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Agranulocytosis is a serious adverse effect of methimazole (MMI) and propylthiouracil (PTU), and although there have been reports suggesting a dose-dependent incidence in relation to both drugs, the evidence has not been conclusive. The objective of our study was to determine whether the incidences of agranulocytosis induced by MMI and PTU exhibit dose-dependency. The subjects were 27,784 patients with untreated Graves’ disease, 22,993 of whom were on an antithyroid drug treatment regimen for more than 90 days. Within this subset, 18,259 patients had been treated with MMI, and 4,734 had been treated with PTU. The incidence of agranulocytosis according to dose in the MMI group was 0.13% at 10 mg/day, 0.20% at 15 mg/day, 0.32% at 20 mg/day, and 0.47% at 30 mg/day, revealing a significant dose-dependent increase. In the PTU group, there were 0 cases of agranulocytosis at doses of 125 mg/day and below, 0.33% at 150 mg/day, 0.31% at 200 mg/day, and 0.81% at 300 mg/day, also revealing a significant dose-dependent increase. The incidence of agranulocytosis at MMI 15 mg and PTU 300 mg, i.e., at the same potency in terms of hormone synthesis inhibition, was 0.20% and 0.81%, respectively, and significantly higher in the PTU group. Our findings confirm a dose-dependent increase in the incidence of agranulocytosis with both drugs, but that at comparable thyroid hormone synthesis inhibitory doses PTU has a considerably higher propensity to induce agranulocytosis than MMI does.

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.

Background Although living alone versus with others is a key social element for cardiovascular prevention in diabetes, evidence is lacking about whether the benefit of intensive glycemic and blood pressure (BP) control differs by living arrangements. We thus aim to investigate heterogeneity in the joint effect of intensive glycemic and BP control on cardiovascular events by living arrangements among participants with diabetes. Methods and Results This study included 4731 participants with diabetes in the ACCORD‐BP (Action to Control Cardiovascular Risk in Diabetes‐Blood Pressure) trial. They were randomized into 4 study arms, each with glycated hemoglobin target (intensive,

Background The relationship between adverse childhood experiences (ACEs) and depression risk has been well documented. However, it remains unclear whether stress-related chronic conditions associated with ACEs, such as asthma, increase the long-term mental health burden of ACEs.Objective To investigate the joint association of ACEs and asthma with subsequent depressive symptoms among US adults.Methods This study used data from the Behavioural Risk Factor Surveillance System 2010, including 21 544 participants over 18 years old from four states where participants were questioned about ACEs. We used logistic regression models to calculate the adjusted OR (aOR) for elevated depressive symptoms evaluated by Patient Health Questionnaire-8 according to ACEs and asthma, along with marginal structural models (MSM) to consider ACE-related confounders between asthma and depression. We evaluated the additive interaction between ACEs and asthma on depressive symptoms with the relative excess risk due to interaction (RERI).Findings Of the 21 544 participants (mean age: 56, women: 59.5%), 52.3% reported ≥1 ACEs, 14.9% reported a history of asthma and 4.0% had depressive symptoms. ACEs and asthma were independently associated with elevated depressive symptoms (aORs (95% CI) were 2.85 (2.30 to 3.55) and 2.24 (1.50 to 3.27), respectively). Furthermore, our MSM revealed an additive interaction between ACEs and asthma for depressive symptoms (RERI (95% CI)=+1.63 (0.54 to 2.71)).Conclusions These findings suggest that asthma amplifies the risk of depressive symptoms associated with ACEs.Clinical implications Prevention and treatment of asthma, along with establishing preventive environments and services against ACEs, are effective in mitigating the potential burden of ACEs on mental health.

Abstract Adrenal venous sampling (AVS) is crucial for subtyping primary aldosteronism (PA) to explore the possibility of curing hypertension. Because AVS availability is limited, efforts have been made to develop strategies to bypass it. However, it has so far proven unsuccessful in applying clinical practice, partly due to heterogeneity and missing values of the cohorts. For this purpose, we retrospectively assessed 210 PA cases from three institutions where segment-selective AVS, which is more accurate and sensitive for detecting PA cases with surgical indications, was available. A machine learning-based classification model featuring a new cross-center domain adaptation capability was developed. The model identified 102 patients with PA who benefited from surgery in the present cohort. A new data imputation technique was used to address cross-center heterogeneity, making a common prediction model applicable across multiple cohorts. Logistic regression demonstrated higher accuracy than Random Forest and Deep Learning [(0.89, 0.86) vs. (0.84, 0.84), (0.82, 0.84) for surgical or medical indications in terms of f-score]. A derived integrated flowchart revealed that 35.2% of PA cases required AVS with 94.1% accuracy. The present model enabled us to reduce the burden of AVS on patients who would benefit the most.

Background: We assessed damaged anterior capsulolabral motion during axial shoulder rotation in patients with anterior shoulder instability. Methods: Twenty-nine shoulders of 28 patients with anterior shoulder instability who underwent cine-magnetic resonance imaging during axial rotation of the adducted arm were included. The motion was captured after an intra-articular injection of saline solution (10-20 mL). During imaging, the shoulder was rotated passively from maximum internal rotation to maximum external rotation in the first 10 s and then back to maximum internal rotation in the subsequent 10 s. We assessed the rotational angles of the damaged labrum during compressing and pulling the humeral head against the glenoid. Evaluation of the rotational angles was performed on a series of axial images through the humeral head center. Results: The mean angles that damaged labrum compressed and pulled off against the glenoid were 12.0 ± 19.1° and 2.8 ± 21.2°, respectively. Additionally, seven of the 29 shoulders showed that the damaged labrum compressed on the glenoid rim before the rotational angle exceeded 0° during external rotation. In 13 shoulders, the damaged labrum could remain repositioned on the glenoid rim over the neutral position during internal rotation. In two shoulders, the damaged labrum was not compressed against the glenoid at the maximum external rotation. The injected saline moved from the posterior to the anterior side of the glenohumeral joint during internal rotation in each shoulder. Conclusion: The damaged labrum could be positioned on the glenoid when the arm was in a traditional internal immobilization.

