Longitudinal relationships between BMI and hs-CRP among people with schizophrenia.

In people with schizophrenia (PwS), inflammation and metabolic issues significantly increase morbidity and mortality. However, our ability to understand inflammatory-metabolic mechanisms in this population has been limited to cross-sectional studies. This study involved 169 PwS and 156 non-psychiatric comparisons (NCs), aged 25-65, observed between 2012 and 2022 with 0 to 5 follow-ups post-baseline. High-sensitivity C-reactive protein (hs-CRP), a marker of inflammation, was measured via a particle-enhanced immuno-turbidimetric assay. Body mass index (BMI) was used as a proxy for metabolic function. The measurement intervals for hs-CRP and BMI ranged between 6 and 48 months. Linear mixed models (LMM) results revealed that at all time points, PwS has a higher hs-CRP (t (316) = 4.73, p < .001) and BMI (t (315) = 4.13, p < .001) than NCs; however, for BMI, this difference decreased over time (t (524) = -5.15, p < .001). To study interrelationships between hs-CRP and BMI, continuous time structural equational modeling (CTSEM) was used, accounting for uneven measurement intervals. CTSEM results showed that both hs-CRP predicted future BMI (Est. = 12.91, 95 % CI [7.70; 17.88]) and BMI predicted future hs-CRP (Est. = 1.54, 95 % CI [1.00; 2.04]), indicating a bidirectional relationship between inflammation and metabolic function. Notably, the influence of hs-CRP on future BMI was more robust than the other lagged relationship (p = .015), especially in PwS (Est. = 2.43, 95 % CI [0.39; 0.97]). Our study highlights the important role of inflammation in metabolic function and offers insights into potential interventions targeting inflammation in PwS.

Testing the causal impact of amyloidosis on total Tau using a genetically informative sample of adult male twins.

INTRODUCTION: The amyloid cascade hypothesis predicts that amyloid-beta (Aß) aggregation drives tau tangle accumulation. We tested competing causal and non-causal hypotheses regarding the direction of causation between Aß40 and Aß42 and total Tau (t-Tau) plasma biomarkers. METHODS: Plasma Aß40, Aß42, t-Tau, and neurofilament light chain (NFL) were measured in 1,035 men (mean = 67.0 years) using Simoa immunoassays. Genetically informative twin modeling tested the direction of causation between Aßs and t-Tau. RESULTS: No clear evidence that Aß40 or Aß42 directly causes changes in t-Tau was observed; the alternative causal hypotheses also fit the data well. In contrast, exploratory analyses suggested a causal impact of the Aß biomarkers on NFL. Separately, reciprocal causation was observed between t-Tau and NFL. DISCUSSION: Plasma Aß40 or Aß42 do not appear to have a direct causal impact on t-Tau. In contrast, Aß aggregation may causally impact NFL in cognitively unimpaired men in their late 60s.

A New Paradigm for High-dimensional Data: Distance-Based Semiparametric Feature Aggregation Framework via Between-Subject Attributes.

This article proposes a distance-based framework incentivized by the paradigm shift towards feature aggregation for high-dimensional data, which does not rely on the sparse-feature assumption or the permutation-based inference. Focusing on distance-based outcomes that preserve information without truncating any features, a class of semiparametric regression has been developed, which encapsulates multiple sources of high-dimensional variables using pairwise outcomes of between-subject attributes. Further, we propose a strategy to address the interlocking correlations among pairs via the U-statistics-based estimating equations (UGEE), which correspond to their unique efficient influence function (EIF). Hence, the resulting semiparametric estimators are robust to distributional misspecification while enjoying root-n consistency and asymptotic optimality to facilitate inference. In essence, the proposed approach not only circumvents information loss due to feature selection but also improves the model's interpretability and computational feasibility. Simulation studies and applications to the human microbiome and wearables data are provided, where the feature dimensions are tens of thousands.

Non-invasive ventral cervical magnetoneurography as a proxy of in vivo lipopolysaccharide-induced inflammation.

