main Measures Primary outcomes included (1) healthcare spending on cardiac procedures, (2) diagnostic cardiac catheterization volumes, and (3) rates of coronary stenting. Secondary outcomes were total expenditures for all drugs and for antiplatelet drugs. Key Results Industry payments for antiplatelet drugs were associated with higher healthcare spending on cardiac procedures (adjusted difference, +$50.9 for additional $100 industry payments; 95% CI, +$25.5 to +$76.2; P < 0.001), diagnostic cardiac catheterizations (+0.1 procedures per cardiologist; 95% CI, +0.03 to +0.1; P=0.001), and stent use (+0.5 per 1000 diagnostic cardiac catheterizations per cardiologist; 95% CI, +0.2 to +0.9; P=0.002). Industry payments for antiplatelet drugs were associated with higher total costs for all drugs and antiplatelet drugs. Conclusions Industry payments to cardiologists for antiplatelet drugs were associated with both prescribing of antiplatelet drugs and the use of cardiac procedures and stents. Further research is warranted to understand whether the observed associations are causal or reflect a greater propensity for higher volume proceduralists to have relationships with industry.

Introduction Hypertension is one of the most common clinical features of patients with overt and subclinical hypercortisolism. Although previous studies have shown the coexistence of autonomous cortisol and aldosterone secretion, it is unclear whether aldosterone plays a role in hypertension among patients with hypercortisolism. Therefore, we examined the associations of plasma aldosterone concentrations (PACs) with hypertension among patients with overt and subclinical hypercortisolism. Methods This single-center retrospective cohort study included patients with adrenal tumor and serum cortisol levels after 1-mg dexamethasone suppression test >1.8 µg/dL (50 nmol/L). Using multivariable regression models adjusting for baseline characteristics, we investigated the association of PACs with systolic blood pressure and postoperative improvement of hypertension after the adrenalectomy. Results Among 89 patients enrolled in this study (median age, 51 years), 21 showed clinical signs of Cushing syndrome (overt hypercortisolism) and 68 did not show clinical presentations (subclinical hypercortisolism). We found that higher PACs were significantly associated with elevated systolic blood pressure among patients with subclinical hypercortisolism (adjusted difference [95% CI] = +0.59 [0.19-0.99], P = 0.008) but not among those with overt hypercortisolism. Among 33 patients with subclinical hypercortisolism and hypertension who underwent adrenalectomy, the postoperative improvement of hypertension was significantly associated with higher PACs at baseline (adjusted risk difference [95% CI] = +1.45% [0.35-2.55], P = 0.01). Conclusion These findings indicate that aldosterone may contribute to hypertension among patients with subclinical hypercortisolism. Further multi-institutional and population-based studies are required to validate our findings and examine the clinical effectiveness of the intervention targeting aldosterone for such patients.

Iodine-induced thyroid dysfunction is a potential risk among susceptible individuals. Iodinated contrast media is a common source of an acute iodine load used in the healthcare setting and is frequently required for diagnostic computed tomography scans, coronary angiograms, and other radiologic studies. However, the epidemiologic risks of iodine-thyroid dysfunction have not been fully established in the U.S.This population-based retrospective cohort study used the U.S. Veterans Health Administration database between 1998-2021 and included adults aged ≥18 years with a serum thyrotropin (TSH) measurement. Multivariable logistic regression was employed to ascertain the risk of incident thyroid dysfunction (defined by repeated measurements of serum thyroid function) following iodine exposure, adjusting for age, sex, race/ethnicity, baseline serum TSH concentration, and duration between baseline and follow up TSH concentration.The cohort was composed of N=4,253,119 Veterans (mean±SD, 63.5±14.3 years; 92.9% male; 65.6% non-Hispanic Whites) with 8,729,155 corresponding pairs of serum TSH measurements, from which there were 499,897 TSH pairs with intervening iodine exposure. Thyroid dysfunction occurred in 4.8% of those pairs who had received iodine contrast and 3.6% of those without iodine exposure. Iodinated exposure was associated with an increased risk of thyroid dysfunction (OR 1.39, 95% CI 1.37-1.41, p0.001) and consistent for all types of serum thyroid dysfunction (overt or subclinical hypo-/hyper-thyroidism). Males were at higher risk for the development of thyroid dysfunction than females (males, OR 1.42, 95% CI 1.40-1.44; females, OR 1.16, 95% CI 1.11-1.21; p-for-interaction0.001).In this largest analysis of U.S. adults to date, iodine exposure was associated with only clinically small absolute increased risks of thyroid dysfunction, particularly in males. These findings suggest that screening of thyroid function following iodinated contrast administration should be targeted to high-risk individuals.