Appropriate administration of anti-inflammatory and immunosuppressive treatment (AIIST) is important for patients with Graves’ orbitopathy (GO). This study aimed to clarify the incidence and risk factors for GO treated with AIIST and propose a predictive score, among newly diagnosed Graves’ disease (GD) patients in Japan. A total of 1,553 GD patients who were newly diagnosed during the year 2011 were investigated. AIIST included local and/or systemic glucocorticoid administration and retrobulbar irradiation. A multivariable Cox proportional hazards model was used to investigate the risk factors for GO underwent AIIST during medical treatment, including at diagnosis, of GD. Then, a GO score was created by summing each point assigned to risk factors based on their coefficient obtained in the Cox model. AIIST was administered to 107 patients (6.9%). The risk factors and hazard ratios for GO underwent AIIST were: age (per 10 years), 1.32 (95% confidence interval: 1.16–1.50), p < 0.0001; TSH binding inhibitory immunoglobulin (TBII) (per 10 IU/L), 1.33 (1.15–1.54), p = 0.0001; and thyroglobulin antibody (TgAb) negativity, 2.98 (1.96–4.59), p < 0.0001. The GO score, ranging from 0 to 8 points, showed moderate performance (area under the curve: 0.71, cut-off value: 5 points, sensitivity: 0.76, specificity: 0.59, positive predictive value: 0.12, negative predictive value: 0.97). AIIST was performed for patients with active manifestations of GO in 6.9% of newly diagnosed GD patients. The risk factors for GO underwent AIIST were higher age, higher TBII, and TgAb negativity. The GO score based on these factors may be useful in managing GO.

A complete resection of tongue cancer is often difficult. We investigate the usefulness of administering G47Δ (teserpaturev), a triple-mutated oncolytic herpes simplex virus type 1, prior to resection. G47Δ exhibits good cytopathic effects and replication capabilities in all head and neck cancer cell lines tested. In an orthotopic SCCVII tongue cancer model of C3H/He mice, an intratumoral inoculation with G47Δ significantly prolongs the survival. Further, mice with orthotopic tongue cancer received neoadjuvant G47Δ (or mock) therapy with or without “hemilateral” resection, the maximum extent avoiding surgical deaths. Neoadjuvant G47Δ and resection led to 10/10 survival (120 days), whereas the survivals for G47Δ alone and resection alone were 6/10 and 5/10, respectively: all control animals died by day 11. Furthermore, 100% survival was achieved with neoadjuvant G47Δ therapy even when the resection area was narrowed to “partial,” providing insufficient resection margins, whereas hemilateral resection alone caused death by local recurrence in half of the animals. G47Δ therapy caused increased number of tumor-infiltrating CD8+ and CD4+ cells, increased F4/80+ cells within the residual tongues, and increased expression of immune-related genes in and around the tumor. These results imply that neoadjuvant use of G47Δ is useful for preventing local recurrence after tongue cancer surgery.

Objective: To examine differences in the association between educational attainment and mortality by the presence of diabetes and diabetic retinopathy (DR)—a major complication of diabetes. Patients and Methods: We used a nationally representative sample of 54,924 US adults aged 20 years or older with diabetes from the National Health and Nutrition Examination Survey 1999-2018 and its mortality data through 2019. We applied the multivariable Cox proportional hazard models to investigate the associations between educational attainment (low, less than high school; middle, high school; and high, more than high school) and all-cause mortality according to diabetes status: nondiabetes, diabetes without DR, and diabetes with DR. Differences in the survival rate by educational attainment were evaluated using the slope inequality index (SII). Results: Among the 54,924 participants (mean age, 49.9 years), adults in the low educational group reported an increased risk of all-cause mortality compared with those of the high educational group in any diabetes status (nondiabetes—hazard ratio [HR], 1.69; 95% CI, 1.56-1.82; diabetes without DR—HR, 1.61; 95% CI, 1.37-1.90; diabetes with DR—HR, 1.43; 95% CI, 1.10-1.86). SIIs among the diabetes without DR group and diabetes with DR group were 22.17 and 20.87 per 1000 person-years, respectively, which were 2 times greater than those among the nondiabetes group (SII=9.94). Conclusion: The differences in the mortality risks owing to the educational attainment increased by the presence of diabetes regardless of the complication of DR. Our findings indicate that prevention of diabetes itself is critical to mitigate health disparities by socioeconomic status such as education status.

