Association of APOE gene with longitudinal changes of CSF amyloid beta and tau levels in Alzheimer's disease: racial differences.

BACKGROUND: The Apolipoprotein E (APOE) ε4 allele is a risk factor for late-onset Alzheimer's disease (AD). However, no investigation has focused on racial differences in the longitudinal effect of APOE genotypes on CSF amyloid beta (Aß42) and tau levels in AD. METHODS: This study used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI): 222 participants with AD, 264 with cognitive normal (CN), and 692 with mild cognitive impairment (MCI) at baseline and two years follow-up. We used a linear mixed model to investigate the effect of APOE-ε4-genotypes on longitudinal changes in the amyloid beta and tau levels. RESULTS: Individuals with 1 or 2 APOE ε4 alleles revealed significantly higher t-Tau and p-Tau, but lower amyloid beta Aß42 compared with individuals without APOE ε4 alleles. Significantly higher levels of log-t-Tau, log-p-Tau, and low levels of log-Aß42 were observed in the subjects with older age, being female, and the two diagnostic groups (AD and MCI). The higher p-Tau and Aß42 values are associated with poor Mini-Mental State Examination (MMSE) performance. Non-Hispanic Africa American (AA) and Hispanic participants were associated with decreased log-t-Tau levels (ß = - 0.154, p = 0.0112; ß = - 0.207, and p = 0.0016, respectively) as compared to those observed in Whites. Furthermore, Hispanic participants were associated with a decreased log-p-Tau level (ß = - 0.224, p = 0.0023) compared to those observed in Whites. There were no differences in Aß42 level for non-Hispanic AA and Hispanic participants compared with White participants. CONCLUSION: Our study, for the first time, showed that the APOE ε4 allele was associated with these biomarkers, however with differing degrees among racial groups.

Early-onset alcohol, tobacco, and illicit drug use with age at onset of hypertension: a survival analysis.

PURPOSE: To examine the associations of age when first substance use and early-onset substance use before age 18 with age at onset (AAO) of hypertension. METHODS: This study included 19,270 individuals with AAO of hypertension from the 2015-2019 National Survey on Drug Use and Health. Age when first use of 10 substance use variables included alcohol, daily cigarettes, cigars, smokeless tobacco, marijuana, cocaine, hallucinogens, lysergic acid diethylamide (LSD), inhalants, and methamphetamine use. The outcome was AAO of hypertension and variable cluster analysis was used to classify the exposures and outcome. Substance use status was classified into three categories: early-onset substance use (first used substance before age 18), late-onset substance use (first used substance after age 18), and never used. RESULTS: The mean AAO of hypertension was 42.7 years. Age when first use of 10 substance use variables had significant correlations with AAO of hypertension (all p values < 0.001). Individuals with early-onset alcohol, cigars, smokeless tobacco, marijuana, hallucinogens, inhalants, cocaine, LSD, and methamphetamine use revealed significantly earlier onset of hypertension than those never used. Compared with never used substances, the Cox regression model showed that early-onset alcohol, smokeless tobacco, marijuana, inhalants, and methamphetamine use had an increased risk of AAO of hypertension [hazard ratio (HR) (95%CI) = 1.22 (1.13, 1.31), 1.36 (1.24, 1.49), 1.85 (1.75, 1.95), 1.41 (1.30, 1.52), and 1.27 (1.07,1.50), respectively]. CONCLUSION: These findings suggest that intervention strategies or programs focusing on preventing early-onset substance use before age 18 may delay the onset of adult hypertension.

The influence of spirituality on caregiver burden and quality of life in older adult informal caregivers.

BACKGROUND: Caregiver burden (CB) reduces quality of life (QOL) and causes poor health outcomes. Spirituality impacts this relationship. AIMS: To determine prevalence of CB and investigate relationships among CB, spirituality, and QOL in older U.S. adult informal caregivers (n = 754). METHODS: This was a cross-sectional, descriptive secondary analysis of data from the 2020 Health and Retirement Study using GLM and SEM. RESULTS: Caregiver mean age was 65.93 (SD=8.37). Caregivers were primarily female (n = 456, 54.0%), White (n = 500, 79.5%), and married (n = 469, 65.3%). Most caregivers had moderate CB (n = 369, 49.8%). Black caregivers who were spiritual (p=.031) and caregivers with a high school diploma/GED who were spiritual (p=.021) had lower CB. Lower CB was correlated with higher QOL (p=< 0.001). SEM depicting an influencing effect of spirituality revealed good model fit (NFI=0.988; IFI=0.993; TLI=0.983; PCFI=0.397, RMSEA=0.043; χ2=9.577, p=.048, DF=4) CONCLUSIONS: Fostering spirituality in older adult caregivers could reduce CB and improve QOL.

