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Intensive longitudinal biomarker data are increasingly common in scientific studies that seek temporally granular understanding of the role of behavioral and physiological factors in relation to outcomes of interest. Intensive longitudinal biomarker data, such as those obtained from wearable devices, are often obtained at a high frequency typically resulting in several hundred to thousand observations per individual measured over minutes, hours, or days. Often in longitudinal studies, the primary focus is on relating the means of biomarker trajectories to an outcome, and the variances are treated as nuisance parameters, although they may also be informative for the outcomes. In this paper, we propose a Bayesian hierarchical model to jointly model a cross-sectional outcome and the intensive longitudinal biomarkers. To model the variability of biomarkers and deal with the high intensity of data, we develop subject-level cubic B-splines and allow the sharing of information across individuals for both the residual variability and the random effects variability. Then different levels of variability are extracted and incorporated into an outcome submodel for inferential and predictive purposes. We demonstrate the utility of the proposed model via an application involving bio-monitoring of hertz-level heart rate information from a study on social stress., (© 2024 The Author(s). Statistics in Medicine published by John Wiley & Sons Ltd.)

Paneth cells (PCs), a subset of intestinal epithelial cells (IECs) found at the base of small intestinal crypts, play an essential role in maintaining intestinal homeostasis. Altered PCs function is associated with diverse intestinal pathologies, including ileal Crohn's disease (CD). CD patients with ileal involvement have been previously demonstrated to display impairment in PCs and decreased levels of anti-microbial peptides. Although the immunosuppressive drug Azathioprine (AZA) is widely used in CD therapy, the impact of AZA on IEC differentiation remains largely elusive. In the present study, we hypothesized that the orally administered drug AZA also exerts its effect through modulation of the intestinal epithelium and specifically via modulation of PC function. AZA-treated CD patients exhibited an ileal upregulation of AMPs on both mRNA and protein levels compared to non-AZA treated patients. Upon in vitro AZA stimulation, intestinal epithelial cell line MODE-K exhibited heightened expression levels of PC marker in concert with diminished cell proliferation but boosted mitochondrial OXPHOS activity. Moreover, differentiation of IECs, including PCs differentiation, was boosted in AZA-treated murine small intestinal organoids and was associated with decreased D-glucose consumption and decreased growth rates. Of note, AZA treatment strongly decreased Lgr5 mRNA expression as well as Ki67 positive cells. Further, AZA restored dysregulated PCs associated with mitochondrial dysfunction. AZA-dependent inhibition of IEC proliferation is accompanied by boosted mitochondria function and IEC differentiation into PC., (© 2024. The Author(s).)

Background and Objectives: Elevated circulating cystatin C is associated with cognitive impairment in non-Hispanic Whites, but its role in racial disparities in dementia is understudied. In a nationally representative sample of older non-Hispanic White, non-Hispanic Black, and Hispanic adults in the United States, we use mediation-interaction analysis to understand how racial disparities in the cystatin C physiological pathway may contribute to racial disparities in prevalent dementia., Methods: In a pooled cross-sectional sample of the Health and Retirement Study ( n = 9,923), we employed Poisson regression to estimate prevalence ratios and to test the relationship between elevated cystatin C (>1.24 vs. ≤1.24 mg/L) and impaired cognition, adjusted for demographics, behavioral risk factors, other biomarkers, and chronic conditions. Self-reported racialized social categories were a proxy measure for exposure to racism. We calculated additive interaction measures and conducted four-way mediation-interaction decomposition analysis to test the moderating effect of race/ethnicity and mediating effect of cystatin C on the racial disparity., Results: Overall, elevated cystatin C was associated with dementia (prevalence ratio [PR] = 1.2; 95% CI: 1.0, 1.5). Among non-Hispanic Black relative to non-Hispanic White participants, the relative excess risk due to interaction was 0.7 (95% CI: -0.1, 2.4), the attributable proportion was 0.1 (95% CI: -0.2, 0.4), and the synergy index was 1.1 (95% CI: 0.8, 1.8) in a fully adjusted model. Elevated cystatin C was estimated to account for 2% (95% CI: -0, 4%) for the racial disparity in prevalent dementia, and the interaction accounted for 8% (95% CI: -5, 22%). Analyses for Hispanic relative to non-white participants suggested moderation by race/ethnicity, but not mediation., Discussion: Elevated cystatin C was associated with dementia prevalence. Our mediation-interaction decomposition analysis suggested that the effect of elevated cystatin C on the racial disparity might be moderated by race/ethnicity, which indicates that the racialization process affects not only the distribution of circulating cystatin C across minoritized racial groups, but also the strength of association between the biomarker and dementia prevalence. These results provide evidence that cystatin C is associated with adverse brain health and this effect is larger than expected for individuals racialized as minorities had they been racialized and treated as non-Hispanic White., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Higgins Tejera, Ware, Kobayashi, Fu, Hicken, Zawistowski, Mukherjee and Bakulski.)