Abstract Background Although many conventional healthcare services to prevent postpartum depression are provided face-to-face, physical and psychosocial barriers remain. These barriers may be overcome by using mobile health services (mHealth). To examine the effectiveness of mHealth professional consultation services in preventing postpartum depressive symptoms in real-world settings, we conducted this randomized controlled trial in Japan, where universal free face-to-face perinatal care is available. Methods This study included 734 pregnant women living in Yokohama city who could communicate in Japanese, recruited at public offices and childcare support facilities. The participants were randomized to the mHealth group (intervention, n = 365), where they could use a free app-based mHealth consultation service with gynecologists/obstetricians, pediatricians, and midwives whenever and as many times as they wanted between 6 p.m. and 10 p.m. on weekdays throughout their pregnancy and postpartum periods (funded by the City of Yokohama government) or the usual care group (control, n = 369). The primary outcome was the risk of elevated postpartum depressive symptoms, defined as Edinburgh Postnatal Depression Scale score ≥ 9. Secondary outcomes were self-efficacy, loneliness, perceived barriers to healthcare access, number of clinic visits, and ambulance usage. All outcomes were collected three months post-delivery. We also conducted subgroup analyses assessing the differences in the treatment effect by sociodemographic status. Results Most women completed all questionnaires (n = 639 of 734, response rate: 87%). The mean baseline age was 32.9 ± 4.2 years, and 62% were primipara. Three months post-delivery, women in the mHealth group had a lower risk of elevated postpartum depressive symptoms (47/310 [15.2%]) compared to the usual care group (75/329 [22.8%], risk ratio: 0.67 [95% confidence interval: 0.48–0.93]). Compared with the usual care group, women in the mHealth group had higher self-efficacy, less loneliness, and fewer perceived barriers to healthcare access. No differences were observed in the frequency of clinic visits or ambulance usage. Furthermore, in the subgroup analyses, we did not find differences in the treatment effect by sociodemographic status. Conclusions Local government-funded mHealth consultation services have a preventive effect on postpartum depressive symptoms, removing physical and psychological barriers to healthcare access in real-world settings. Trial registration UMIN-CTR identifier: UMIN000041611. Registered 31 August 2021.

Research suggests that women experience greater cardiovascular ischemic effects from stress than men. Visceral adiposity is an endocrine tissue that differs by sex and interacts with stress hormones. We hypothesized that urinary cortisol would be associated with increased cardiovascular events and change in coronary artery calcium score (CAC) in women, and these relationships would vary by central obesity. In the Multi-Ethnic Study of Atherosclerosis Stress Ancillary study, cortisol was quantified by 12-h overnight urine collection. Central obesity was estimated by waist-hip ratio (WHR). Multivariable Cox models estimated the relationship between cortisol and cardiovascular events and assessed for moderation by WHR. The relationship between cortisol and change in CAC Agatston score was assessed by Tobit regression models. 918 patients were analyzed with median follow up of 11 years. There was no association between urinary cortisol and cardiovascular events in the cohort. However, in individuals with below median WHR, higher urinary cortisol levels (upper tertile) were associated with higher cardiovascular event rates in the full cohort, women, and men, but not in groups with above median WHR. There was significant moderation by WHR in women, but not men, whereby the association between elevated cortisol and increased cardiovascular events diminished as WHR increased. Urinary cortisol was associated with increased change in CAC in women (P = 0.003) but not men, without moderation by WHR. Our study highlights associations between cortisol and subclinical atherosclerosis in women, and moderation of the relationship between cortisol and cardiovascular events by central obesity in both genders.

Unique microorganisms of a fossil river delta in the Atacama Desert unveil the current limits of life detection on Mars.

Background Although most individuals can adapt to a large iodine load and remain euthyroid, hypothyroidism can develop after iodine exposure. Hypothyroidism is associated with adverse cardiovascular consequences, including heart failure. This study was performed to investigate the relationships between iodine‐induced hypothyroidism and incident heart failure. Methods and Results This cohort study of the US Veterans Health Administration (1998–2021) included adults aged ≥18 years with a serum thyroid‐stimulating hormone (thyrotropin)

Summary: Background: Although ample evidence has shown the link between childhood obesity and socioeconomic status including family income and household education levels, the mediating role of poverty in the association between household education levels and childhood obesity is unclear. This study aimed to quantify the extent to which family poverty levels contribute to the association between household education levels and obesity among US children and adolescents. Methods: This cohort study used the nationally representative data of 21,754 US children and adolescents aged 6–17 years (National Health and Nutrition Examination Survey 1999–2018). We applied mediation analysis of the association between household education levels (less than high school, high school, and college or above) and obesity mediated through poverty (≤138% vs. >138% federal poverty level), adjusting for demographic characteristics of household head and their offspring. Obesity was defined as age- and sex-specific body mass index in the 95th percentile or greater using the 2000 Centers for Disease Control and Prevention growth charts. Findings: Among 21,754 children and adolescents (weighted N = 43,544,684; mean age, 11.6 years; female, 49%), 9720 (weighted percentage, 33.0%) were classified as living in poverty and 4671 (weighted percentage, 19.1%) met the criteria for obesity. Low household education level (less than high school) showed increased risks of poverty (adjusted relative risk [95% CI], 5.82 [4.90–6.91]) and obesity (adjusted relative risk [95% CI], 1.94 [1.68–2.25]) compared to high household education level (college or above). We also quantified that poverty mediated 18.9% of the association between household education levels and obesity among children and adolescents. The mediation effect was consistently observed across age, gender, and race/ethnicity. Interpretation: Poverty mediated the association between the low educational status of household heads and their offspring’s obesity. Our findings highlight the importance of reducing obesity risk among the low-income population to minimize the burden of intergenerational health disparities due to socioeconomic status. Funding: Japan Society for the Promotion of Sciences (22K17392).

Background: 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. Methods: 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. Results: 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. Conclusion: 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.