Racial differences in the effect of APOE-ε4 genotypes on trail making test B in Alzheimer's disease: A longitudinal study.

OBJECTIVES: The trail making test part B (TMT-B) evaluates executive functions, memory, and sensorimotor functions. No previous study was found to examine the longitudinal effect of APOE-ε4 genotypes on the TMT-B scores in Alzheimer's disease (AD) across racial groups. METHODS: This study used the data from Alzheimer's Disease Neuroimaging Initiative (ADNI): 382 participants with AD, 503 with cognitive normal (CN), 1293 with mild cognitive impairment (MCI) at baseline and follow-up of four years. The multivariable linear mixed model was used to investigate the effect of APOE-ε4 genotypes on changes in TMT-B scores. RESULTS: Compared with Whites, African Americans (AA) and Hispanics had higher TMT-B scores (poor cognitive function). Furthermore, Whites subjects with 1 or 2 APOE-ε4 alleles had significantly higher TMT-B scores compared with individuals without APOE-ε4 allele at baseline and four follow-up visits; however, no differences in TMT-B were found between APOE-ε4 alleles in the Hispanic and AA groups. No APOE-ε4 by visit interactions was found for 3 racial groups. Stratified by AD diagnosis, the APOE-ε4 allele was associated with TMT-B scores only in the MCI group, while there were significant interactions for visit by education, APOE-ε4 allele, and the Mini Mental State Examination (MMSE) score in the MCI group. In addition, TMT-B was significantly correlated with the MMSE, AD Assessment Scale-cognitive subscale 13 (ADAS13), tTau, pTau, Aß42, and hippocampus. CONCLUSIONS: APOE-ɛ4 allele is associated with TMT-B scores in Whites subjects, but not in the Hispanic and AA groups. APOE-ε4 showed interaction with visit in the MCI group.

Differences in smoking behaviors and readiness to change for patients with COPD and differing categories of depressive symptoms: a descriptive cross-sectional design.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the world with nearly 90% of cases caused by tobacco smoking. Nearly 40% of people with COPD are diagnosed with depression which impacts quality of life and smoking cessation. The purpose of this study was to describe factors influencing smoking behaviors and readiness to change in people with comorbid COPD and depression. METHODS: A descriptive cross-sectional design was used. A convenience sample of 222 participants self-reported and/or had a documented diagnosis of COPD. Participants completed study measures which included the PHQ-9 for depressive symptoms, assessment of smoking behaviors using The Cigarette Dependence Scale, report of readiness to change using The Smoking Stage of Change Questionnaire, The Smoking Decisional Balance Questionnaire, and The Processes of Change Questionnaire. Electronic and paper questionnaires were used. Data was stored in RedCap and analyzed using SPSS version 26. Based on variable type, descriptive and comparative analyses were conducted using ANOVA, t-test, chi-square, Pearson correlation, linear regression, and multiple linear regression to determine the relationships between smoking behaviors, COPD, and depressive symptoms. RESULTS: Only 18 participants were classified as having no depressive symptoms. Participants who smoked had high nicotine dependence and wanted to quit smoking. Overall, participants saw more cons to smoking and were engaged in the processes of change. The majority of participants were in the maintenance or contemplation stage. Cigarette dependence could decrease by 9% if depressive symptoms are treated. CONCLUSIONS: There is a need to assess COPD patients for depression and to assess COPD patients' smoking behaviors and readiness to change. Adequate treatment of depression could promote an individual to move through the stages of change from chronic contemplation to action, thus improving smoking cessation efforts for individuals with COPD. Understanding patients' smoking behaviors and readiness to change can aid in developing personalized interventions to achieve smoking cessation and improve long-term outcomes.

Linear Mixed Model Analysis of Polygenic Hazard Score on Verbal Memory Decline in Alzheimer's Disease.

