Association of α-klotho and lead and cadmium: A cross-sectional study.

Epigenetic aging is associated with harmful health effects such as oxidative stress from heavy metal exposure. We considered the relationship between genes and heavy metals in association with oxidative stress and then investigated the association between serum α- klotho and lead and cadmium exposure among adults in the United States from 2007 to 2016 participating in the National Health and Nutrition Examination Survey (NHANES). Samples included 9800 adults aged 40 to 79 years with measurements of serum α-klotho, lead and cadmium, and complete covariate data. Lead and cadmium levels were measured by inductively coupled plasma mass spectrometry and serum α-klotho levels were measured using enzyme-linked immunosorbent assay (ELISA). Multivariate linear regression analysis was used to estimate the association between serum α-klotho and blood lead, blood cadmium, and urinary cadmium. A percent increase in blood lead, blood cadmium, and urinary cadmium was associated with a statistically significant 4.0 % (p < 0.001), 2.0 %, (p = 0.003) and 1.0 % (p = 0.020) decrease in serum klotho. After adjustment, a percent increase in blood lead was associated with a statistically significant 4.0 % (p < 0.001) decrease in serum klotho; blood and urinary cadmium did not show any statistically significant associations after adjustment (ß (95 % CI), p-value for blood cadmium: 0.00 (-0.02-0.01), p = 0.573; urinary cadmium: -0.01 (-0.03-0.01), p = 0.210). Mean serum klotho levels showed a statistically significant decreasing trend with increasing blood lead quartiles (unadjusted and all-adjusted geometric means and 95 % confidence intervals of serum klotho (in pg/mL) for Q1, Q2, Q3, and Q4: unadjusted: 827.49 (814.20-840.92), 811.92 (794.73-829.48), 791.48 (775.11-808.19), and 772.01 (754.23-790.29); adjusted: 830.64 (805.53-856.45), 816.07 (789.18-843.87), 800.71 (773.71-828.57), and 784.31 (757.94-811.59)). Blood lead and levels were negatively associated with serum α-klotho levels in a representative population of US adults. These results suggest that blood lead levels may be associated with the serum levels of a protein associated with cognition and aging. Further research is recommended to investigate the causality behind such relationship.

Asymmetrical Handgrip Strength Is Associated with Lower Cognitive Performance in the Elderly.

(1) Background: Several studies have reported that handgrip strength (HGS) may be a sign of lower cognitive performance. However, studies supporting an association between asymmetrical HGS and cognitive function are lacking. This study aimed to determine the association between asymmetrical HGS and cognitive performance among the elderly. (2) Methods: The study sample included 2729 individuals aged ≥60 years-old who participated in the 2011-2014 National Health and Nutrition Examination Survey. The cognitive tests consisted of the word learning and recall modules from the Consortium to Establish a Registry for Alzheimer's Disease (CERAD), Animal Fluency Test, and Digit Symbol Substitution Test (DSST). HGS was measured using a handgrip dynamometer, and asymmetrical HGS was used to calculate HGS. (3) Results: Of the 2729 participants, 53.0% were aged 60 to 69 years-old, and 47.0% were aged 70 years and older. All cognitive performance scores were significantly correlated with asymmetrical HGS in both age groups. After adjusting for confounders, there was a significant association between DSST and HGS asymmetry in both age groups. Contrastingly, a significant association was only observed for the relationship between the CERAD test and HGS asymmetry in the ≥70 year-old group. (4) Conclusions: We found that low cognitive function was associated with asymmetrical HGS in elderly participants in the United States. Thus, asymmetrical HGS may be an important predictor of cognitive deficits. However, further research is required to confirm our results and to establish possible mechanisms.

Association between Serum Lipid Parameters and Cognitive Performance in Older Adults.