BackgroundIodine and particularly its oxidated forms have long been recognized for its effective antiseptic properties. Limited in vitro and in vivo data suggest that iodine exposure may rapidly inactivate, reduce transmission, and reduce infectivity of SARS-CoV-2. We hypothesized that iodine exposure may be associated with decreased incident COVID-19 infection.MethodsA retrospective population-level cohort analysis was performed of the U.S. Veterans Health Administration between 1 March 2020 and 31 December 2020, before the widespread availability of vaccines against SARS-CoV-2. Multivariable logistic regression models estimated the adjusted odds ratios (OR) and 95% confidence intervals (CI) of the associations between iodinated contrast exposure and incident COVID-19 infection, adjusting for age, sex, race/ethnicity, place of residence, socioeconomic status, and insurance status.Results530,942 COVID-19 tests from 333,841 Veterans (mean ± SD age, 62.7 ± 15.2 years; 90.2% men; 61.9% non-Hispanic Whites) were analyzed, of whom 9% had received iodinated contrast ≤60 days of a COVID-19 test. Iodine exposure was associated with decreased incident COVID-19 test positivity (OR, 0.75 95% CI, 0.71–0.78). In stratified analyses, the associations between iodinated contrast use and decreased COVID-19 infection risk did not differ by age, sex, and race/ethnicity.ConclusionIodine exposure may be protective against incident COVID-19 infection. Weighed against the risks of supraphysiologic iodine intake, dietary, and supplemental iodine nutrition not to exceed its Tolerable Upper Limit may confer an antimicrobial benefit against SARS-CoV-2. A safe but antimicrobial level of iodine supplementation may be considered in susceptible individuals, particularly in geographic regions where effective COVID-19 vaccines are not yet readily available.

Background Japan has conducted a nationwide annual health check-up program since 2008, focusing on metabolic syndrome and subsequent health guidance in individuals at high risk for cardiovascular disease. However, the adherence rate to health guidance invitations was assumed to be low in previous reports. Therefore, this study aimed to characterize adherence patterns in the program and identify major predictors of adherence to health guidance invitations. Methods We studied 186,316 adults (aged 40–74 years) who were included in a nationwide employer-sponsored insurer’s database in Japan at the beginning of the fiscal year 2017. We first described adherence to health check-ups, the proportion of individuals with high cardiovascular risk, and adherence to health guidance invitations. Predictors of adherence to the invitation were then identified among eligible high-risk individuals. Results In 2017, 71.7% of the study population (n = 133,573) underwent health check-ups, among whom 23.2% (n = 30,979) were invited for health guidance because of their high cardiovascular risk. Among those individuals, 35.2% (n = 10,614) received health guidance. Predictors of improved adherence to health guidance invitation were older age, more concerning blood pressure or laboratory data results, and self-reported motivation for a lifestyle change. Conclusion Though 70% of eligible adults attended Japan’s annual cardiovascular risk check-ups, only 35% of individuals with high cardiovascular risk adhered to health guidance invitations. Future policy reforms to improve adherence to this program should target younger individuals and those with mild stages of hypertension, diabetes, or dyslipidemia.

In patients with primary aldosteronism diagnosed with unilateral lesions through adrenal venous sampling, excess aldosterone occasionally persists after adrenalectomy. We investigated whether aldosterone values from unresected adrenals would be associated with postoperative outcomes. Overall, 102 primary aldosteronism patients, who underwent segmental adrenal venous sampling and unilateral adrenalectomy, were assessed for biochemical success (as outlined in the PASO [Primary Aldosteronism Surgical Outcomes] Study) at 1 year after surgery by using the saline infusion test. We divided patients into the biochemical complete or incomplete success group. Eighty-seven and 15 patients had complete and incomplete biochemical success, respectively. The biochemical incomplete group, compared with the biochemical complete group, had higher maximum aldosterone in tributary veins (11 000 versus 7030 pg/mL, P =0.006), maximum aldosterone/cortisol in tributary veins (18.05 versus 9.13, P P =0.011), and aldosterone/cortisol in the central vein (13.67 versus 8.08, P