Background: Exposure to systemic racism is linked to increased dementia burden. To assess systemic inflammation as a potential pathway linking exposure to racism and dementia disparities, we investigated the mediating role of C-reactive protein (CRP), a systemic inflammation marker, and the moderating role of race/ethnicity on racialized disparities in incident dementia., Methods: In the US Health and Retirement Study (n=5,143), serum CRP was measured at baseline (2006, 2008 waves). Incident dementia was classified by cognitive tests over a six-year follow-up. Self-reported racialized categories were a proxy for exposure to the racialization process. We decomposed racialized disparities in dementia incidence (non-Hispanic Black and/or Hispanic vs. non-Hispanic White) into 1) the mediated effect of CRP, 2) the moderated portion attributable to the interaction between racialized group membership and CRP, and 3) the controlled direct effect (other pathways through which racism operates)., Results: The 6-year cumulative incidence of dementia was 15.5%. Among minoritized participants (i.e., non-Hispanic Black and/or Hispanic), high CRP levels (> 75th percentile or 4.57mcg/mL) was associated with 1.27 (95%CI: 1.01,1.59) times greater risk of incident dementia than low CRP (<4.57mcg/mL). Decomposition analysis comparing minoritized versus non-Hispanic White participants showed that the mediating effect of CRP accounted for 2% (95% CI: 0%, 6%) of the racial disparity, while the interaction effect between minoritized group status and high CRP accounted for 12% (95% CI: 2%, 22%) of the disparity. Findings were robust to potential violations of causal mediation assumptions., Conclusions: Systemic inflammation mediates racialized disparities in incident dementia.

Objective: This study seeks to examine neighborhood characteristics, physical activity, and health status and their roles in promoting healthy cognitive aging. Methods: Using data from the REasons for Geographic And Racial Difference in Stroke (REGARDS) study ( N =10,289, mean age=73.4 years), we used multilevel linear regression to examine the relationships between walkable neighborhoods (both objectively measured and subjective perceptions), walking behavior, physical activity, health status, and cognitive function. Results: Engaging in any moderate physical activity (β=0.47, p < 0.001), having better health status (β=0.02, p < 0.001), living in neighborhoods with greater street connectivity (β=0.15, p < 0.05), and positive perceptions of neighborhood traffic ( p < 0.01) and parks ( p < 0.05), were associated with higher cognitive function. Residence in socioeconomically disadvantaged neighborhoods (β=-0.01, p < 0.01) was negatively associated with cognitive function . Discussion: Both perceived and objective features of walkable environments may have consequences for cognitive health, and can inform the development of health promoting communities.

To enable rapid proliferation, colorectal tumor cells up-regulate epidermal growth factor receptor (EGFR) signaling and aerobic glycolysis, resulting in substantial lactate release into the tumor microenvironment and impaired anti-tumor immune responses. We hypothesized that a nutritional intervention designed to reduce aerobic glycolysis may boost the EGFR-directed antibody (Ab)-based therapy of pre-existing colitis-driven colorectal carcinoma (CRC). CRC development was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS) administration to C57BL/6 mice. AOM/DSS-treated mice were fed a glucose-free, high-protein diet (GFHPD) or an isoenergetic control diet (CD) in the presence or absence of an i.p. injection of an anti-EGFR mIgG2a or respective controls. AOM/DSS-treated mice on a GFHPD displayed a reduced systemic glucose metabolism associated with reduced oxidative phosphorylation (OXPHOS) complex IV expression and diminished tumor loads. Comparable but not additive to an anti-EGFR-Ab therapy, the GFHPD was accompanied by enhanced tumoral goblet cell differentiation and decreased colonic PD-L1 and splenic CD3ε, as well as PD-1 immune checkpoint expression. In vitro, glucose-free, high-amino acid culture conditions reduced proliferation but improved goblet cell differentiation of murine and human CRC cell lines MC-38 and HT29-MTX in combination with down-regulation of PD-L1 expression. We here found GFHPD to systemically dampen glycolysis activity, thereby reducing CRC progression with a similar efficacy to EGFR-directed antibody therapy.