(1) Background: Previous studies have suggested the association between lipid profiles and cognitive function in older adults. However, they generated inconsistent results. We aim to determine the relationship between lipid profiles and cognitive performance in older adults. (2) Methods: We used the 2011-2014 National Health and Nutrition Examination Survey. This study included 2215 participants who were aged more than 60 years old and free of coronary heart disease or stroke. Lipid profiles included total cholesterol (TC), low density lipid cholesterol (LDL), high density lipid cholesterol (HDL), and triglyceride (TG). Cognitive function was assessed using the digit symbol substitution test (DSST). (3) Results: Positive correlations of DSST were observed with TC (r = 0.111; p < 0.0001), HDL (r = 0.127; p < 0.0001), and LDL (r = 0.107; p = 0.0005). However, there was no significant relationship between TG and DSST. A one-unit increase in HDL was associated with an increase in DSST score (beta coefficient: 0.036; p = 0.018); but the association was not significant for LDL, TG, and TC. In the categorical analysis, the high HDL group had a higher DSST score than the low HDL group (beta = 3.113; p < 0.0001) and the low TG group was more likely to show a lower DSST score than the high TC group (beta = -1.837; p = 0.0461). However, LDL and TC showed no statistically significant associations. Moreover, HDL was only associated with a 0.701 times increased risk of cognitive impairment (95% CI = 0.523-0.938) in the logistic regression analysis. (4) Conclusions: Higher blood concentrations of HDL levels were positively associated with DSST scores in older adults. We suggest that the high levels of HDL may be a protective factor against cognitive impairment.

The age-standardized incidence, mortality, and case fatality rates of COVID-19 in 79 countries: a cross-sectional comparison and their correlations with associated factors.

OBJECTIVES: During the coronavirus disease 2019 (COVID-19) pandemic, crude incidence and mortality rates have been widely reported; however, age-standardized rates are more suitable for comparisons. In this study, we estimated and compared the age-standardized incidence, mortality, and case fatality rates (CFRs) among countries and investigated the relationship between these rates and factors associated with healthcare resources: gross domestic product per capita, number of hospital beds per population, and number of doctors per population. METHODS: The incidence, mortality, and CFRs of 79 countries were age-standardized using the World Health Organization standard population. The rates for persons 60 years or older were also calculated. The relationships among the rates were analysed using trend lines and coefficients of determination (R2). Pearson correlation coefficients between the rates and the healthcare resource-related factors were calculated. RESULTS: The countries with the highest age-standardized incidence, mortality, and CFRs were Czechia (14,253 cases/100,000), Mexico (182 deaths/100,000), and Mexico (6.7%), respectively. The R2 between the incidence and mortality rates was 0.852 for all ages and 0.945 for those 60 years or older. The healthcare resources-related factors were associated positively with incidence rates and negatively with CFRs, with weaker correlations among the elderly. CONCLUSIONS: Compared to age-standardized rates, crude rates showed greater variation among countries. Medical resources may be important in preventing COVID-19-related deaths; however, considering the small variation in fatality among the elderly, preventive measures such as vaccination are more important, especially for the elderly population, to minimize the mortality rates.

Serum sodium in relation to various domains of cognitive function in the elderly US population.

BACKGROUND: Recent evidence suggests that sodium imbalances may be associated with cognitive impairment; however, the association between specific domains of cognition remains unclear. This study examines the association between serum sodium levels and immediate and delayed verbal memory as measured by the CERAD Word Learning Test (CERAD WLT), executive function as measured by the Animal Fluency test (AFT), and sustained attention, working memory, and processing speed as measured by the Digit Symbol Substitution test (DSST) in the elderly population of the US aged 60 and older who participated in the 2011-2014 National Health and Nutrition Examination Surveys (n = 2,541). METHODS: Cognitive function tests were performed by trained interviewers and sodium levels were measured using indirect ion selective electrode methodology. RESULTS: After adjusting for all covariates, quintiles of CERAD WLT scores showed significant positive associations with log-transformed sodium levels (Immediate recall (IR) ß = 4.25 (SE = 1.83, p-value 0.027); Delayed recall (DR) ß = 6.54 (SE = 1.82, p-value 0.001)). Compared to normal sodium levels, hyponatremia was significantly associated with lower CERAD WLT-IR (ß = -0.34, SE = 0.15, p-value 0.035) and CERAD WLT-DR scores (ß -0.48, SE = 0.10, p-value < 0.001) and showed borderline significance with AFT scores (ß = = -0.38, SE = 0.19, p-value 0.052). Hypernatremia did not show any significant relationships with cognitive test scores, compared to normal sodium levels. CONCLUSIONS: Our cross-sectional study showed that lower sodium levels were associated with cognitive change, especially regarding memory and executive function.