Maintenance of autonomic homeostasis is continuously calibrated by sensory fibers of the vagus nerve and sympathetic chain that convey compound action potentials (CAPs) to the central nervous system. Lipopolysaccharide (LPS) intravenous challenge reliably elicits a robust inflammatory response that can resemble systemic inflammation and acute endotoxemia. Here, we administered LPS intravenously in nine healthy subjects while recording ventral cervical magnetoneurography (vcMNG)-derived CAPs at the rostral Right Nodose Ganglion (RNG) and the caudal Right Carotid Artery (RCA) with optically pumped magnetometers (OPM). We observed vcMNG RNG and RCA neural firing rates that tracked changes in TNF-α levels in the systemic circulation. Further, endotype subgroups based on high and low IL-6 responders segregate RNG CAP frequency (at 30-120 min) and based on high and low IL-10 response discriminate RCA CAP frequency (at 0-30 min). These vcMNG tools may enhance understanding and management of the neuroimmune axis that can guide personalized treatment based on an individual's distinct endophenotype.

Rest-activity rhythm disruption and metabolic health in schizophrenia: a cross-sectional actigraphy study of community-dwelling people living with schizophrenia and nonpsychiatric comparison participants.

STUDY OBJECTIVES: People living with schizophrenia (PLWS) have increased physical comorbidities and premature mortality which may be linked to dysregulated rest-activity rhythms (RARs). This study aimed to compare RARs between PLWS and nonpsychiatric comparison participants (NCs) and to examine the relationships of RARs with age, sleep, metabolic, and physical health outcomes and, among PLWS, relationships of RARs with illness-related factors. METHODS: The study sample included 26 PLWS and 36 NCs, assessed with wrist-worn actigraphy to compute RAR variables and general sleep variables. Participants completed assessments for clinical symptoms, physical health, sleep quality, medication use, and assays for fasting glycosylated hemoglobin (hemoglobin A1c) levels. We examined group differences in RAR and sleep variables, relationships of RAR variables with metabolic and physical health measures, and, among PLWS, relationships between RAR variables and illness-related measures. RESULTS: PLWS had significantly shorter active periods, lower relative amplitude, and lower mean activity during their most active 10 hours compared to the NCs (Cohen's d = 0.79, 0.58, and 0.62, respectively). PLWS had poorer sleep quality, greater mean percent sleep, less wake after sleep onset, and higher total sleep time variability compared to NCs. PLWS had higher rates of antidepressant, anxiolytic, and antipsychotic medication use compared to NCs, which may have impacted sleep quality and objective sleep measures. Across both groups, more fragmented and variable RARs were associated with higher HbA1c levels (ηp2 = .10) and worse physical health (ηp2 = .21). Among PLWS, RARs were correlated with total sleep time (rs = .789, P < .01) and percent sleep (rs = .509, P < .05), but not with age, sleep quality, or other illness-related factors. CONCLUSIONS: RARs provide unique information about sleep and activity for PLWS and have the potential for targeted interventions to improve metabolic health and mortality. CITATION: Mahmood Z, Ramsey A, Kidambi N, et al. Rest-activity rhythm disruption and metabolic health in schizophrenia: a cross-sectional actigraphy study of community-dwelling people living with schizophrenia and nonpsychiatric comparison participants. J Clin Sleep Med. 2024;20(9):1505-1516.

The heritability of blood-based biomarkers related to risk of Alzheimer's disease in a population-based sample of early old-age men.

INTRODUCTION: Despite their increased application, the heritability of Alzheimer's disease (AD)-related blood-based biomarkers remains unexplored. METHODS: Plasma amyloid beta 40 (Aß40), Aß42, the Aß42/40 ratio, total tau (t-tau), and neurofilament light (NfL) data came from 1035 men 60 to 73 years of age (µ = 67.0, SD = 2.6). Twin models were used to calculate heritability and the genetic and environmental correlations between them. RESULTS: Additive genetics explained 44% to 52% of Aß42, Aß40, t-tau, and NfL. The Aß42/40 ratio was not heritable. Aß40 and Aß42 were genetically near identical (rg  = 0.94). Both Aß40 and Aß42 were genetically correlated with NfL (rg  = 0.35 to 0.38), but genetically unrelated to t-tau. DISCUSSION: Except for Aß42/40, plasma biomarkers are heritable. Aß40 and Aß42 share mostly the same genetic influences, whereas genetic influences on plasma t-tau and NfL are largely unique in early old-age men. The absence of genetic associations between the Aßs and t-tau is not consistent with the amyloid cascade hypothesis.