Background & Aims: Cell differentiation in the colonic crypt is driven by a metabolic switch from glycolysis to mitochondrial oxidation. Mitochondrial and goblet cell dysfunction have been attributed to the pathology of ulcerative colitis (UC). We hypothesized that p32/gC1qR/HABP1, which critically maintains oxidative phosphorylation, is involved in goblet cell differentiation and hence in the pathogenesis of UC., Methods: Ex vivo, goblet cell differentiation in relation to p32 expression and mitochondrial function was studied in tissue biopsies from UC patients versus controls. Functional studies were performed in goblet cell-like HT29-MTX cells in vitro. Mitochondrial respiratory chain complex V-deficient, ATP8 mutant mice were utilized as a confirmatory model. Nutritional intervention studies were performed in C57BL/6 mice., Results: In UC patients in remission, colonic goblet cell differentiation was significantly decreased compared to controls in a p32-dependent manner. Plasma/serum L-lactate and colonic pAMPK level were increased, pointing at high glycolytic activity and energy deficiency. Consistently, p32 silencing in mucus-secreting HT29-MTX cells abolished butyrate-induced differentiation and induced a shift towards glycolysis. In ATP8 mutant mice, colonic p32 expression correlated with loss of differentiated goblet cells, resulting in a thinner mucus layer. Conversely, feeding mice an isocaloric glucose-free, high-protein diet increased mucosal energy supply that promoted colonic p32 level, goblet cell differentiation and mucus production., Conclusion: We here describe a new molecular mechanism linking mucosal energy deficiency in UC to impaired, p32-dependent goblet cell differentiation that may be therapeutically prevented by nutritional intervention., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Self-sustained cell proliferation constitutes one hallmark of cancer enabled by aerobic glycolysis which is characterized by imbalanced glycolysis and mitochondrial oxidative phosphorylation (OXPHOS) activity, named the Warburg effect. The C1q binding protein ( C1QBP ; gC1qR) is pivotal for mitochondrial protein translation and thus OXPHOS activity. Due to its fundamental role in balancing OXPHOS and glycolysis, c1qbp -/- mice display embryonic lethality, while gC1qR is excessively up-regulated in cancer. Although gC1qR encompasses an N -terminal mitochondrial leader it is also located in other cellular compartments. Hence, we aimed to investigate mechanisms regulating gC1qR cellular localization and its impact on tumor cell metabolism. We identified two caspase-1 cleavage sites in human gC1qR. GC1qR cleavage by active caspase-1 was unraveled as a cellular mechanism that prevents mitochondrial gC1qR import, thereby enabling aerobic glycolysis and enhanced cell proliferation. Ex vivo , tumor grading correlated with non-mitochondrial-located gC1qR as well as with caspase-1 activation in colorectal carcinoma patients. Together, active caspase-1 cleaves gC1qR and boosts aerobic glycolysis in tumor cells., (Copyright © 2020 Sünderhauf, Raschdorf, Hicken, Schlichting, Fetzer, Brethack, Perner, Kemper, Ghebrehiwet, Sina and Derer.)

The luminosities of type Ia supernovae (SNe), the thermonuclear explosions of white-dwarf stars, vary systematically with their intrinsic color and the rate at which they fade. From images taken with the Galaxy Evolution Explorer (GALEX), we identified SNe Ia that erupted in environments that have high ultraviolet surface brightness and star-formation surface density. When we apply a steep model extinction law, we calibrate these SNe using their broadband optical light curves to within ~0.065 to 0.075 magnitude, corresponding to <4% in distance. The tight scatter, probably arising from a small dispersion among progenitor ages, suggests that variation in only one progenitor property primarily accounts for the relationship between their light-curve widths, colors, and luminosities., (Copyright © 2015, American Association for the Advancement of Science.)

Background: Research suggests that reports of interpersonal discrimination result in poor mental health. Because personality characteristics may either confound or mediate the link between these reports and mental health, there is a need to disentangle its role in order to better understand the nature of discrimination-mental health association. We examined whether hostility, anger repression and expression, pessimism, optimism, and self-esteem served as confounders in the association between perceived interpersonal discrimination and CESD-based depressive symptoms in a race/ethnic heterogeneous probability-based sample of community-dwelling adults., Methods: We employed a series of ordinary least squares regression analyses to examine the potential confounding effect of hostility, anger repression and expression, pessimism, optimism, and self-esteem between interpersonal discrimination and depressive symptoms., Results: Hostility, anger repression, pessimism and self-esteem were significant as possible confounders of the relationship between interpersonal discrimination and depressive symptoms, together accounting for approximately 38% of the total association (beta: 0.1892, p < 0.001). However, interpersonal discrimination remained a positive predictor of depressive symptoms (beta: 0.1176, p < 0.001)., Conclusion: As one of the first empirical attempts to examine the potential confounding role of personality characteristics in the association between reports of interpersonal discrimination and mental health, our results suggest that personality-related characteristics may serve as potential confounders. Nevertheless, our results also suggest that, net of these characteristics, reports of interpersonal discrimination are associated with poor mental health.