Types of COVID-19 clusters and their relationship with social distancing in the Seoul metropolitan area, South Korea.

BACKGROUND: The complete contact tracing of coronavirus disease-19 (COVID-19) cases in South Korea allows a unique opportunity to investigate cluster characteristics. This study aimed to investigate all reported COVID-19 clusters in the Seoul metropolitan area from January 23 to September 24, 2020. METHODS: Publicly available COVID-19 data was collected from the Seoul Metropolitan City and Gyeonggi Province. Community clusters with ≥5 cases were characterized by size and duration, categorized using K-means clustering, and the correlation between the types of clusters and the level of social distancing investigated. RESULTS: A total of 134 clusters comprised of 4033 cases were identified. The clusters were categorized into small (type I and II), medium (type III), and large (type IV) clusters. A comparable number of daily reported cases in different time periods were composed of different types of clusters. Increased social distancing was related to a shift from large to small-sized clusters. CONCLUSIONS: Classification of clusters may provide opportunities to understand the pattern of COVID-19 outbreaks better and implement more effective suppression strategies. Social distancing administered by the government may effectively suppress large clusters but may not effectively control small and sporadic clusters.

Increased cold injuries and the effect of body mass index in patients with peripheral vascular disease.

BACKGROUND: Exposure to extremely or moderate low temperatures is associated with increased morbidity and mortality risk. Peripheral vascular disease (PVD) is a slow and progressive circulation disorder. Given that cold temperature causes constriction of the small arteries and veins in the skin, patients who suffer from peripheral circulation problems, like PVD, may be vulnerable to cold injuries. This study aimed to investigate the association between PVD and cold-induced injuries in the winter among Korean adults. We further analyzed the association stratified by body mass index (BMI) classification. METHODS: We used the 2002-2015 National Health Insurance Service-National Sample Cohort data and included a total of 535,186 adults as the study population. Patients with underlying PVD were identified by ICD-10 code I73. Cold-related illnesses were defined by ICD-10 codes (T690, T691, T698, T699, T330 ~ T339, T340 ~ T349, and T350 ~ T357). Body mass index (BMI) was categorized into underweight, normal weight, overweight, and obese. RESULTS: A total of 23.21% (n = 124,224) were PVD patients, and 0.59% (n = 3154) had cold-induced injuries. PVD patients were more likely to be diagnosed with cold injuries, but it was valid only in the underweight or normal weight groups. After adjusting for age, sex, income, cigarette smoking, alcohol consumption, regular exercise, high blood pressure, and hyperglycemia, PVD patients had a significantly increased odds ratio (OR) for cold injuries [adjusted OR = 1.11; 95% confidence intervals (95% CI): 1.01-1.21]. Increased OR for cold injuries in PVD patients was also observed in adults (adjusted OR = 1.14; 95% CI: 1.03-1.25 in Model 2), but not in the elderly. When we classified study subjects into the four BMI groups, the adjusted OR of cold injuries in PVD patients was significant in the underweight group (OR = 1.83; 95% CI, 1.26-2.66) and normal weight group (OR = 1.15; 95% CI, 1.03-1.27), not in those with overweight and obese. In adults, a consistent result was found in adults in the underweight group (OR = 1.63; 95% CI, 1.08-2.47 in Model 2) and normal weight group (OR = 1.19; 95% CI, 1.07-1.33 in Model 2). In the elderly, the adjusted OR for cold injuries was only significant in the underweight group (OR = 3.37; 95% CI, 1.08-10.53 in Model 2). CONCLUSIONS: We found a significant association between PVD and cold-induced injuries in the general population. BMI modified the association. Thus, the association observed appears to be clinically applicable to PVD patients being low to normal BMI.

High and low ambient temperature at night and the prescription of hypnotics.