Executive functioning trajectories and their prospective association with inflammatory biomarkers in schizophrenia and non-psychiatric comparison participants.

BACKGROUND AND HYPOTHESIS: Cognitive change in people with schizophrenia (PwS) is challenging to assess, but important to understand. Previous studies with limited age ranges and follow-up were subject to practice effects. Controlling for practice effects in a well-established cohort, we examined executive functioning trajectories and their association with inflammatory biomarkers, hypothesizing that PwS will have worsening executive functioning over time compared to non-psychiatric comparison participants (NCs), predicted by higher baseline inflammation with a stronger relationship in PwS than NCs. STUDY DESIGN: Executive functioning was assessed in 350 participants (n = 186 PwS, 164 NCs) at 12-16-month intervals (0 to 7 follow-up visits). Inflammatory biomarkers at baseline included high sensitivity C-Reactive Protein (hs-CRP), Interferon-gamma, Tumor Necrosis Factor (TNF)-alpha, and Interleukin(IL)-6, -8, and - 10. Executive functioning trajectories across diagnostic groups were estimated using a linear mixed-effects model controlling for age, sex, race/ethnicity, and education level, with additional models to assess prediction by baseline inflammation. STUDY RESULTS: Over 4.4 years average follow-up, improvements in executive functioning were attenuated in PwS and older participants. Controlling for practice effects negated improvements, revealing declines among highly educated participants regardless of diagnosis. Higher baseline hs-CRP predicted worse executive functioning only among NCs, while TNF-alpha was predictive of change in all participants only after controlling for practice effects. Only the main effect of hs-CRP on executive function was significant after adjusting for multiple comparisons. None of the other inflammatory biomarkers predicted executive functioning or trajectories of performance among study participants. CONCLUSIONS: Systemic inflammation as reflected by baseline inflammatory biomarker levels did not predict longitudinal declines in executive functioning. Additional studies examining the temporal dynamics of inflammation and cognition in PwS will help further clarify their relationship and associated mechanisms.

Urinary Glyphosate, 2,4-D and DEET Biomarkers in Relation to Neurobehavioral Performance in Ecuadorian Adolescents in the ESPINA Cohort.

BACKGROUND: Herbicides are the most used class of pesticides worldwide, and insect repellents are widely used globally. Yet, there is a dearth of studies characterizing the associations between these chemical groups and human neurobehavior. Experimental studies suggest that glyphosate and 2,4-dichlorophenoxyacetic acid (2,4-D) herbicides can affect neurobehavior and the cholinergic and glutamatergic pathways in the brain. We aim to assess whether herbicides and insect repellents are associated with neurobehavioral performance in adolescents. METHODS: We assessed 519 participants (11-17 years of age) living in agricultural communities in Ecuador. We quantified urinary concentrations of glyphosate, 2,4-D, and two N,N-diethyl-meta-toluamide (DEET) insect repellent metabolites [3-(diethylcarbamoyl)benzoic acid (DCBA) and 3-(ethylcarbamoyl)benzoic acid (ECBA)] using isotope-dilution mass spectrometry. We assessed neurobehavioral performance using 9 subtests across 5 domains (attention/inhibitory control, memory/learning, language, visuospatial processing, and social perception). We characterized the associations using generalized estimating equations and multiple imputation for metabolites below detection limits. Models were adjusted for demographic and anthropometric characteristics, urinary creatinine, and sexual maturation. Mediation by salivary cortisol, dehydroepiandrosterone, 17ß-estradiol, and testosterone was assessed using structural equation modeling. RESULTS: The mean of each neurobehavioral domain score was between 7.0 and 8.7 [standard deviation (SD) range: 2.0-2.3]. Glyphosate was detected in 98.3% of participants, 2,4-D in 66.2%, DCBA in 63.3%, and ECBA in 33.4%. 2,4-D was negatively associated with all neurobehavioral domains, but statistically significant associations were observed with attention/inhibition [score difference per 50% higher metabolite concentration (ß)=-0.19 95% confidence interval (CI): -0.31, -0.07], language [ß=-0.12 (95% CI: -0.23, -0.01)], and memory/learning [ß=-0.11 (95% CI: -0.22, 0.01)]. Glyphosate had a statistically significant negative association only with social perception [ß=-0.08 (95% CI: -0.14, -0.01)]. DEET metabolites were not associated with neurobehavioral performance. Mediation by gender and adrenal hormones was not observed. CONCLUSION: This study describes worse neurobehavioral performance associated with herbicide exposures in adolescents, particularly with 2,4-D. Replication of these findings among other pediatric and adult populations is needed. https://doi.org/10.1289/EHP11383.