Context The preventive effect of sodium-glucose cotransporter 2 (SGLT2) inhibitors for new-onset diabetes was investigated in secondary analyses of several randomized controlled trials (RCTs). However, the results were inconsistent. Objective This work aimed to synthesize available evidence and evaluate whether SGLT2 inhibitors are effective in preventing new-onset diabetes. Methods In this systematic review and meta-analysis of RCTs, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched through February 11, 2022. Two independent authors screened the search results and extracted summary data from eligible RCTs (including original and post hoc analyses) comparing SGLT2 inhibitors and placebo for the risk of new-onset diabetes among adults with prediabetes. Meta-analysis was conducted using random-effects models to calculate risk ratios and 95% CIs. Results We included 4 RCTs with 5655 participants who had prediabetes. Based on the random-effects meta-analysis, SGLT2 inhibitors were significantly associated with a lower risk of new-onset diabetes (relative risk, 0.79; 95% CI, 0.68-0.93). The relative risks of new-onset diabetes in dapagliflozin and empagliflozin were 0.68 (95% CI, 0.52-0.89) and 0.87 (95% CI, 0.72-1.04), respectively (P-for-heterogeneity = .14). The frequency of severe hypoglycemia was not elevated in the SGLT2 inhibitors group compared to the placebo group. Conclusion In this meta-analysis, SGLT2 inhibitors were associated with a reduced risk of new-onset type 2 diabetes among adults with prediabetes and heart failure or chronic kidney disease. These findings indicate the potential usefulness of SGLT2 inhibitors in preventing diabetes among high-risk populations with prediabetes.

Background Primary aldosteronism can cause cardiac dysfunction, including left ventricular hypertrophy, left ventricular diastolic dysfunction, and left atrial enlargement. A few studies have compared the cardioprotective effects between surgery and medication for primary aldosteronism, although most have not adjusted for baseline disease status. In this study, we investigated the difference in cardiovascular outcomes between surgery and medication treatment for primary aldosteronism after adjusting for baseline clinical characteristics, including aldosterone level and pretreatment echocardiographic information. Methods and Results We retrospectively analyzed 220 patients diagnosed with primary aldosteronism who underwent adrenalectomy (n=144) or medication treatment (n=76) between 2009 and 2019. Echocardiographic changes were evaluated pretreatment and 1 year posttreatment. The surgery group had lower potassium, lower plasma renin activity, and higher plasma aldosterone concentration than the medication group, indicating a severe primary aldosteronism phenotype in the former. The decrease in left ventricular mass index after treatment was significantly greater in the surgery group than in the medication group ( P =0.047). However, this relationship was not noted after multivariable regression analysis (standard β=−0.08, P =0.17). Additionally, decreased parameter values related to left ventricular diastolic dysfunction and left atrial enlargement were not different between the groups. Pretreatment echocardiographic values were most associated with changes in all echocardiographic parameters. The findings were consistent in the propensity score‐matched analysis. Conclusions This study's findings suggest that there is no difference in cardioprotective efficacy between surgical and medication treatment under similar disease severity; however, it should be considered that several study participants with severe hyperaldosteronism were managed surgically.

Regular visits with healthcare professionals are important for preventing serious complications in patients with diabetes. The purpose of this retrospective cohort study was to clarify whether there was any suppression of physician visits among patients with diabetes during the spread of the novel coronavirus 2019 (COVID-19) in Japan and to assess whether telemedicine contributed to continued visits.We used the JMDC Claims database, which contains the monthly claims reported from July 2018 to May 2020 and included 4,595 (type 1) and 123,686 (type 2) patients with diabetes. Using a difference-in-differences analysis, we estimated the changes in the monthly numbers of physician visits or telemedicine per 100 patients in April and May 2020 compared with the same months in 2019.For patients with type 1 diabetes, the estimates for total overall physician visits were -2.53 (95% confidence interval [CI], -4.63 to 0.44) in April and -8.80 (95% CI, -10.85 to -6.74) in May; those for telemedicine visits were 0.71 (95% CI, 0.47-0.96) in April and 0.54 (95% CI, 0.32-0.76) in May. For patients with type 2 diabetes, the estimates for overall physician visits were -2.50 (95% CI, -2.95 to -2.04) in April and -3.74 (95% CI, -4.16 to -3.32) in May; those for telemedicine visits were 1.13 (95% CI, 1.07-1.20) in April and 0.73 (95% CI, 0.68-0.78) in May.The COVID-19 pandemic was associated with suppression of physician visits and a slight increase in the utilization of telemedicine among patients with diabetes during April and May 2020.