STUDY OBJECTIVES: This study investigated the association between ambient nighttime temperature and sleep problems assessed by the prescription dose of sleeping pills in South Korean adults. METHODS: We used the 2002-2015 National Health Insurance Service-National Sample Cohort. A total of 711,079 adults who were 20 years old or older were included, wherein 42,858 adults (~6%) had been prescribed hypnotic medications including zolpidem (N05CF02) and triazolam (N05CD05). Ambient temperature data was calculated as the mean highest temperature of nighttime (23:00-07:00) for every month from January to December. We combined the drug-prescribed date with the administrative districts-level daily nighttime temperature between 2002 and 2015. RESULTS: We found that a non-linear, U-shaped relationship between nighttime temperature and hypnotic medication prescription. With an increase per 1°C temperature or an increase in a square per 1°C, the prescription dose of sleeping pills was significantly increased (both p < 0.05). At each 5°C nighttime temperature, subjects belonging to low (≤0°C and 0-5°C) or high (20-25°C and ≥25°C) temperature categories had significantly higher doses of sleeping pills than those at the reference temperature (10-15°C). Changes in nighttime temperature had a significant non-linear effect on the prescribed dosage of hypnotic medications for both adults (p < 0.0001) and the elderly (p = 0.0006). CONCLUSION: We found that either a high or low nighttime temperature was significantly associated with a high daily dose of hypnotic medications in the Korean population.

Caffeine and Caffeine Metabolites in Relation to Insulin Resistance and Beta Cell Function in U.S. Adults.

The relationship between caffeine and insulin resistance (IR) has been assessed only in terms of caffeine intake, and the association between caffeine and beta cell function (BCF) remains unclear. This study examines the association between urinary caffeine and its metabolites, IR, and BCF in nondiabetic, noninstitutionalized US adults in order to account for the inter-individual differences in caffeine metabolism. Data on urinary caffeine and its metabolites, IR and BCF from adults aged 20 years and older who participated in the 2009-2010 and 2011-2012 National Health and Nutrition Examination Surveys were analyzed (n for caffeine = 994). IR and BCF were assessed using homeostatic model assessment (HOMA) and urinary caffeine and its metabolites were measured using high-performance liquid chromatography-electrospray ionization-tandem quadrupole mass spectrometry. After adjusting for all covariates, increases in urinary 1,3-DMU, 1,7-DMU, 1,3,7-TMU, theophylline, paraxanthine, caffeine, and AAMU were significantly associated with increased HOMA-IR and HOMA-ß (HOMA of insulin resistance and beta cell function). Compared with individuals in the lowest quartile of urinary 1,3-DMU, 1,7-DMU, 1,3,7-TMU, theophylline, paraxanthine, caffeine, and AAMU, the regression coefficients for HOMA-IR and HOMA-ß were significantly higher among those in the highest quartile. After stratification by prediabetes status, HOMA-IR and HOMA-ß showed significant positive associations with urinary caffeine and its metabolites among subjects with normal fasting plasma glucose levels. Our cross-sectional study showed that caffeine and its metabolites were positively related to IR and BCF.

Association Between the Frequency of Eating Non-home-prepared Meals and Women Infertility in the United States.

OBJECTIVES: The purpose of this study was to determine whether eating non-home-prepared meals (NHPM), including fast food, ready-to-eat foods, and frozen foods, was associated with self-reported infertility in the United States women. METHODS: Data on diet and infertility from women aged 20-49 years who participated in the 2013-2014 and 2015-2016 National Health and Nutrition Examination Surveys were analyzed (n=2143). Dietary information, including the number and types of NHPM consumed, was obtained from a self-reported questionnaire, and infertility status was analyzed using the following question, "Have you ever attempted to become pregnant over a period of at least a year without becoming pregnant?" RESULTS: The frequency of NHPM consumption was positively associated with self-reported infertility after adjusting for confounding effects (odds ratio [OR], 2.82; 95% confidence interval [CI], 1.48 to 5.38 of >1 vs. 0 NHPM/d). The odds of infertility were 2-3 times higher in women who consumed fast food than in those who did not consume fast food (OR, 2.73; 95% CI, 1.15 to 6.48 of >1 vs. 0 times/d). CONCLUSIONS: The frequency and types of NHPM may be a factor contributing to infertility. Although our findings require confirmation, they suggest that eating out may be deleterious to women fecundity.