BACKGROUND: Alzheimer's disease (AD) is a chronic, progressive, degenerative disease characterized by cognitive dysfunction, including verbal memory loss. Studies were lacking in examining the longitudinal effect of polygenic hazard score on the Rey Auditory Verbal Learning Test-Delayed Total (AVDELTOT) score (a common measure of verbal memory). A key step in analyzing longitudinal changes in cognitive measures using a linear mixed model (LMM) is choosing a suitable covariance structure. OBJECTIVES: The study aims to determine the association between the polygenic hazard score and the AVDELTOT score accounting for repeated measures (the covariance structure). METHODS: The AVDELTOT scores were collected at baseline, 12 months, 24 months, 36 months, and 48 months from 283 participants with AD, 347 with cognitive normal, and 846 with mild cognitive impairment in the Alzheimer's Disease Neuroimaging Initiative. The Bayesian information criterion statistic was used to select the best covariance structure from 10 covariance structures in longitudinal analysis of AVDELTOT scores. The multivariable LMM was used to investigate the effect of polygenic hazard score status (low vs. medium vs. high) on changes in AVDELTOT scores while adjusted for age, gender, education, APOE-ε4 genotype, and baseline Mini-Mental State Examination score. RESULTS: One-way analysis of variance revealed significant differences in AVDELTOT scores, Mini-Mental State Examination scores, and polygenic hazard scores among AD diagnoses at baseline. Bayesian information criterion favored the compound symmetry covariance structure in the LMM analysis. Using the multivariate LMM, the APOE-ε4 allele and high polygenic hazard score value was significantly associated with AVDELTOT declines. Significant polygenic hazard score status by follow-up visit interactions was discovered. CONCLUSION: Our findings provide the first evidence of the effect of polygenic hazard score status and APOE-ε4 allele on declines in verbal memory in people with AD.

COVID-19 Caregiving Strategies, Quality of Life, and Stress Among Faith Community Nurses and Faith Leaders in Appalachia.

ABSTRACT: Faith community nurses (FCNs), pastors, and priests faced many challenges from the COVID-19 pandemic, serving as frontline sources of support for congregants. The aim of this study was to identify the most common care strategies used during the COVID-19 pandemic and examine professional quality of life, perceived stress, and associated factors in faith leaders and FCNs in rural Appalachia. Using a cross-sectional, descriptive survey design, high compassion satisfaction was reported along with compassion fatigue as caregiving moved to virtual platforms, suggesting the need for greater support.

White matter integrity and key structures affected in Alzheimer's disease characterized by diffusion tensor imaging.

White matter (WM) degeneration is suggested to predict the early signs of Alzheimer's disease (AD). The exact structural regions of brain circuitry involved are not known. This study aims to examine the associations between WM tract integrity, represented by the diffusion tensor imaging (DTI) measures, and AD diagnosis and to denote the key substrates in predicting AD. It included DTI measures of mean diffusivity (MD), fractional anisotropy, radial diffusivity and axial diffusivity of 18 main WM tracts in 84 non-Hispanic white participants from the Alzheimer's Disease Neuroimaging Initiative dataset. The multivariable general linear model was used to examine the association of AD diagnosis with each DTI measure adjusting for age, gender and education. The corpus callosum, fornix, cingulum hippocampus, uncinate fasciculus, sagittal striatum, left posterior thalamic radiation and fornix-stria terminalis showed significant increases in MD, radial and axial diffusivity, whereas the splenium of corpus callosum and the fornix showed significant decreases in fractional anisotropy among AD patients. Variable cluster analysis identified that hippocampus volume, mini-mental state examination (MMSE), cingulate gyrus/hippocampus, inferior fronto-occipital fasciculus and uncinate fasciculus are highly correlated in one cluster with MD measures. In conclusion, there were significant differences in DTI measures between the brain WM of AD patients and controls. Age is the risk factor associated with AD, not gender or education. Right cingulum gyrus and right uncinate fasciculus are particularly affected, correlating well with a cognitive test MMSE and MD measures for dementia in AD patients and could be a region of focus for AD staging.

Internal heating method of loop-mediated isothermal amplification for detection of HPV-6 DNA.