Blacks have persistently higher rates of high blood pressure, or hypertension, compared to whites, resulting in higher health costs and mortality rates. Recent research has shown that social and environmental factors-such as high levels of stress and exposure to lead-may explain racial disparities in hypertension. Based on these findings, we recommend a fundamental shift in approaches to health disparities to focus on these sorts of cumulative risks and health effects. Federal and state agencies and research institutions should develop strategic plans to learn more about these connections and apply the broader findings to policies to reduce health disparities.

Objectives: To describe age patterns of hypertension prevalence in young through middle-aged adults and to test the hypothesis that hypertension prevalence rises more rapidly with age among Blacks than Whites in the United States., Design, Setting, and Participants: Using multiple logistics regression, we predicted probability of being hypertensive for participants ages 15-65 years in the National Health and Nutrition Examination Survey (NHANES) IV, 1999-2002. We estimated age-specific Black-to-White odds ratios of hypertension overall, by sex, and adjusted for body mass index (BMI) and poverty income ratio. We also followed NHANES cohorts to test whether differential age patterns of hypertension prevalence by race or gender represented cohort effects., Main Outcome Measure: Hypertension: systolic blood pressure > or = 140 mm Hg, diastolic blood pressure > or = 90 mm Hg, or current antihypertensive medication use., Results: Black/White odds of hypertension increased from 1.71 to 3.12 between ages 15 and 65. Odds for women increased faster, from 2.11 to 4.04. By age 40, Black women had the highest hypertension rates and steepest age-gradient of race/sex groups. Adjustment for poverty income ratio did not affect results. Adjustment for BMI reduced Black women's hypertension risk somewhat but not men's. Cohort analysis confirmed a more rapid increase in hypertension prevalence among Blacks and women., Conclusions: Hypertension screening of Blacks should begin at young ages. Early diagnosis and vigilant management are critical to addressing racial and sex differences and their effect on cardiovascular disease, life expectancy, and maternal and infant health. Psychosocial stressors merit consideration as candidates for primary prevention. Addressing fundamental causes is needed. Understanding the growing age-gradient increase among US Black women is pressing.

Objectives: We considered whether US Blacks experience early health deterioration, as measured across biological indicators of repeated exposure and adaptation to stressors., Methods: Using National Health and Nutrition Examination Survey data, we examined allostatic load scores for adults aged 18-64 years. We estimated probability of a high score by age, race, gender, and poverty status and Blacks' odds of having a high score relative to Whites' odds., Results: Blacks had higher scores than did Whites and had a greater probability of a high score at all ages, particularly at 35-64 years. Racial differences were not explained by poverty. Poor and nonpoor Black women had the highest and second highest probability of high allostatic load scores, respectively, and the highest excess scores compared with their male or White counterparts., Conclusions: We found evidence that racial inequalities in health exist across a range of biological systems among adults and are not explained by racial differences in poverty. The weathering effects of living in a race-conscious society may be greatest among those Blacks most likely to engage in high-effort coping.

To deliver a comprehensive and efficient service to all the community, public libraries must first identify needs and allocate an appropriate level of resources. This article focuses on public libraries in England. It outlines: the Government's policy on social inclusion; the needs of the various socially excluded groups; partnerships and funding; staff training and motivation; and examples of good practice.

Background: Although many birth defect surveillance systems were developed for the primary purpose of monitoring trends and conducting epidemiologic studies, a number of programs have recognized the potential of birth defects monitoring systems for identifying and referring children who may be eligible for services. Because almost all surveillance programs maintain a registry of all children who have been diagnosed with birth defects in a particular state or other defined geographic region, registries can play an important role in identifying eligible children and providing timely referral to specialized services., Methods: We sent electronically an 18-question survey to the Centers for Disease Control and Prevention's list of State Birth Defects Surveillance Contacts in all 50 states, the District of Columbia, and Puerto Rico. The survey queried states as to whether they had or were developing a birth defect surveillance program, the extent to which they were currently using or were considering using their program as a means of identifying and referring children for services, and if so, the manner in which referrals were made., Results: We received completed surveys from all 50 states, Washington, DC, and Puerto Rico. Thirty-two of the fifty-two respondents stated that their state or entity has an operational birth defect surveillance program. Of these, 13 have implemented an identification and referral system within the surveillance program. All 16 states that were planning a surveillance program are also are planning or beginning to implement a program that would include an identification and referral system. Respondents cited lack of resources and confidentiality concerns as being the major barriers to implementing a referral system for their registry., Conclusions: For many registries, using their surveillance data for program development purposes represents a new undertaking. This trend reflects increasing recognition of the role that state-based birth defect surveillance systems can play in supporting child-find efforts for children with special needs. In the long run, this expanded focus may further enhance the public health usefulness of birth defect surveillance programs.