Female Infertility Associated with Blood Lead and Cadmium Levels.

Lead and cadmium are known to be potential female reproductive toxins. However, studies on the relationship between these metals and infertility are limited. This study examines the association between self-reported infertility and blood lead and cadmium levels in US women by comparing metal levels in infertile and pregnant women. Data on blood lead, blood cadmium, and infertility from women aged 20-39 years who participated in the 2013-2014 and 2015-2016 National Health and Nutrition Examination Surveys were analyzed (n = 124, 'pregnant' n = 42, 'infertile' n = 82). Blood lead and cadmium levels were measured using inductively coupled plasma mass spectrometry, and infertility and pregnancy status were assessed using a self-reported questionnaire. Low blood lead and cadmium levels (geometric mean of blood lead = 0.50 µg/dL and blood cadmium = 0.26 µg/L) were positively associated with self-reported infertility after adjusting for confounding effects (odds ratio (OR) for lead per two-fold increase in blood metal levels = 2.60; 95% confidence interval (95% CI), 1.05-6.41 and OR for cadmium per two-fold increase = 1.84; 95% CI, 1.07-3.15). Although our findings require confirmation, they suggest that even low blood cadmium and lead levels may be deleterious to female fecundity.

Loss of Activin Receptor Type 1B Accelerates Development of Intraductal Papillary Mucinous Neoplasms in Mice With Activated KRAS.

BACKGROUND & AIMS: Activin, a member of the transforming growth factor-ß (TGFB) family, might be involved in pancreatic tumorigenesis, similar to other members of the TGFB family. Human pancreatic ductal adenocarcinomas contain somatic mutations in the activin A receptor type IB (ACVR1B) gene, indicating that ACVR1B could be a suppressor of pancreatic tumorigenesis. METHODS: We disrupted Acvr1b specifically in pancreata of mice (Acvr1b(flox/flox);Pdx1-Cre mice) and crossed them with LSL-KRAS(G12D) mice, which express an activated form of KRAS and develop spontaneous pancreatic tumors. The resulting Acvr1b(flox/flox);LSL-KRAS(G12D);Pdx1-Cre mice were monitored; pancreatic tissues were collected and analyzed by histology and immunohistochemical analyses. We also analyzed p16(flox/flox);LSL-Kras(G12D);Pdx1-Cre mice and Cre-negative littermates (controls). Genomic DNA, total RNA, and protein were isolated from mouse tissues and primary pancreatic tumor cell lines and analyzed by reverse-transcription polymerase chain reaction, sequencing, and immunoblot analyses. Human intraductal papillary mucinous neoplasm (IPMN) specimens were analyzed by immunohistochemistry. RESULTS: Loss of ACVR1B from pancreata of mice increased the proliferation of pancreatic epithelial cells, led to formation of acinar to ductal metaplasia, and induced focal inflammatory changes compared with control mice. Disruption of Acvr1b in LSL-KRAS(G12D);Pdx1-Cre mice accelerated the growth of pancreatic IPMNs compared with LSL-KRAS(G12D);Pdx1-Cre mice, but did not alter growth of pancreatic intraepithelial neoplasias. We associated perinuclear localization of the activated NOTCH4 intracellular domain to the apical cytoplasm of neoplastic cells with the expansion of IPMN lesions in Acvr1b(flox/flox);LSL-KRAS(G12D);Pdx1-Cre mice. Loss of the gene that encodes p16 (Cdkn2a) was required for progression of IPMNs to pancreatic ductal adenocarcinomas in Acvr1b(flox/flox);LSL-Kras(G12D);Pdx1-Cre mice. We also observed progressive loss of p16 in human IPMNs of increasing grades. CONCLUSIONS: Loss of ACVR1B accelerates growth of mutant KRAS-induced pancreatic IPMNs in mice; this process appears to involve NOTCH4 and loss of p16. ACVR1B suppresses early stages of pancreatic tumorigenesis; the activin signaling pathway therefore might be a therapeutic target for pancreatic cancer.