BACKGROUND: An inappropriately low frequency of healthcare utilization has been reported to be associated with poor control of chronic diseases, accelerating healthcare disparities. However, the evidence is limited regarding the association between no healthcare utilization and mortality. OBJECTIVES: To examine whether individuals without healthcare utilization have the increased risks of mortality among the US general population. DESIGN: Prospective cohort study PARTICIPANTS: Adults aged ≥ 20 years (n = 39,067) in the National Health and Nutrition Examination Survey (NHANES)1999–2014 linked to national mortality data through December 2015. MAIN MEASURES: The exposure was the number of visits to healthcare providers during the past year (healthcare utilization): none, 1–3 times (referent), 4–9 times, or ≥ 10 times. Cox hazard regression models were employed to estimate the adjusted hazard ratios (aHR) of all-cause, cardiovascular, and cancer mortality adjusting for socio-demographic characteristics and comorbidities. KEY RESULTS: During a median follow-up of 7.4 years, participants without visit over the past year showed higher risks of all-cause mortality (aHR [95% CI] = 1.16 [1.04–1.30]) and cardiovascular mortality (aHR [95% CI] = 1.62 [1.28–2.05]) than those who visited the office 1–3 times. We found no evidence of the association between no visit and cancer mortality. The association between no providers’ office visit and all-cause mortality was stronger among males (aHR [95% CI] = 1.22 [1.06–1.40]) than females (aHR [95% CI] = 0.97 [0.79–1.19]; p-for-interaction = 0.01) and among uninsured individuals (aHR [95% CI] = 1.22 [0.98–1.51]) than insured individuals (aHR [95% CI] = 1.09 [0.95–1.25]; p-for-interaction = 0.04). CONCLUSION: No providers’ office visit over a year was associated with increased risks of all-cause and cardiovascular mortality. Further investigations are warranted to identify the underlying reasons for the elevated mortality risks due to no healthcare utilization. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s11606-021-07138-0.

Although endoscopic resection with careful surveillance instead of total proctocolectomy become to be permitted for visible low-grade dysplasia, it is unclear how accurately endoscopists can differentiate these lesions, as classifying neoplasias occurring in inflammatory bowel disease (IBDN) is exceedingly challenging due to background chronic inflammation. We evaluated a pilot model of an artificial intelligence (AI) system for classifying IBDN and compared it with the endoscopist's ability.This study used a deep convolutional neural network, the EfficientNet-B3. Among patients who underwent treatment for IBDN at two hospitals between 2003 and 2021, we selected 862 non-magnified endoscopic images from 99 IBDN lesions and utilized 6 375 352 images that were increased by data augmentation for the development of AI. We evaluated the diagnostic ability of AI using two classifications: the "adenocarcinoma/high-grade dysplasia" and "low-grade dysplasia/sporadic adenoma/normal mucosa" groups. We compared the diagnostic accuracy between AI and endoscopists (three non-experts and four experts) using 186 test set images.The diagnostic ability of the experts/non-experts/AI for the two classifications in the test set images had a sensitivity of 60.5% (95% confidence interval [CI]: 54.5-66.3)/70.5% (95% CI: 63.8-76.6)/72.5% (95% CI: 60.4-82.5), specificity of 88.0% (95% CI: 84.7-90.8)/78.8% (95% CI: 74.3-83.1)/82.9% (95% CI: 74.8-89.2), and accuracy of 77.8% (95% CI: 74.7-80.8)/75.8% (95% CI: 72-79.3)/79.0% (95% CI: 72.5-84.6), respectively.The diagnostic accuracy of the two classifications of IBDN was higher than that of the experts. Our AI system is valuable enough to contribute to the next generation of clinical practice.