Abstract Aims/Introduction 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. Materials and Methods 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. Results 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 aged

BackgroundAlthough remote communication technologies have been widely used to maintain connections with others against interpersonal contact restrictions and exacerbated loneliness during the COVID-19 pandemic, it is unclear whether and what types of remote communication technologies are effective in mitigating loneliness. ObjectiveThis study aimed to investigate the association between remote communication and loneliness when face-to-face meetings with others were strongly prohibited and whether this association varied across types of communication tools, age, and gender. MethodsWe used cross-sectional data from the Japan COVID-19 and Society Internet Survey conducted from August to September 2020. From registered panelists of the research agency, 28,000 randomly sampled participants completed the survey on the website. We created 2 study cohorts who stopped meeting with family members living apart and friends during the pandemic. We categorized whether participants had technology-based remote communication (voice calling, text messaging, and video calling) with family and friends. Loneliness was assessed using the 3-item University of California, Los Angeles Loneliness Scale. We used a modified Poisson regression model to investigate the association between loneliness and remote communication with family members living apart or friends. We also conducted subgroup analyses based on age and gender. ResultsA total of 4483 participants stopped meeting with family members living apart, and 6783 participants stopped meeting with friends during the COVID-19 pandemic. Remote communication with family members living apart did not show an association with loneliness, whereas remote communication with friends was associated with a low prevalence of loneliness (family: adjusted prevalence ratio [aPR]=0.89, 95% CI 0.74-1.08; P=.24 and friends: aPR=0.82, 95% CI 0.73-0.91; P

Abstract 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.

BackgroundJapan 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.MethodsWe 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.ResultsIn 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.ConclusionThough 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.

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.

Abstract Background Pheochromocytoma and paraganglioma caused by succinate dehydrogenase gene mutations is called hereditary pheochromocytoma/paraganglioma syndrome. In particular, succinate dehydrogenase subunit B mutations are important because they are strongly associated with the malignant behavior of pheochromocytoma and paraganglioma . This is a case report of a family of hereditary pheochromocytoma/paraganglioma syndrome carrying a novel mutation in succinate dehydrogenase subunit B. Case presentation A 19-year-old Japanese woman, whose father died of metastatic paraganglioma, was diagnosed with abdominal paraganglioma, and underwent total resection. Succinate dehydrogenase subunit B genetic testing detected a splice-site mutation, c.424-2delA, in her germline and paraganglioma tissue. Afterwards, the same succinate dehydrogenase subunit B mutation was detected in her father’s paraganglioma tissues. In silico analysis predicted the mutation as “disease causing.” She is under close follow-up, and no recurrence or metastasis has been observed for 4 years since surgery. Conclusions We detected a novel succinate dehydrogenase subunit B mutation, c.424-2delA, in a Japanese family afflicted with hereditary pheochromocytoma/paraganglioma syndrome and found the mutation to be responsible for hereditary pheochromocytoma/paraganglioma syndrome. This case emphasizes the importance of performing genetic testing for patients with pheochromocytoma and paraganglioma suspected of harboring the succinate dehydrogenase subunit B mutation (that is, metastatic, extra-adrenal, multiple, early onset, and family history of pheochromocytoma and paraganglioma) and offer surveillance screening to mutation carriers.

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.

Abstract 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.

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.

Primary aldosteronism (PA) usually accompanies suppressed plasma renin activity (PRA) through a negative feedback mechanism. While some cases of PA with unsuppressed PRA were reported, there have been no studies about the characteristics of PA with unsuppressed PRA; thus, these characteristics were examined herein. Nine patients with unsuppressed PRA and 86 patients with suppressed PRA were examined. All patients underwent segmental adrenal venous sampling (sAVS) and adrenalectomy, and were pathologically confirmed to have cytochrome P450 11B2 (CYP11B2)-positive aldosterone-producing adenoma according to international histopathology consensus criteria. Unsuppressed and suppressed PRA were defined as PRA levels of > 1.0 and ≤ 1.0 ng/mL/hr, respectively, in multiple blood samples obtained in the resting position. The unsuppressed PRA group had higher morning cortisol levels (12.6 [8.5, 13.5] vs. 8.5 [7.1, 11.0] μg/dL, P = 0.03) and higher cortisol levels after a 1 mg dexamethasone suppression test (DST) (2.2 [1.6, 2.5] vs. 1.3 [1.0, 1.9] μ g/dL, P = 0.004) than the suppressed PRA group. The unsuppressed PRA group also showed higher aldosterone levels on the non-surgical side during sAVS (P = 0.02 before adrenocorticotropic hormone (ACTH) stimulation, P = 0.002 after ACTH stimulation), a higher intensity of CYP17 expression in the resected adrenal gland (P = 0.02), and a lower clinical complete success rate 1 year after surgery (P = 0.04) compared with those in the suppressed PRA group. These findings suggest that PA should not be ruled out by unsuppressed PRA among patients with hypertension, particularly when their cortisol levels remain unsuppressed in the 1 mg DST. Meanwhile, it should be acknowledged that patients with unsuppressed PRA have higher aldosterone levels on the non-surgical side, and a lower likelihood of postoperative complete clinical success is to be expected.

Abstract 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.

Introduction Sleep disorders and short sleep duration are common symptoms among people with diabetes. However, the evidence is limited about the associations of post-challenge hyperglycemia and sleep quality or quantity with all-cause mortality in the US general population.Research design and methods Our study included 8795 adults from the National Health and Nutrition Examination Survey 2005–2014. Mortality data were ascertained through 2015. Multivariable Cox proportional-hazards models were used to estimate adjusted HRs (aHRs) for all-cause mortality according to 2-hour plasma glucose levels during the 75 g oral glucose tolerance test—normal glucose tolerance (NGT),