Exploring the Effect of Adding an Interactive Lecture to a Standardized Patient Curriculum on the Attitudes of Third-Year Medical Students About Patients With Obesity: A Quasi-Experimental Study.

OBJECTIVES: Anti-obesity bias is pervasive among medical professionals, students, and trainees. Stigmatization of patients leads to suboptimal care and clinical outcomes. Educational strategies in medical training are needed to reverse these attitudes. The aim of this study was to evaluate the effect of an innovative didactic intervention and a standardized patient (SP) exercise on attitudes towards patients with obesity among medical students. METHODS: In 2016, a quasi-experimental study design was used at a US medical school. The class was divided into 2 groups according to a pre-determined protocol based on their clinical schedule, one assessed after exposure to a SP group and the other after exposure to the SP and an interactive lecture (IL + SP group) with real patients. The Attitudes about Treating Patients with Obesity and The Perceived Causes of Obesity questionnaires measured changes in several domains. A generalized estimating equations model was used to estimate the effect of the interventions both within and between groups. RESULTS: Both groups showed improvements in negative and positive attitudes, although the reduction in scores for the negative attitude domain did not reach statistical significance in the IL + SP group (for the SP group, P = .01 and < .001, respectively; for the IL + SP group, P = .15 and .01, respectively). For perceived causes of obesity, there were no statistically significant changes for pre-post survey measures within each group, except for the physiologic causes domain in the SP group (P = .03). The addition of an IL to a SP curriculum did not result in any changes for any domain in between-group analyses. CONCLUSIONS: Although adding a novel intervention utilizing real patients to a SP curriculum failed to show an additional educational benefit, our study showed that it is possible to influence attitudes of medical students regarding patients with obesity.

Survey response over 15 years of follow-up in the Millennium Cohort Study.

BACKGROUND: Patterns of survey response and the characteristics associated with response over time in longitudinal studies are important to discern for the development of tailored retention efforts aimed at minimizing response bias. The Millennium Cohort Study, the largest and longest running cohort study of military personnel and veterans, is designed to examine the long-term health effects of military service and experiences and thus relies on continued participant survey responses over time. Here, we describe the response rates for follow-up survey data collected over 15 years and identify characteristics associated with follow-up survey response and mode of response (paper vs. web). METHOD: Patterns of follow-up survey response and response mode (web, paper, none) were examined among eligible participants (n=198,833), who were initially recruited in four panels from 2001 to 2013 in the Millennium Cohort Study, for a follow-up period of 3-15 years (2004-2016). Military and sociodemographic factors (i.e., enrollment panel, sex, birth year, race and ethnicity, educational attainment, marital status, service component, service branch, pay grade, military occupation, length of service, and time deployed), life experiences and health-related factors (i.e., military deployment/combat experience, life stressors, mental health, physical health, and unhealthy behaviors) were used to examine follow-up response and survey mode over time in multivariable generalized estimating equation models. RESULTS: Overall, an average response rate of 60% was observed across all follow-up waves. Factors associated with follow-up survey response over time included increased educational attainment, married status, female sex, older age, military deployment (regardless of combat experience), and higher number of life stressors, mental health issues, and physical health diagnoses. CONCLUSION: Despite the challenges associated with collecting multiple waves of follow-up survey data from members of the U.S. military during and after service, the Millennium Cohort Study has maintained a relatively robust response rate over time. The incorporation of tailored messages and outreach to those groups least likely to respond over time may improve retention and thereby increase the representativeness and generalizability of collected survey data.