Background It is often challenging to determine which variables need to be included in the g-computation algorithm under the time-varying setting. Conditioning on instrumental variables (IVs) is known to introduce greater bias when there is unmeasured confounding in the point-treatment settings, and this is also true for near-IVs which are weakly associated with the outcome not through the treatment. However, it is unknown whether adjusting for (near-)IVs amplifies bias in the g-computation algorithm estimators for time-varying treatments compared to the estimators ignoring such variables. We thus aimed to compare the magnitude of bias by adjusting for (near-)IVs across their different relationships with treatments in the time-varying settings. Methods After showing a case study of the association between the receipt of industry payments and physicians’ opioid prescribing rate in the US, we demonstrated Monte Carlo simulation to investigate the extent to which the bias due to unmeasured confounders is amplified by adjusting for (near-)IV across several g-computation algorithms. Results In our simulation study, adjusting for a perfect IV of time-varying treatments in the g-computation algorithm increased bias due to unmeasured confounding, particularly when the IV had a strong relationship with the treatment. We also found the increase in bias even adjusting for near-IV when such variable had a very weak association with unmeasured confounders between the treatment and the outcome compared to its association with the time-varying treatments. Instead, this bias amplifying feature was not observed (i.e., bias due to unmeasured confounders decreased) by adjusting for near-IV when it had a stronger association with the unmeasured confounders (≥0.1 correlation coefficient in our multivariate normal setting). Conclusion It would be recommended to avoid adjusting for perfect IV in the g-computation algorithm to obtain a less biased estimate of the time-varying treatment effect. On the other hand, it may be recommended to include near-IV in the algorithm unless their association with unmeasured confounders is very weak. These findings would help researchers to consider the magnitude of bias when adjusting for (near-)IVs and select variables in the g-computation algorithm for the time-varying setting when they are aware of the presence of unmeasured confounding.

Despite the potential burden of social isolation on mental health, it is unclear which component of social isolation (living alone, lack of social support, and lack of social participation) is mostly associated with depression among older adults and whether it varies by gender. Moreover, previous observational studies have suffered from several systematic biases such as confounding, misclassification, and selection bias. We thus aimed to investigate the risk of social isolation on subsequent depressive symptoms among older men and women, fully taking account of such systematic biases simultaneously.This study included 15,311 adults from a nationwide longitudinal cohort study of older adults aged ≥65 years in Japan. We employed modified Poisson regression models to estimate the adjusted risk ratio (aRR) of elevated depressive symptoms (the Geriatric Depression Scale: ≥5 vs.5) in 2016 according to the social isolation index (SII) score (0-5 points) in 2013. Non-probabilistic multiple bias analyses with weighting approach and bounding factor were conducted to adjust for possible confounding, exposure misclassification, and selection biases.The mean age (SD) of participants was 72.1 (4.9) years. Adults with the SII score ≥2 showed an increased risk of elevated depressive symptoms than those with the SII score2 (aRR [95% CI] = 1.57 [1.41-1.76]). All components of SII were associated with elevated depressive symptoms except living alone for women. Our multiple bias analysis showed that an unmeasured confounder needed to have at least moderate relationship (RR=2.0-3.0) with both exposure and outcome to explain away the observed association particularly when social isolation status was independently and non-differentially misclassified.Among older adults in Japan, social isolation was associated with an increased risk of elevated depressive symptoms, even after taking account of systematic biases simultaneously. Increasing social connection may mitigate the risk of depression, which should be the subject of future research.

PURPOSE OF REVIEW: Review how to use metabolomic profiling in causal mediation analysis to assess epidemiological evidence for air pollution impacts on birth outcomes. RECENT FINDINGS: Maternal exposures to air pollutants have been associated with pregnancy complications and adverse pregnancy and birth outcomes. Causal mediation analysis enables us to estimate direct and indirect effects on outcomes (i.e., effect decomposition), elucidating causal mechanisms or effect pathways. Maternal metabolites and metabolic pathways are perturbed by air pollution exposures may lead to adverse pregnancy and birth outcomes, thus they can be considered mediators in the causal pathways. Metabolomic markers have been used to explain the biological mechanisms linking air pollution and respiratory function, and of arsenic exposure and birth weight. However, mediation analysis of metabolomic markers has not been used to assess air pollution effects on adverse birth outcomes. In this article, we describe the assumptions and applications of mediation analysis using metabolomic markers that elucidate the potential mechanisms of the effects of air pollution on adverse pregnancy and birth outcomes. SUMMARY: The hypothesis of mediation along specified pathways can be assessed within the structural causal modeling framework. For causal inferences, several assumptions that go beyond the data—including no uncontrolled confounding—need to be made to justify the effect decomposition. Nevertheless, studies that integrate metabolomic information in causal mediation analysis may greatly improve our understanding of the effects of ambient air pollution on adverse pregnancy and birth outcomes as they allow us to suggest and test hypotheses about underlying biological mechanisms in studies of pregnant women.