BackgroundThe rapidly increased spending on insulin is a major public health issue in the United States. Industry marketing might be one of the upstream determinants of physicians' prescription of long-acting insulin-the most commonly used and costly type of insulin, but the evidence is lacking. We therefore aimed to investigate the association between industry payments to physicians and subsequent prescriptions of long-acting insulin.Methods and findingsUsing the databases of Open Payments and Medicare Part D, we examined the association between the receipt of industry payments for long-acting insulin in 2016 and (1) the number of claims; (2) the costs paid for all claims; and (3) the costs per claim of long-acting insulin in 2017. We also examined the association between the receipt of payments and the change in these outcomes from 2016 to 2017. We employed propensity score matching to adjust for the physician-level characteristics (sex, years in practice, specialty, and medical school attended). Among 145,587 eligible physicians treating Medicare beneficiaries, 51,851 physicians received industry payments for long-acting insulin worth $22.3 million. In the propensity score-matched analysis including 102,590 physicians, we found that physicians who received the payments prescribed a higher number of claims (adjusted difference, 57.8; 95% CI, 55.8 to 59.7), higher costs for total claims (adjusted difference, +$22,111; 95% CI, $21,387 to $22,836), and higher costs per claim (adjusted difference, +$71.1; 95% CI, $69.0 to $73.2) of long-acting insulin, compared with physicians who did not receive the payments. The association was also found for changes in these outcomes from 2016 to 2017. Limitations to our study include limited generalizability, confounding, and possible reverse causation.ConclusionsIndustry marketing payments to physicians for long-acting insulin were associated with the physicians' prescriptions and costs of long-acting insulin in the subsequent year. Future research is needed to assess whether policy interventions on physician-industry financial relationships will help to ensure appropriate prescriptions and limit overall costs of this essential drug for diabetes care.

The hypothalamus-pituitary-adrenal (HPA) axis plays an important role in primary aldosteronism. Aldosterone biosynthesis is regulated not only by angiotensin II in the renin-angiotensin-aldosterone system, but also by adrenocorticotropic hormone (ACTH), one of the key components of the HPA axis. Although previous studies have reported cortisol cosecretion in primary aldosteronism, particularly aldosterone-producing adenoma (APA), the clinical relevance of such aldosterone and cortisol cosecretion from APA and hypertension or other metabolic disorders has not been fully established. Several somatic mutations including KCNJ5 and CACNA1D are known to induce autonomous production of aldosterone in APA, and the aldosterone responsiveness to ACTH may vary according to each mutation. The ACTH stimulation test has been reported to be a useful tool to distinguish the subtypes of primary aldosteronism (e.g., unilateral vs bilateral) in some studies, but it has not been commonly applied in clinical practice due to limited evidence. Given the recent advancement of imaging, omics research, and computational approach, it is important to summarize the most updated evidence to disentangle the potential impact of cortisol excess in primary aldosteronism and whether the ACTH stimulation test needs to be considered during the diagnostic process of primary aldosteronism. In this article, we conducted a systematic review of epidemiological studies about (i) cortisol cosecretion in primary aldosteronism and (ii) the ACTH stimulation test for the diagnosis of primary aldosteronism (including subtype diagnosis). Then, we discussed potential biases (e.g., confounding bias, overadjustment, information bias, selection bias, and sampling bias) in the previous studies and introduced some advanced epidemiological/statistical methods to minimize these limitations. A better understanding of biases and epidemiological perspective on this topic would allow us to produce further robust evidence and balanced discussion about the causal mechanisms involving the HPA axis and clinical usefulness of the ACTH stimulation test among patients with primary aldosteronism.

Abstract Background Hypereosinophilic syndrome (HES) consists of a group of disorders characterized by abnormal accumulation of eosinophils in the blood or peripheral tissues, independent of known secondary causes of eosinophilia. Clinical manifestations of HES are highly variable, ranging from asymptomatic eosinophilia to severe tissue damage and end-organ failure. Case presentation We herein present the case of a 65-year-old female with a 38-year history of hemodialysis who presented with lower leg pain, fever, skin eruption with leg edema, and diarrhea. Two months before admission, she underwent placement of a stent made of nickel and titanium for abdominal aortic stenosis. Lower leg pain occurred during hemodialysis, followed by fever, pedal edema with skin eruption, and diarrhea. Gastrointestinal endoscopy, colonoscopy, and biopsy histopathology revealed colitis with massive infiltration of eosinophils, compatible with eosinophilic gastroenteritis and colitis. The patient was treated with prednisolone at an initial dose of 40 mg daily and later reduced to 10 mg daily, after which her symptoms improved and her laboratory parameters normalized. She has not experienced a relapse after 1 year of follow-up. Conclusions Our case of HES manifested as eosinophilic gastroenteritis and colitis and was successfully treated with corticosteroids. Clinicians should consider the differential diagnosis of HES when faced with similar cases in order to effect timely and appropriate treatment.

Neuronal intranuclear inclusion disease (NIID) is a relatively new entity identified as a progressive neurodegenerative disease characterised by eosinophilic hyaline intranuclear inclusions widely observed in neuronal and somatic cells. Renal biopsy from one of our patients with NIID showed lupus nephritis–like pathology. He was treated with steroids and angiotensin-converting enzyme inhibitors and his proteinuria improved. The present case highlights that immune-mediated glomerulonephritis can be a presenting feature of NIID, which can be controlled with proper treatment. Keywords: Neuronal intranuclear inclusion disease, Lupus nephritis–like nephropathy

Confounding adjustment is important for observational studies to derive valid effect estimates for inference. Despite the theoretical advancement of confounding selection procedure, it is often challenging to distinguish between confounders and mediators due to the lack of information about the time-ordering and latency of each variable in the data. This is also the case for the studies of perfluoroalkyl substances (PFAS), a group of synthetic chemicals used in industry and consumer products that are persistent and have endocrine-disrupting properties on health outcomes. In this article, we used directed acyclic graphs to describe potential biases introduced by adjusting for or stratifying by the measure of obesity as an intermediate variable in PFAS exposure analyses. We compared results with or without adjusting for body mass index in two cross-sectional data analyses: (1) PFAS levels and maternal thyroid function during early pregnancy using the Danish National Birth Cohort and (2) PFAS levels and cardiovascular disease in adults using the National Health and Nutrition Examination Survey. In these examples, we showed that the potential heterogeneity observed in stratified analyses by overweight or obese status needs to be interpreted cautiously considering collider stratification bias. This article highlights the complexity of seemingly simple adjustment or stratification analyses, and the need for careful consideration of the confounding and/or mediating role of obesity in PFAS studies.