On testing proportional odds assumptions for proportional odds models.

Proportional odds models are commonly used to model ordinal responses, but the proportional odds assumption may not hold in practice, leading to biased inference. Tests such as score, Wald and likelihood ratio (LR) have been proposed to evaluate the proportional odds assumption based on models without the assumption. Brant has proposed an independent binary model-based Wald-type test, and Wolfe and Gould have extended the idea to propose an LR-type test. This paper provides a brief review of the Brant and Wolfe-Gould tests for evaluating the proportional odds assumption and evaluates their performance through simulation studies and a real data example. Sample programs are provided in SAS, SPSS and Stata to facilitate the implementation of these tests using standard statistical software packages. This study highlights the importance of evaluating the proportional odds assumption when using proportional odds models for ordinal responses. The sample programs provided in this paper make it easy for researchers to apply these tests in their own analyses using standard statistical software packages.

Common antibiotics, azithromycin and amoxicillin, affect gut metagenomics within a household.

BACKGROUND: The microbiome of the human gut serves a role in a number of physiological processes, but can be altered through effects of age, diet, and disturbances such as antibiotics. Several studies have demonstrated that commonly used antibiotics can have sustained impacts on the diversity and the composition of the gut microbiome. The impact of the two most overused antibiotics, azithromycin, and amoxicillin, in the human microbiome has not been thoroughly described. In this study, we recruited a group of individuals and unrelated controls to decipher the effects of the commonly used antibiotics amoxicillin and azithromycin on their gut microbiomes. RESULTS: We characterized the gut microbiomes by metagenomic sequencing followed by characterization of the resulting microbial communities. We found that there were clear and sustained effects of the antibiotics on the gut microbial community with significant alterations in the representations of Bifidobacterium species in response to azithromycin (macrolide antibiotic). These results were supported by significant increases identified in putative antibiotic resistance genes associated with macrolide resistance. Importantly, we did not identify these trends in the unrelated control individuals. There were no significant changes observed in other members of the microbial community. CONCLUSIONS: As we continue to focus on the role that the gut microbiome plays and how disturbances induced by antibiotics might affect our overall health, elucidating members of the community most affected by their use is of critical importance to understanding the impacts of common antibiotics on those who take them. Clinical Trial Registration Number NCT05169255. This trial was retrospectively registered on 23-12-2021.

Fecal virome transplantation is sufficient to alter fecal microbiota and drive lean and obese body phenotypes in mice.

The gastrointestinal microbiome plays a significant role in modulating numerous host processes, including metabolism. Prior studies show that when mice receive fecal transplants from obese donors on high-fat diets (HFD) (even when recipient mice are fed normal diets after transplantation), they develop obese phenotypes, demonstrating the prominent role that gut microbiota play in determining lean and obese phenotypes. While much of the credit has been given to gut bacteria, the impact of gut viruses on these phenotypes is understudied. To address this shortcoming, we gavaged mice with viromes isolated from donors fed HFD or normal chow over a 4-week study. By characterizing the gut bacterial biota via 16S rRNA amplicon sequencing and measuring mouse weights over time, we demonstrate that transplanted viruses affect the gut bacterial community, as well as weight gain/loss. Notably, mice fed chow but gavaged with HFD-derived viromes gained more weight than their counterparts receiving chow-derived viromes. The converse was also true: mice fed HFD but gavaged with chow-derived viromes gained less weight than their counterparts receiving HFD-derived viromes. Results were replicated in two independent experiments and phenotypic changes were accompanied by significant and identifiable differences in the fecal bacterial biota. Due to methodological limitations, we were unable to identify the specific bacterial strains responsible for respective phenotypic changes. This study confirms that virome-mediated perturbations can alter the fecal microbiome in vivo and indicates that such perturbations are sufficient to drive lean and obese phenotypes in mice.