Loop-mediated isothermal amplification (LAMP) is a promising diagnostic tool for genetic amplification, which is known for its rapid process, simple operation, high amplification efficiency, and excellent sensitivity. However, most of the existing heating methods are external for completion of molecular amplification with possibility of contamination of specimens. The present research provided an internal heating method for LAMP using magnetic nanoparticles (MNPs), which is called nano-LAMP. Near-infrared light with an excitation wavelength of 808 nm was employed as the heating source; hydroxy naphthol blue (HNB) was used as an indicator to conduct methodological research. We demonstrate that the best temperature was controlled at a working power of 2 W and 4.8 µg/µL concentration of nanoparticles. The lowest limit for the detection of HPV by the nano-LAMP method is 102 copies/mL, which was confirmed by a gel electrophoresis assay. In the feasibility investigation of validated clinical samples, all 10 positive HPV-6 specimens amplified by nano-LAMP were consistent with conventional LAMP methods. Therefore, the nano-LAMP detection method using internal heating of MNPs may bring a new vision to the exploration of thermostatic detection in the future.

Ethnic group differences in obesity in Asian Americans in California, 2013-2014.

BACKGROUND: Obesity has been generally understudied in Asian Americans. It is important to identify subgroups of Asian Americans at high risk of obesity to help develop targeted interventions for those subgroups. This study aimed to examine the disparities in obesity among Asians (i.e., Chinese, Filipino, Japanese, Korean, and Vietnamese) living in California. METHODS: A sample of Adult Americans in California (n = 47,970) including Asian American adults (n = 3810) aged 18 years or older were obtained from the 2013-2014 California Health Interview Survey (the U.S. nation's largest state cross-sectional health survey). Body mass index was calculated using self-reported height and weight. Weight status was determined using the WHO Asian BMI cut points in 4 categories: < 18.5 kg/m2 (underweight), 18.5-22.9 kg/m2 (normal weight), 23-27.5 kg/m2 (overweight), and ≥ 27.5 kg/m2 (obese). Multiple logistic regression analyses were used to estimate odds ratio (OR) and 95% confidence interval (CI) after adjustment for covariates. RESULTS: Overall, the prevalence of Asians was 23.3% for obesity and 40.0% for overweight. The obesity prevalence was higher in Asians who were males, aged 45-64 years old, had higher family income, were current smokers, never got married, had lower education level, had an insufficient level of physical activity, and had more frequent consumption of fast foods. After adjusting for other factors, compared to Whites, being Hispanics and Blacks were associated with higher odds of obesity (OR = 1.47, 95%CI = 1.31-1.65; OR = 2.04, 95%CI = 1.65-2.53, respectively); being Chinese, Korean, and Vietnamese were associated with lower odds of obesity (OR = 0.28, 95%CI = 0.18-0.45; OR = 0.14, 95%CI = 0.04-0.46; OR = 0.28, 95%CI = 0.14-0.58, respectively). Compared to Chinese, being Japanese and Filipino were associated with higher odds of obesity (OR = 2.75, 95%CI = 1.52-4.95; OR = 2.90, 95%CI = 1.87-4.49, respectively). CONCLUSIONS: The prevalence of adult obesity was high among Asian Americans in California. Ethnic/racial disparities in obesity among Asian Americans in California were observed in 2013-2014. Compared to Whites, being Chinese, Korean, Vietnamese were associated with lower odds of obesity. Among Asians, compared to Chinese, being Japanese and being Filipino were associated with higher odds of obesity. These findings can help design better interventions to reduce racial and ethnic disparities in obesity, especially for Asian Americans.

High-fat diet induces fibrosis in mice lacking CYP2A5 and PPARα: a new model for steatohepatitis-associated fibrosis.