DNA logic circuits utilizing DNA hybridization and/or enzymatic reactions have drawn increasing attention for their potential applications in the diagnosis and treatment of cellular diseases. The compartmentalization of such a system into a microdroplet considerably helps to precisely regulate local interactions and reactions between molecules. In this study, we introduced a relay approach for enabling the transfer of DNA from one droplet to another to implement multi-step sequential logic operations. We proposed electrical fusion and mechanical splitting of droplets to facilitate the DNA flow at the inputs, logic operation, output, and serial connection between two logic gates. We developed Negative-OR operations integrated by a serial connection of the OR gate and NOT gate incorporated in a series of droplets. The four types of input defined by the presence/absence of DNA in the input droplet pair were correctly reflected in the readout at the Negative-OR gate. The proposed approach potentially allows for serial and parallel logic operations that could be used for complex diagnostic applications.

Elucidation of the mechanical interaction between an erythrocyte and an endothelial cell is an important issue that may lead to clarification of mechanisms of cardiovascular diseases and development of new treatments. In order to clarify the interaction, frictional characteristics of erythrocytes moving on various plates have been measured using an inclined centrifuge microscope. The objective of this study was to clarify the mechanical interaction between an erythrocyte moving in medium subject to inclined centrifugal force and endothelial cells on a plate. Three-dimensional (3D) analysis was performed with contact force models between an erythrocyte and glycocalyx on the surface of endothelial cells and two-dimensional (2D) analysis was conducted using a lubrication theory for compressible porous media and a simple erythrocyte model. In the 3D analysis, two contact force models were adopted in which shear stresses acting on the bottom surface of an erythrocyte varied proportional or inversely proportional to the distance to the base plate. As a result, the experimental frictional characteristics for an endothelia-cultured plate were properly reproduced by the inverse proportion model. In the 2D analysis using the lubrication theory, the result without the porous media qualitatively agreed with those of the experiment for the plain and material-coated plates and that of the 3D analysis without contact force models, whereas the result with the porous media was qualitatively different from those of the experiment and the 3D analysis.

The goal of this study is elucidation of propulsion mechanism of small creatures by ciliated swimming legs. For this purpose, a ciliated pereiopod of an opossum shrimp was introduced and it was modeled with a straight cylindrical stem with 10 much narrower cylindrical poles perpendicularly projecting on the stem. Flow drag acting on the pereiopod in a steady flow, which corresponds to the thrust force by paddling of the pereiopod, was computed with a variety of clearance between each adjacent pair of cilia d and the flow velocity U. It was found that the drag increased with the increase in d to be saturated with a certain value in the range of d ≥ 0.04 mm where influence of boundary layers of adjacent cilia is negligible, and the drag agreed well with that estimated from drag of a two-dimensional cylinder. This result suggests that the opossum shrimp is propelled with the drag-based swimming and the ciliated pereiopods supply greater thrust force than tabular pereiopods with the same projection area. It was also found that the drag decreased in the range of d > 0.07 mm in which some cilia come into the boundary layer of body of the shrimp. It was optically observed that distance between adjacent cilia is around 0.07 mm on the stem and cilia near the root of the pereiopod are shorter than those near the tip. The present results suggest that the ciliated pereiopod is well designed to efficiently generate the thrust force within a limited length and mass by preventing influence of the boundary layers.

In vitro blood vessel biomodeling with realistic mechanical properties and geometrical structures is helpful for training in surgical procedures, especial those used in endovascular treatment. Poly (vinyl alcohol) hydrogel (PVA-H), which is made of Poly (vinyl alcohol) (PVA) and water, may be useful as a material for blood vessel biomodeling due to its low surface friction resistance and good transparency. In order to simulate the mechanical properties of blood vessels, measurements of mechanical properties of PVA-H were carried out with a dynamic mechanical analyzer, and the storage modulus (G’) and loss modulus (G”) of PVA-H were obtained. PVA-Hs were prepared by the low-temperature crystallization method. They were made of PVA with various concentrations (C) and degrees of polymerization (DP), and made by blending two kinds of PVA having different DP or saponification values (SV). The G’ and G” of PVA-H increased, as the C or DP of PVA increased, or as the proportion of PVA with higher DP or SV increased. These results indicate that it is possible to obtain PVA-H with desirable dynamic viscoelasticity. Furthermore, it is suggested that PVA-H is stable in the temperature range of 0°C to 40°C, indicating that biomodeling made of PVA-H should be available at 37°C, the physiological temperature. The dynamic viscoelasticity of PVA-H obtained was similar to that of the dog blood vessel measured in previous reports. In conclusion, PVA-H is suggested to be useful as a material of blood vessel biomodeling.

Cardiovascular diseases are closely related to blood flow. Ultrasonic-Measurement-Integrated (UMI) simulation, in which results of ultrasonic measurement are fed back to the flow simulation, was proposed in a previous study in order to reproduce the real blood flow accurately and efficiently. The usability of the UMI simulation was confirmed by numerical experiment, but the effectiveness of this simulation was strongly affected by the accuracy of the ultrasonic measurement. In this paper, we examined the accuracy of a commercial ultrasonic measurement device by an experiment with a PVA-H straight tube phantom. By analyzing the measured color Doppler images for a developed laminar flow inside the phantom, we obtained the relationship between the color Doppler value and the Doppler velocity (C-V relationship). It was revealed that the original C-V relationship provided in the device as a color bar was not suitable for quantitative evaluation of Doppler velocity to be used in UMI simulation. Compared with the original C-V relationship, the present C-V relationship results are in far better agreement with the analytic solution. Investigation of the normalized error confirmed that the result obtained with the present C-V relationship was reliable in cases of relatively high Reynolds number in the flow domain except near the wall. The two signal conditioning factors of the device had little influence on the Doppler velocity. Finally, we investigated the effect of temporal and spatial averaging of ultrasonic measurement data to clarify the relation between the number of averagings and the level of agreement with the analytic solution.