Aldosterone is a steroid hormone regulating fluid and electrolyte homeostasis and is known to increase the risk of atherosclerosis. In this study, we examined the associations of serum aldosterone concentrations with subclinical atherosclerosis and all-cause mortality. This study included 948 adults aged 46 to 88 years from the MESA (Multi-Ethnic Study of Atherosclerosis) with measurements of serum aldosterone and plasma renin activity and not taking antihypertensive medications. Coronary calcification was longitudinally assessed using Agatston coronary artery calcium score from computed tomography scans. All-cause mortality was ascertained from the medical record. The average age (SD) was 62.3 (9.4) years and 53% were male. Among 700 subjects who had follow-up coronary artery calcium score (median follow-up of 6.4 years), higher aldosterone levels (per 100 pg/mL) were associated with higher coronary artery calcium (relative ratio, 1.17 [95% CI, 1.04–1.32]), with the association being stronger in individuals with suppressed plasma renin activity (≤0.5 μg/L/hr). Systolic or diastolic blood pressure mediated around 45% of the total effect of aldosterone on coronary artery calcium. Over a median follow-up of 12.5 years (120 deaths identified among 948 subjects), aldosterone was associated with the increased risk of all-cause mortality when plasma renin activity was suppressed; hazard ratio per 100 pg/mL, 1.70 (95% CI, 1.10–2.63). In this study, we found that higher aldosterone levels were associated with the increased risk of subclinical coronary atherosclerosis and all-cause mortality particularly when renin was suppressed. Our findings indicate the importance of aldosterone levels (even within the reference range) with respect to the cardiovascular system and overall health.

Discovering pathophysiologic networks in a blood-based approach may help to generate valuable tools for early treatment or preventive measures in autism. To date targeted or untargeted metabolomics approaches to identify metabolic features and pathways affecting fetal neurodevelopment have rarely been applied to pregnancy samples, that is, an early period potentially relevant for the development of autism spectrum disorders (ASD). We conducted a population-based study relying on autism diagnoses retrieved from California Department of Developmental Services record. After linking cases to and sampling controls from birth certificates, we retrieved stored maternal mid-pregnancy serum samples collected as part of the California Prenatal Screening Program from the California Biobank for children born 2004 to 2010 in the central valley of California. We retrieved serum for 52 mothers whose children developed autism and 62 population controls originally selected from all eligible children matched by birth year and child's sex. Also, we required that these mothers were relatively low or unexposed to air pollution and select pesticides during early pregnancy. We identified differences in metabolite levels in several metabolic pathways, including glycosphingolipid biosynthesis and metabolism, N-glycan and pyrimidine metabolism, bile acid pathways and, importantly, C21-steroid hormone biosynthesis and metabolism. Disturbances in these pathways have been shown to be relevant for neurodevelopment in rare genetic syndromes or implicated in previous studies of autism. This study provides new insight into maternal mid-pregnancy metabolic features possibly related to the development of autism and an incentive to explore whether these pathways and metabolites are useful for early diagnosis, treatment, or prevention. LAY SUMMARY: This study found that in mid-pregnancy the blood of mothers who give birth to a child that develops autism has some characteristic features that are different from those of blood samples taken from control mothers. These features are related to biologic mechanisms that can affect fetal brain development. In the future, these insights may help identify biomarkers for early autism diagnosis and treatment or preventive measures. Autism Res 2020, 13: 1258-1269. © 2020 International Society for Autism Research, Wiley Periodicals, Inc.

The association of intra‐individual variability in insulin requirements with C‐reactive protein levels among acute phase patients remains unclear. This retrospective cohort study aimed to evaluate this association. Patients with type 2 diabetes undergoing surgery for lumbar spinal canal stenosis were included in the study. We analyzed 286 records of 49 patients using the linear mixed effects model. The model showed C‐reactive protein levels to be significantly associated with insulin requirements, with an effect size of 0.60 U/day for an elevation of 1 mg/dL. The effect size was increased in patients with higher hemoglobin A1c levels. Our findings imply that C‐reactive protein levels could be a useful clinical biomarker when blood glucose levels are controlled in acute phase patients., Our study aimed to show the association between C‐reactive protein levels and insulin requirement in acute phase patients, using longitudinal data and the linear mixed effects model. The model showed that C‐reactive protein levels were significantly associated with the amount of insulin administered in postoperative patients with lumbar spinal canal stenosis. Our findings showed that C‐reactive protein levels could be a metric for controlling insulin administration, which would help clinicians control blood glucose levels.