Obesity is linked to nonalcoholic steatohepatitis. Peroxisome proliferator-activated receptor-α (PPARα) regulates lipid metabolism. Cytochrome P-450 2A5 (CYP2A5) is a potential antioxidant and CYP2A5 induction by ethanol is CYP2E1 dependent. High-fat diet (HFD)-induced obesity and steatosis are more severe in CYP2A5 knockout (cyp2a5-/-) mice than in wild-type mice although PPARα is elevated in cyp2a5-/- mice. To examine why the upregulated PPARα failed to prevent the enhanced steatosis in cyp2a5-/- mice, we abrogate the upregulated PPARα in cyp2a5-/- mice by cross-breeding cyp2a5-/- mice with PPARα knockout (pparα-/-) mice to create pparα-/-/cyp2a5-/- mice. The pparα-/-/cyp2a5-/- mice, pparα-/- mice, and cyp2a5-/- mice were fed HFD to induce steatosis. After HFD feeding, more severe steatosis was developed in pparα-/-/cyp2a5-/- mice than in pparα-/- mice and cyp2a5-/- mice. The pparα-/-/cyp2a5-/- mice and pparα-/- mice exhibited comparable and impaired lipid metabolism. Elevated serum alanine transaminase and liver interleukin-1ß, liver inflammatory cell infiltration, and foci of hepatocellular ballooning were observed in pparα-/-/cyp2a5-/- mice but not in pparα-/- mice and cyp2a5-/- mice. In pparα-/-/cyp2a5-/- mice, although redox-sensitive transcription factor nuclear factor erythroid 2-related factor 2 and its target antioxidant genes were upregulated as a compensation, thioredoxin was suppressed, and phosphorylation of JNK and formation of nitrotyrosine adduct were increased. Liver glutathione was decreased, and lipid peroxidation was increased. Interestingly, inflammation and fibrosis were all observed within the clusters of lipid droplets, and these lipid droplet clusters were all located inside the area with CYP2E1-positive staining. These results suggest that HFD-induced fibrosis in pparα-/-/cyp2a5-/- mice is associated with steatosis, and CYP2A5 interacts with PPARα to participate in regulating steatohepatitis-associated fibrosis.

Smokefree home rules and cigarette smoking intensity among smokers in different stages of smoking cessation from 20 low-and-middle income countries.

Smokefree environment created by smokefree policies is associated with smoking reduction; however, there is paucity of literature on the relationship between smokefree home rules and smoking intensity in low-and-middle income countries (LMICs), and how smokefree policy affects smoking behavior of smokers at different stages of smoking cessation. This study examined the relationship between smokefree home rules and average number of cigarettes smoked per day (CPD) among daily smokers at different stages of the transtheoretical model (TTM) of change. Data from 18,718 current daily cigarette smokers from the Global Adult Tobacco Survey (GATS) conducted from 2011 to 2017 in 20 LMICs were analyzed. Weighted multivariable linear regression analyses were conducted using the log of CPD as the outcome variable with smokefree home rules as the exposure variable, controlling for selected covariates. Approximately 15% of the participants were in precontemplation, 5% were in preparation, 15% lived in partial smokefree homes, and 30% lived in complete smokefree homes. The average number of CPD was 12.3, 12.0, and 10.6 among participants living in homes where smoking was allowed, partial smokefree homes, and complete smokefree homes, respectively. Compared to living in homes where smoking was allowed, living in complete smokefree homes were associated with 22.5% (95%CI = 18.4%-26.5%), 17.9% (95%CI = 8.4%-27.3%), and 29.3% (95% CI = 17.1%-41.5%) fewer CPD among participants in precontemplation, contemplation, and preparation stages, respectively. These findings suggest that complete smokefree home policy will benefit smokers in LMICs irrespective of their intention to quit smoking in addition to protecting non-smokers from secondhand smoke exposure.

A Fault Diagnostic Scheme Based on Capsule Network for Rolling Bearing under Different Rotational Speeds.

Deep learning-based intelligent fault diagnosis methods have attracted increasing attention for their automatic feature extraction ability. However, existing works are usually under the assumption that the training and test dataset share similar distributions, which unfortunately always violates real practice due to the variety of working conditions. In this paper, an end-to-end scheme of joint use of two-direction signals and capsule network (CN) is proposed for fault diagnosis of rolling bearing. With the help of the superior ability of CN in capturing the spatial position information between features, more valuable information can be mined. Aiming to eliminate the influence of different rotational speeds, vertical and horizontal vibration signals are fused as the input to CN, so that invariant features can be extracted automatically from the raw signals. The effectiveness of the proposed method is verified by experimental data of rolling bearing under different rotational speeds and compared with a deep convolutional neural network (DCNN). The results demonstrate that the proposed scheme is able to recognize the fault types of rolling bearing under scenarios of different rotational speeds.