BackgroundHeat shock protein beta-1 (HSPB1, also known as HSP27) is a small heat shock protein involved in many cellular processes and reportedly protects cells against oxidative stress. Autophagy protects cells from many types of stress and is thought to play a key role in preventing stress in acute kidney injury (AKI). However, little is known about the role of HSPB1 in autophagy and apoptosis in the pathogenesis of AKI.MethodsWe used a rat ischemia/reperfusion AKI model and cultured renal tubular cells as an in vitro model. To elucidate the regulation of HSPB1, we evaluated the promoter activity and expression of HSPB1 in normal rat kidney (NRK)-52E cells in the presence of H2O2. To examine the regulation of autophagy by HSPB1, we established NRK-light chain 3 (NRK-LC3) cells that were stably transfected with a fusion protein of green fluorescent protein and LC3.ResultsThe results of immunohistological examination showed that HSPB1 was expressed in proximal tubule cells after AKI. Real-time quantitative reverse transcription-polymerase chain reaction and western blot analysis showed that HSPB1 messenger RNA and protein expression were upregulated 6-72 h and 12-72 h, respectively, after ischemia/reperfusion injury. HSPB1 promoter activity as well as messenger RNA and protein expression indicated dose-dependent induction by H2O2. HSPB1 overexpression-induced autophagy in NRK-LC3 cells under normoxic conditions was confirmed with confocal microscopy, which revealed the presence of LC3-positive granules. Furthermore, H2O2-induced autophagy was inhibited by the transfection of small interfering RNAs for HSPB1. Overexpression of HSPB1 reduced BAX activation and H2O2-induced apoptosis, as measured by caspase 3 activity and terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling assay.ConclusionsWe showed that HSPB1 expression increased during oxidative stress in AKI. Incremental HSPB1 expression increased autophagic flux and inhibited apoptosis in renal tubular cells. These results indicate that HSPB1 upregulation plays a role in the pathophysiology of AKI.

The adrenocorticotropin (ACTH) stimulation test (AST) has been reported to be useful for diagnosing primary aldosteronism (PA), particularly for differentiating PA subtypes under 1-mg dexamethasone suppression (DS). The aim of our study was to clarify the effect of 1-mg DS on AST results. A retrospective cohort study was conducted using data for 48 patients (PA: 30/48). We estimated the difference in plasma aldosterone concentration (PAC) responsiveness to ACTH stimulation with single (AST alone) and combined (AST under 1-mg DS) tests within the same patient. We compared the diagnostic accuracy of these two tests for PA and the laterality of hyperaldosteronism. We found no differences in PAC responsiveness to ACTH stimulation between single and combined tests, and observed a significant positive linear relationship (30 min, R2 = 0.75, p-value < 0.01). Both tests showed the highest diagnostic accuracy for PA following 30 min of ACTH stimulation. The ability to detect the laterality of hyperaldosteronism was inconsistent and differed according to the two definitions: lateralization ratio and the absolute aldosterone levels in adrenal venous sampling. PAC responsiveness to ACTH stimulation was similar for AST with and without 1-mg DS. AST can be performed under both conditions with similar accuracy to detect PA.

Nephrotoxicity is a frequent and major limitation in cisplatin (CDDP)-based chemotherapy. 5-Aminolevulinic acid (ALA) is widely distributed in animal cells, and it is a precursor of tetrapyrole compounds such as heme that is fundamentally important in aerobic energy metabolism. The aim of this study is to evaluate the protective role of ALA in CDDP-induced acute kidney injury (AKI).We used CDDP-induced AKI rat model and cultured renal tubular cells (NRK-52E). We divided four groups of rats: control, CDDP only, CDDP + ALA(post);(ALA 10 mg/kg + Fe in drinking water) after CDDP, CDDP + ALA(pre & post).CDDP increased Cr up to 6.5 mg/dl, BUN up to 230 mg/dl, and ALA significantly reduced these changes. ALA ameliorates CDDP-induced morphological renal damages, and reduced tubular apoptosis evaluated by TUNEL staining and cleaved caspase 3. Protein and mRNA levels of ATP5α, complex(COX) IV, UCP2, PGC-1α in renal tissue were significantly decreased by CDDP, and ALA ameliorates reduction of these enzymes. In contrast, Heme Oxigenase (HO)-1 level is induced by CDDP treatment, and ALA treatment further up-regulates HO-1 levels. In NRK-52E cells, the CDDP-induced reduction of protein and mRNA levels of mitochondrial enzymes was significantly recovered by ALA + Fe. CDDP-induced apoptosis were ameliorated by ALA + Fe treatment. Furthermore, we evaluated the size of transplantated bladder carcinoma to the rat skin, and ALA did not change the anti cancer effects of CDDP.These data suggested that the protective role of ALA in cisplatin-induced AKI is via protection of mitochondrial viability and prevents tubular apoptosis. Also there are no significant effects of ALA on anticancer efficiency of CDDP in rats. Thus, ALA has the potential to prevent CDDP nephrotoxicity without compromising its anticancer efficacy.