Although scatter correction improves SPECT image contrast and thus image quality, the effects of quantitation accuracy under various conditions remain unclear. The present study aimed to empirically define the conditions for the optimal scatter correction of quantitative bone SPECT/CT images. Scatter correction was performed by applying dual and triple energy windows (DEW and TEW) with different sub-energy window widths, and effective scatter source estimation (ESSE) to CT-based scatter correction. Scattered radiation was corrected on images acquired using a triple line source (TLSP) phantom and an uniform cylinder phantom. The TLSP consisted of a line source containing 74.0 MBq of 99mTc in the middle, and a background component containing air, water or a K2HPO4 solution with a density equivalent to that of bone. The sum of all pixels in air, water and the K2HPO4 solution was measured on SPECT images. Scatter fraction (SF) and normalized mean square error (NMSE) based on counts from the air background as a reference were then calculated to assess quantitative errors due to scatter correction. The uniform cylinder phantom contained the same K2HPO4 solution and 222.0 MBq of 99mTc. The coefficient of variation (CV) was calculated from the count profile of this phantom to assess the uniformity of SPECT images across scatter correction under various conditions. Both SF and NMSE in SPECT images of phantoms containing water in the background were lower at a TEW sub-window of 3% (TEW3%), than in other scatter corrections, whereas those in K2HPO4 were lower at a DEW sub-window of 20% (DEW20%). Larger DEW and smaller TEW sub-energy windows allowed more effective correction. The CV of the uniform cylinder phantom, DEW20%, was inferior to all other tested scatter corrections. The quantitative accuracy of bone SPECT images substantially differed according to the method of scatter correction. The optimal scatter correction for quantitative bone SPECT was DEW20% (k = 1), but at the cost of slightly decreased image uniformity.

金沢大学理工研究域地球社会基盤学系, Relative abundance of magnetite originated from magnetotactic bacteria (magnetofossils) in sediments may influence relative paleointensity (RPI) estimations of the geomagnetic field, as some studies reported an inverse correlation between RPI and the ratio of anhysteretic remanent magnetization susceptibility to saturation isothermal remanent magnetization (kARM/SIRM), a proxy of the proportion of biogenic to terrigenous magnetic minerals as well as magnetic grain size. This study aims to evaluate the influence of magnetofossils on RPI estimations more selectively using first-order reversal curve (FORC) diagrams. We studied three cores (KR0515-PC4, MD982187, and MR1402-PC1) from the western equatorial Pacific, among which large differences exist in the average natural remanent magnetization intensity normalized by ARM and kARM/SIRM. Principal component analyses (PCAs) were applied to FORC diagrams measured on bulk specimens from the three cores and silicate-hosted magnetic inclusions extracted from Core MD982187, and three endmembers (EMs) were revealed (EM1: silicate-hosted magnetic inclusions, EM2: other terrigenous, EM3: biogenic). EM3 proportions vary widely among the three cores. The average RPI decreases with increasing EM3 proportion, which is probably caused by higher ARM acquisition efficiency of magnetofossils due to small magnetostatic interactions. EM3 proportion correlates with kARM/SIRM, which confirms that kARM/SIRM represents the proportion of biogenic to terrigenous magnetic components. Core MR1402-PC1 has the highest EM3 proportion, and its within-core variation is small. From FORC-PCA applied solely to this core, we infer that the configurations of biogenic magnetite chains such as bending and collapse may also influence kARM/SIRM and RPI estimations. © 2021. The Authors.

Background Preexisting diabetes may contribute to the indication for adjuvant chemotherapy among patients with colorectal cancer (CRC); however, the association between diabetes and its implementation is largely unknown. Methods We analyzed the hospital-based cancer registry and health claims data of patients with stage III CRC who received curative surgery in 2013 in Japan (n = 6,344). Chemotherapy and diabetes was identified based on procedure, prescription, and diabetes codes in claims data. We examined the association between diabetes and implementation rate of adjuvant chemotherapy using the generalized linear model adjusted for age, sex, and updated Charlson Comorbidity Index, hospital type, and prefecture. We further applied a mediation analysis to examine the extent to which postoperative complications mediated the association. Results Of these, 1,236 (19.5%) had diabetes. Compared with those without diabetes, patients with diabetes were less likely to receive adjuvant chemotherapy (crude rate: 58.9% and 49.8%; adjusted percentage point difference: 4.7% [95% confidence limits: 1.7, 7.5]). Mediation analysis indicated that postoperative complications explained 9.4% of the association between diabetes and adjuvant chemotherapy implementation. Conclusions Our findings suggest that patients with stage III CRC and diabetes are less likely to receive adjuvant chemotherapy than those without diabetes, and postoperative complications may partially account for the association. Key messages Concomitant diabetes might negatively impact the implementation rate of adjuvant chemotherapy in patients with stage III CRC.