Feasibility of a self-management intervention in adolescents with headache (SMI-AH).

PURPOSE: This study assessed the acceptability and limited efficacy of a self-management intervention to improve lifestyle behaviors and headache outcomes among rural adolescents with recurrent headache. DESIGN AND METHODS: Participants were randomly assigned to a self-management intervention for adolescent headache (SMI-AH, n = 13) or standard care group (n = 17). The SMI-AH group participated in goal-setting, self-monitoring, and information processing to modify lifestyle behaviors (missed meals, caffeine intake, and poor sleep). Independent samples t-test was used to compare the means of outcomes at baseline and 6-week follow-up between the treatment group and control group. Linear mixed model (LMM) was used to examine the intervention effects over time. RESULTS: The mean age was 14.8 years (sd = 1.6, range, 12-17); with female participants accounting for 80% of the sample (n = 24) and persons reporting white race were 97% (n = 29). The SMI-AH group demonstrated a greater magnitude of change in lifestyle behaviors, including increased days of eating breakfast and lunch. The multivariate LMM showed significant intervention effect of lunch intake (p = 0.042 with Cohen's d = 0.42) and borderline significant effect of breakfast intake (p = 0.064 with Cohen's d = 0.38). Participants reported the intervention was easy to use and helpful to monitor behaviors. CONCLUSIONS: Among rural adolescents, a self-management intervention is a feasible approach for engaging youth. The SMI-AH provides an opportunity for the adolescents to talk about their behaviors and participate in goal setting as well as the plan of care with the provider. Challenges identified in this study are manageable and a full study is feasible with modifications.

KTN1 variants and risk for attention deficit hyperactivity disorder.

Individuals with attention deficit hyperactivity disorder (ADHD) show gray matter volume (GMV) reduction in the putamen. KTN1 variants may regulate kinectin 1 expression in the putamen and influence putamen structure and function. We aim to test the hypothesis that the KTN1 variants may represent a genetic risk factor of ADHD. Two independent family-based Caucasian samples were analyzed, including 922 parent-child trios (a total of 2,757 subjects with 924 ADHD children) and 735 parent-child trios (a total of 1,383 subjects with 613 ADHD children). The association between ADHD and a total of 143 KTN1 SNPs was analyzed in the first sample, and the nominally-significant (p < .05) risk SNPs were classified into independent haplotype blocks. All SNPs, including imputed SNPs within these blocks, and haplotypes across each block, were explored for replication of associations in both samples. The potential biological functions of all risk SNPs were predicted using a series of bioinformatics analyses, their regulatory effects on the putamen volumes were tested, and the KTN1 mRNA expression was examined in three independent human putamen tissue samples. We found that fifteen SNPs were nominally associated with ADHD (p < .05) in the first sample, and three of them remained significant even after correction for multiple testing (1.3 × 10-10 ≤ p ≤ 1.2 × 10-4 ; α = 2.5 × 10-3 ). These 15 risk SNPs were located in five haplotype blocks, and 13 SNPs within four of these blocks were associated with ADHD in the second sample. Six haplotypes within these blocks were also significantly (1.2 × 10-7 ≤ p ≤ .009) associated with ADHD in these samples. These risk variants were located in disease-related transposons and/or transcription-related functional regions. Major alleles of these risk variants significantly increased putamen volumes. Finally, KTN1 mRNA was significantly expressed in putamen across three independent cohorts. We concluded that the KTN1 variants were significantly associated with ADHD. KTN1 may play a functional role in the development of ADHD.

Suppressed hepatocyte proliferation via a ROS-HNE-P21 pathway is associated with nicotine- and cotinine-enhanced alcoholic fatty liver in mice.