Context: Desmopressin orally disintegrating tablets (ODTs) are widely used to treat arginine vasopressin deficiency (AVP-D). However, limited information is available on the dosage regimen; the dosage for each patient is selected based on their response to the initiation dose. Objective: To investigate the relationships between clinical characteristics and the daily dose of ODTs and to identify factors that affect ODT dosages. Methods: This retrospective study included 209 adult patients with AVP-D. Patients were administered ODTs sublingually and instructed to restrict eating and drinking for 30 minutes after taking ODTs using a patient leaflet. ODT dose titration was conducted during hospitalization with close monitoring of urine output, body weight, and serum sodium levels. Multivariable linear regression models were applied to identify clinical factors associated with the daily dose of ODTs at discharge. We also evaluated the dosage at 1 year in 134 patients who were followed up in our hospital. Results: The median daily dose of ODTs at discharge was 90 µg (IQR 60-120 µg). Multivariable linear regression models identified sex, age, and estimated creatinine clearance (eCCr) as significant factors associated with the daily dose of ODTs, with eCCr having the strongest effect. After excluding patients recovering from AVP-D, 71% of those followed up at our hospital took the same daily dose at 1 year after discharge. Conclusion: To achieve the safe and stable treatment of AVP-D, the daily dose of ODT needs to be selected based on a patient’s sex, age, and eCCr under appropriate sublingual administration by patient education. [ABSTRACT FROM AUTHOR]

Context: Although iodine-induced hyperthyroidism is a potential consequence of iodinated radiologic contrast administration, its association with long-term cardiovascular outcomes has not been previously studied. Objective: To investigate the relationships between hyperthyroidism observed after iodine contrast administration and incident atrial fibrillation/ flutter. Methods: 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, subsequent TSH <1 year, and receipt of iodine contrast <60 days before the subsequent TSH. Cox proportional hazards regression was employed to ascertain the adjusted hazard ratio (HR) with 95% CI of incident atrial fibrillation/flutter following iodine-induced hyperthyroidism, compared with iodine-induced euthyroidism. Results: Iodine-induced hyperthyroidism was observed in 2500 (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 (interquartile range 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 with 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 = .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. [ABSTRACT FROM AUTHOR]

BACKGROUND: Renin suppression in primary aldosteronism indicates mineralocorticoid receptor activation via excessive aldosterone secretion, inducing renal damage. We investigated whether the reversal of renin suppression after the initiation of mineralocorticoid receptor antagonist therapy was associated with long-term renal outcomes in medically treated patients with primary aldosteronism. METHODS: This retrospective cohort study included 318 patients with primary aldosteronism treated with mineralocorticoid receptor antagonist between 2008 and 2020 at the Yokohama Rosai Hospital in Japan. The posttreatment renin status was defined as unsuppressed (ie, reversal of renin suppression) when individual plasma renin activity after the initiation of mineralocorticoid receptor antagonist (post-plasma renin activity) was ≥1.0 ng/mL per hour; otherwise, it was defined as suppressed. We analyzed the association of posttreatment renin status with subsequent longitudinal estimated glomerular filtration rate changes using linear mixed-effects models for repeated measurements, adjusting for potential confounders. RESULTS: The posttreatment renin status of 119 patients was unsuppressed (median post-plasma renin activity, 1.7 ng/mL per hour) and that of 199 patients was suppressed (median post-PRA, 0.5 ng/mL per hour). Through the median follow-up period of 3.1 years, the decline in estimated glomerular filtration rate was milder among patients with the unsuppressed posttreatment renin (-0.46 [95% CI, -0.63 to -0.28] mL/min per 1.73 m² per year) than those with suppressed posttreatment renin (-1.41 [95% CI, -1.56 to -1.27] mL/min per 1.73 m² per year; difference, 0.96 [95% CI, 0.72-1.20] mL/min per 1.73 m² per year). CONCLUSIONS: Our findings may highlight the importance of reversing renin suppression with optimal mineralocorticoid receptor antagonist titration in medically treated primary aldosteronism, which could mitigate adverse renal outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

BACKGROUND: Type 2 diabetes is a leading contributor to the global burden of morbidity and mortality. Ozone (O3) exposure has previously been linked to diabetes. OBJECTIVE: We studied the impact of O3 exposure on incident diabetes risk in elderly Mexican Americans and investigated whether outdoor physical activity modifies the association. METHODS: We selected 1,090 Mexican American participants from the Sacramento Area Latino Study on Aging conducted from 1998 to 2007. Ambient O3 exposure levels were modeled with a land-use regression built with saturation monitoring data collected at 49 sites across the Sacramento metropolitan area. Using Cox proportional hazard models, we estimated the risk of developing incident diabetes based on average O3 exposure modeled for 5-y prior to incident diabetes diagnosis or last follow-up. Further, we estimated outdoor leisure-time physical activity at baseline and investigated whether higher vs. lower levels modified the association between O3 exposure and diabetes. RESULTS: In total, 186 incident diabetes cases were identified during 10-y follow-up. Higher levels of physical activity were negatively associated with incident diabetes [hazard ratio (HR)=0.64 (95% CI: 0.43, 0.95)]. The estimated HRs for incident diabetes was 1.13 (95% CI: 1.00, 1.28) per 10- ppb increment of 5-y average O3 exposure; also, this association was stronger among those physically active outdoors [HR=1.52 (95% CI: 1.21, 1.90)], and close to null for those reporting lower levels of outdoor activity [HR=1.04 (95% CI: 0.90, 1.20), 푝interaction =0.01]. CONCLUSIONS: Our findings suggest that ambient O3 exposure contributes to the development of type 2 diabetes, particularly among those with higher levels of leisure-time outdoor physical activity. Policies and strategies are needed to reduce O3 exposure to guarantee that the health benefits of physical activity are not diminished by higher levels of O3 pollution in susceptible populations such as older Hispanics. [ABSTRACT FROM AUTHOR]