Misinterpreting cognitive change over multiple timepoints: When practice effects meet age-related decline.

OBJECTIVE: Practice effects (PE) on cognitive testing have been shown to delay detection of impairment and impede our ability to assess change. When decline over time is expected, as with older adults or progressive diseases, failure to adequately address PEs may lead to inaccurate conclusions because PEs artificially boost scores while pathology- or age-related decline reduces scores. Unlike most methods, a participant-replacement approach can separate pathology- or age-related decline from PEs; however, this approach has only been used across two timepoints. More than two timepoints make it possible to determine if PEs level out after the first follow-up, but it is analytically challenging because individuals may not be assessed at every timepoint. METHOD: We examined 1,190 older adults who were cognitively unimpaired (n = 809) or had mild cognitive impairment (MCI; n = 381). Participants completed six neuropsychological measures at three timepoints (baseline, 12-month, 24-month). We implemented a participant-replacement method using generalized estimating equations in comparisons of matched returnees and replacements to calculate PEs. RESULTS: Without accounting for PEs, cognitive function appeared to improve or stay the same. However, with the participant-replacement method, we observed significant PEs within both groups at all timepoints. PEs did not uniformly decrease across time; some-specifically on episodic memory measures-continued to increase beyond the first follow-up. CONCLUSION: A replacement method of PE adjustment revealed significant PEs across two follow-ups. As expected in these older adults, accounting for PEs revealed cognitive decline. This, in turn, means earlier detection of cognitive deficits, including progression to MCI, and more accurate characterization of longitudinal change. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Associations Between Ambient Air Pollution and Cognitive Abilities from Midlife to Early Old Age: Modification by APOE Genotype.

BACKGROUND: Fine particulate matter (PM2.5) and nitrogen dioxide (NO2) measures of ambient air pollution are associated with accelerated age-related cognitive impairment, and Alzheimer's disease and related dementias (ADRD). OBJECTIVE: We examined associations between air pollution, four cognitive factors, and the moderating role of apolipoprotein E (APOE) genotype in the understudied period of midlife. METHODS: Participants were ∼1,100 men in the Vietnam Era Twin Study of Aging. Baseline cognitive assessments were from 2003 to 2007. Measures included past (1993-1999) and recent (3 years prior to baseline assessment) PM2.5 and NO2 exposure, in-person assessment of episodic memory, executive function, verbal fluency, and processing speed, and APOE genotype. Average baseline age was 56 years with a 12-year follow-up. Analyses adjusted for health and lifestyle covariates. RESULTS: Performance in all cognitive domains declined from age 56 to 68. Higher PM2.5 exposures were associated with worse general verbal fluency. We found significant exposure-by-APOE genotype interactions for specific cognitive domains: PM2.5 with executive function and NO2 with episodic memory. Higher PM2.5 exposure was related to worse executive function in APOE ɛ4 carriers, but not in non-carriers. There were no associations with processing speed. CONCLUSION: These results indicate negative effects of ambient air pollution exposure on fluency alongside intriguing differential modifications of cognitive performance by APOE genotype. APOE ɛ4 carriers appeared more sensitive to environmental differences. The process by which air pollution and its interaction with genetic risk for ADRD affects risk for later life cognitive decline or progression to dementia may begin in midlife.

On modelling relative risks for longitudinal binomial responses: implications from two dueling paradigms.

Although logistic regression is the most popular for modelling regression relationships with binary responses, many find relative risk (RR), or risk ratio, easier to interpret and prefer to use this measure of risk in regression analysis. Indeed, since Zou published his modified Poisson regression approach for modelling RR for cross-sectional data, his paper has been cited over 7 000 times, demonstrating the popularity of this alternative measure of risk in regression analysis involving binary responses. As longitudinal studies have become increasingly popular in clinical trials and observational studies, it is imperative to extend Zou's approach for longitudinal data. The two most popular approaches for longitudinal data analysis are the generalised linear mixed-effects model (GLMM) and generalised estimating equations (GEE). However, the parametric GLMM cannot be used for the extension within the current context, because Zou's approach treats the binary response as a Poisson variable, which is at odds with the Bernoulli distribution for the binary response. On the other hand, as it imposes no mathematical model on data distributions, the semiparametric GEE is coherent with Zou's modified Poisson regression. In this paper, we develop a GEE-based longitudinal model for binary responses to provide inference about RR.