CYP2A5 is a major enzyme responsible for nicotine and cotinine metabolism in mice. Nicotine and cotinine enhance alcoholic fatty liver in wild type (WT) mice but not in CYP2A5 knockout (KO) mice, and reactive oxygen species (ROS) generated during the CYP2A5-mediated metabolism contributes to the enhancing effect. In combination with ethanol, nicotine and cotinine increased lipid peroxidation end product 4-hydroxynonenal (HNE) in WT mice but not in KO mice. In ethanol-fed KO mice, only 5 and 10 genes were regulated by nicotine and cotinine, respectively. However, in ethanol-fed WT mice, 59 and 104 genes were regulated by nicotine and cotinine, respectively, and 7 genes were up-regulated by both nicotine and cotinine. Plin 2 and Cdkn1a are among the 7 genes. Plin2 encodes adipose differentiation-related protein (ADRP), a lipid droplet-associated protein, which was confirmed to be increased by nicotine and cotinine in WT mice but not in KO mice. Cdkn1a encodes P21 and elevated P21 in nuclei was also confirmed. HNE can increase P21 and P21 inhibit cell proliferation. Consistently, hepatocyte proliferation markers proliferating cell nuclear antigen (PCNA) and Ki67 were decreased in WT mice but not in KO mice by nicotine/ethanol and cotinine/ethanol, respectively. These results suggest that inhibition of liver proliferation via a ROS-HNE-P21 pathway is involved in nicotine- and cotinine-enhanced alcoholic fatty liver.

CYP2A6 is associated with obesity: studies in human samples and a high fat diet mouse model.

BACKGROUND/OBJECTIVES: CYP2A6 (CYP2A5 in mice) is mainly expressed in the liver. Hepatic CYP2A6 expression is increased in patients with non-alcoholic fatty liver disease (NAFLD). In mice, hepatic CYP2A5 is induced by high fat diet (HFD) feeding. Hepatic CYP2A5 is also increased in monosodium glutamate-induced obese mice. NAFLD is associated with obesity. In this study, we examined whether obesity is related to CYP2A6. SUBJECTS/METHODS: Obesity genetic association study: The SAGE is a comprehensive genome-wide association study (GWAS) with case subjects having a lifetime history of alcohol dependence and control subjects never addicted to alcohol. We used 1030 control individuals with self-reported height and weight. A total of 12 single nucleotide polymorphisms (SNP) within the CYP2A6 gene were available. Obesity was determined as a BMI ≥30: 30-34.9 (Class I obesity) and ≥35 (Class II and III obesity). Animal experiment study: CYP2A5 knockout (cyp2a5-/-) mice and wild type (cyp2a5+/+) mice were fed HFD for 14 weeks. Body weight was measured weekly. After an overnight fast, the mice were sacrificed. Liver and blood were collected for biochemical assays. RESULTS: Single marker analysis showed that three SNPs (rs8192729, rs7256108, and rs7255443) were associated with class I obesity (p < 0.05). The most significant SNP for obesity was rs8192729 (odds ratio (OR) = 1.94, 95% confidence intervals = 1.21-3.10, p = 0.00582). After HFD feeding, body weight was increased in cyp2a5-/- mice to a greater extent than in cyp2a5+/+ mice, and fatty liver was more pronounced in cyp2a5-/- mice than in cyp2a5+/+ mice. PPARα deficiency in cyp2a5-/- mice developed more severe fatty liver, but body weight was not increased significantly. CONCLUSION: CYP2A6 is associated with human obesity; CYP2A5 protects against obesity and NAFLD in mice. PPARα contributes to the CYP2A5 protective effects on fatty liver but it opposes to the protective effects on obesity.

Health Care Provider Intervention and Utilization of Cessation Assistance in 12 Low- and Middle-Income Countries.

Background and Aim: There is a need to improve utilization of cessation assistance in low- and middle-income countries (LMICs), and tobacco cessation research has been identified as priority in LMICs. This study evaluates the relationship between health care provider intervention and cessation assistance utilization in LMICs. Methods: Data from 13 967 participants (aged ≥15 years, 90.3% males) of the Global Adults Tobacco Survey conducted in 12 LMICs (74.3%-97.3% response rates) were analyzed with utilization of counseling/cessation clinic, WHO-recommended medications, and quitline as outcome variables. Health care provider intervention ("no intervention," only "tobacco screening," "quit advice") was the exposure variable. Weighted multiple logistic regression models were used to examine the relationship between each outcome variable and the exposure variable, adjusting for other covariates. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) are reported. Results: Approximately 52%, 8%, and 40% of participants received no intervention, only tobacco screening, and advice to quit, respectively. Overall, 0.4%, 1.9%, 3.0%, and 4.5% used quitline, WHO-recommended medications, counseling/cessation clinic, and any cessation assistance, respectively. Compared with no intervention, quit advice was associated with increased utilization of quitline (OR = 2.24, 95% CI = 1.2 to 4.4), WHO-recommended medications (OR = 1.67, 95% CI = 1.2 to 2.3), counseling/cessation clinic (OR = 4.41, 95% CI = 3.2 to 6.1), and any assistance (any of the three types) (OR = 2.80, 95% CI = 2.2 to 3.6). Conclusion: The findings of this study suggest that the incorporation of quit advice by health care providers in tobacco control programs and health care systems in LMICs could potentially improve utilization of cessation assistance to improve smoking cessation in LMICs. Implications: This first study of association between health care provider intervention and the utilization of cessation assistance in LMICs reports that there was a missed opportunity to provide quit advice to about 60% of smokers who visited a health care provider in the past year. The odds of utilization of counseling/cessation clinic, WHO-recommended medications, and quitline were significantly increased in participants who were advised to quit smoking. The results suggest that effective integration and implementation of advice to quit in tobacco control programs and the national health care systems may increase the use of cessation assistance to quit smoking.