Adverse childhood experiences (ACEs) have been linked to diminished health achievement across the life course. However, few studies have rigorously investigated the role of adult socioeconomic status (SES) as a mediator and an effect modifier of the association between ACEs and late-life depression. We used a four-way decomposition analysis to examine the relative contributions of mediation and interaction by low adult SES to the association between ACEs and late-life depression.Data came from two waves (2013 and 2016) of the Japan Gerontological Evaluation Study, a nationwide cohort of older people (n = 7271). ACEs were determined as ≥ 2 experiences of the following: parental loss, parental divorce, parental mental illness, domestic violence, physical abuse, psychological neglect, psychological abuse, and economic disadvantage. Low adult SES was defined as earning 2 million yen of income and 10 years of schooling. Depressive symptoms were assessed using the Geriatric Depression Scale.Controlled direct effect (coefficient 0.28; 95% CI 0.08-0.46) accounted for 69.1% of the total effect, which was greater than the other three estimates for the decomposed effects (reference interaction 20.8%, mediated interaction 5.7%, and pure indirect effect 4.4%). Adult SES accounted for 10.1% (via mediation) and 26.5% (via exposure-mediator interaction) of the total association between ACEs and depressive symptoms, respectively.ACEs appeared to be a strong and independent determinant of depressive symptoms in later life. Nonetheless, the interaction between ACEs and adult SES indicates that achieving high adult SES could mitigate the adverse effect of ACEs on late-life depression.

Objective It is unclear whether relatively low glycated haemoglobin (HbA1c) levels are beneficial or harmful for the long-term health outcomes among people without diabetes. We aimed to investigate the association between low HbA1c levels and mortality among the US general population. Methods This study includes a nationally representative sample of 39 453 US adults from the National Health and Nutrition Examination Surveys 1999–2014, linked to mortality data through 2015. We employed the parametric g-formula with pooled logistic regression models and the ensemble machine learning algorithms to estimate the time-varying risk of all-cause and cardiovascular mortality by HbA1c categories (low, 4.0 to Results Over a median follow-up of 7.5 years, 5118 (13%) all-cause deaths, and 1116 (3%) cardiovascular deaths were observed. Logistic regression models and machine learning algorithms showed nearly identical predictive performance of death and risk estimates. Compared with mid-level HbA1c, low HbA1c was associated with a 30% (95% CI, 16 to 48) and a 12% (95% CI, 3 to 22) increased risk of all-cause mortality at 5 years and 10 years of follow-up, respectively. We found no evidence that low HbA1c levels were associated with cardiovascular mortality risk. The diabetes group, but not the prediabetes group, also showed an increased risk of all-cause mortality. Conclusions Using the US national database and adjusting for an extensive set of potential confounders with flexible modelling, we found that adults with low HbA1c were at increased risk of all-cause mortality. Further evaluation and careful monitoring of low HbA1c levels need to be considered.

ObjectiveTo determine changes in industry marketing payments to physicians due to the covid-19 pandemic.DesignQuasi experimental, difference-in-difference study.Data sourceUS nationwide database of licensed physicians, the National Plan and Provider Enumeration System, which was linked to a database of industry marketing payments made to physicians, Open Payments.PopulationAll licensed US physicians from 2018 to 2020 and those who received payments from industry.Main outcome measuresChanges in the value and the number of monthly industry payments physician received before (January-February 2020) and during the pandemic (April-December 2020) were assessed, adjusting for physicians’ characteristics (gender and specialty). As the control, data for the same months in 2019 were used. Industry payments by type of payments (eg, meals, travel, consulting fees, speaker compensation, honorariums), were also examined.ResultsAmong 880 589 US physicians included in this study, 267 463 (30.4%) physicians received a total of 4 117 482 non-research payments with $626 million ($710 per physician; £610; €708) in 2020 (40-44% decrease from $1047m in 2018 and $1115m in 2019). Industry payments decreased significantly in the months of the covid-19 pandemic (adjusted change in the value of −48.4%; 95% confidence interval −50.6 to −46.2; PConclusionsIndustry payments to physicians, particularly those involving physical interactions such as meals and travel, substantially decreased during the pandemic. How such changes affect prescription practices and the quality of clinical practice in the long term should be investigated.

This cross-sectional study uses data from the National Health and Nutrition Examination Surveys to evaluate obesity trends among US adolescents from 1999 to 2018, stratified by household income and head of household education level.