Fecal virome transplantation is sufficient to alter fecal microbiota and drive lean and obese body phenotypes in mice.

Background: The gastrointestinal microbiome plays a significant role in numerous host processes and has an especially large impact on modulating the host metabolism. Prior studies have shown that when mice receive fecal transplants from obese donors that were fed high-fat diets (HFD) (even when recipient mice are fed normal diets after transplantation), they develop obese phenotypes. These studies demonstrate the prominent role that the gut microbiota play in determining lean and obese phenotypes. While much of the credit has been given to gut bacteria, studies have not measured the impact of gut viruses on these phenotypes. To address this shortcoming, we gavaged mice with viromes isolated from donors fed HFD or normal chow. By characterizing the mice’s gut bacterial biota and weight-gain phenotypes over time, we demonstrate that viruses can shape the gut bacterial community and affect weight gain or loss. Results: We gavaged mice longitudinally over 4 weeks while measuring their body weights and collecting fecal samples for 16S rRNA amplicon sequencing. We evaluated mice that were fed normal chow or high-fat diets, and gavaged each group with either chow-derived fecal viromes, HFD-derived fecal viromes, or phosphate buffered saline controls. We found a significant effect of gavage type, where mice fed chow but gavaged with HFD-derived viromes gained significantly more weight than their counterparts receiving chow-derived viromes. The converse was also true: mice fed HFD but gavaged with chow-derived viromes gained significantly less weight than their counterparts receiving HFD-derived viromes. These results were replicated in two separate experiments and the phenotypic changes were accompanied by significant and identifiable differences in the fecal bacterial biota. Notably, there were differences in Lachnospirales and Clostridia in mice fed chow but gavaged with HFD-derived fecal viromes, and in Peptostreptococcales, Oscillospirales, and Lachnospirales in mice fed HFD but gavaged with chow-derived fecal viromes. Due to methodological limitations, we were unable to identify specific bacterial species or strains that were responsible for respective phenotypic changes. Conclusions: This study confirms that virome-mediated perturbations can alter the fecal microbiome in an in vivo model and indicates that such perturbations are sufficient to drive lean and obese phenotypes in mice.

Alcohol use and cognitive aging in middle-aged men: The Vietnam Era Twin Study of Aging.

OBJECTIVE: To determine associations of alcohol use with cognitive aging among middle-aged men. METHOD: 1,608 male twins (mean 57 years at baseline) participated in up to three visits over 12 years, from 2003-2007 to 2016-2019. Participants were classified into six groups based on current and past self-reported alcohol use: lifetime abstainers, former drinkers, very light (1-4 drinks in past 14 days), light (5-14 drinks), moderate (15-28 drinks), and at-risk drinkers (>28 drinks in past 14 days). Linear mixed-effects regressions modeled cognitive trajectories by alcohol group, with time-based models evaluating rate of decline as a function of baseline alcohol use, and age-based models evaluating age-related differences in performance by current alcohol use. Analyses used standardized cognitive domain factor scores and adjusted for sociodemographic and health-related factors. RESULTS: Performance decreased over time in all domains. Relative to very light drinkers, former drinkers showed worse verbal fluency performance, by -0.21 SD (95% CI -0.35, -0.07), and at-risk drinkers showed faster working memory decline, by 0.14 SD (95% CI 0.02, -0.20) per decade. There was no evidence of protective associations of light/moderate drinking on rate of decline. In age-based models, light drinkers displayed better memory performance at advanced ages than very light drinkers (+0.14 SD; 95% CI 0.02, 0.20 per 10-years older age); likely attributable to residual confounding or reverse association. CONCLUSIONS: Alcohol consumption showed minimal associations with cognitive aging among middle-aged men. Stronger associations of alcohol with cognitive aging may become apparent at older ages, when cognitive abilities decline more rapidly.