Motion Periods of Planet Gear Fault Meshing Behavior.

Vibration sensors are, generally, fixed on the housing of planetary gearboxes for vibration monitoring. When a local fault occurred on the tooth of a planet gear, along with the system operating, the faulty tooth will mesh with the ring gear or sun gear at different positions referring to the fixed sensor. With consideration of the attenuation effect, the amplitudes of the fault-induced vibrations will be time-varying due to the time-varying transfer paths. These variations in signals are valuable information to identify the fault existence as well as the severity and types. However, the fault-meshing positions are time-varying and elusive due to the complicated kinematics or the compound motion behaviors of the internal rotating components. It is tough to accurately determine every fault meshing position though acquiring information from multi-sensors. However, there should exist some specific patterns of the fault meshing positions referring to the single sensor. To thoroughly investigate these motion patterns make effective fault diagnosis feasible merely by a single sensor. Unfortunately, so far few pieces of literature explicitly demonstrate these motion patterns in this regard. This article proposes a method to derive the motion periods of the fault-meshing positions with a faulty planet gear tooth, in which two conditions are considered: 1. The fault-meshing position initially occurs at the ring gear; 2. The fault-meshing position initially occurs at the sun gear. For each scenario, we derive the mathematical expression of the motion period in terms of rotational angles. These motion periods are, in essence, based on the teeth number of gears of a given planetary gearbox. Finally, the application of these motion periods for fault diagnosis is explored with experimental studies. The minimal required data length of a single sensor for effective fault diagnosis is revealed based on the motion periods.

Genome-wide significant, replicated and functional risk variants for Alzheimer's disease.

Genome-wide association studies (GWASs) have reported numerous associations between risk variants and Alzheimer's disease (AD). However, these associations do not necessarily indicate a causal relationship. If the risk variants can be demonstrated to be biologically functional, the possibility of a causal relationship would be increased. In this article, we reviewed all of the published GWASs to extract the genome-wide significant (p < 5×10-8) and replicated associations between risk variants and AD or AD-biomarkers. The regulatory effects of these risk variants on the expression of a novel class of non-coding RNAs (piRNAs) and protein-coding RNAs (mRNAs), the alteration of proteins caused by these variants, the associations between AD and these variants in our own sample, the expression of piRNAs, mRNAs and proteins in human brains targeted by these variants, the expression correlations between the risk genes and APOE, the pathways and networks that the risk genes belonged to, and the possible long non-coding RNAs (LncRNAs) that might regulate the risk genes were analyzed, to investigate the potential biological functions of the risk variants and explore the potential mechanisms underlying the SNP-AD associations. We found replicated and significant associations for AD or AD-biomarkers, surprisingly, only at 17 SNPs located in 11 genes/snRNAs/LncRNAs in eight genomic regions. Most of these 17 SNPs enriched some AD-related pathways or networks, and were potentially functional in regulating piRNAs and mRNAs; some SNPs were associated with AD in our sample, and some SNPs altered protein structures. Most of the protein-coding genes regulated by the risk SNPs were expressed in human brain and correlated with APOE expression. We conclude that these variants were most robust risk markers for AD, and their contributions to AD risk was likely to be causal. As expected, APOE and the lipoprotein metabolism pathway possess the highest weight among these contributions.