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Circadian rhythms are critical for human health and are highly conserved across species. Disruptions in these rhythms contribute to many diseases, including psychiatric disorders. Previous results suggest that circadian genes modulate behavior through specific cell types in the nucleus accumbens (NAc), particularly dopamine D1-expressing medium spiny neurons (MSNs). However, diurnal rhythms in transcript expression have not been investigated in NAc MSNs. In this study we identified and characterized rhythmic transcripts in D1- and D2-expressing neurons and compared rhythmicity results to homogenate as well as astrocyte samples taken from the NAc of male and female mice. We find that all cell types have transcripts with diurnal rhythms and that top rhythmic transcripts are largely core clock genes, which peak at approximately the same time of day in each cell type and sex. While clock-controlled rhythmic transcripts are enriched for protein regulation pathways across cell type, cell signaling and signal transduction related processes are most commonly enriched in MSNs. In contrast to core clock genes, these clock-controlled rhythmic transcripts tend to reach their peak in expression about 2-h later in females than males, suggesting diurnal rhythms in reward may be delayed in females. We also find sex differences in pathway enrichment for rhythmic transcripts peaking at different times of day. Protein folding and immune responses are enriched in transcripts that peak in the dark phase, while metabolic processes are primarily enriched in transcripts that peak in the light phase. Importantly, we also find that several classic markers used to categorize MSNs are rhythmic in the NAc. This is critical since the use of rhythmic markers could lead to over- or under-enrichment of targeted cell types depending on the time at which they are sampled. This study greatly expands our knowledge of how individual cell types contribute to rhythms in the NAc., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Alterations in multiple subregions of the human prefrontal cortex (PFC) have been heavily implicated in psychiatric diseases. Moreover, emerging evidence suggests that circadian rhythms in gene expression are present across the brain, including in the PFC, and that these rhythms are altered in disease. However, investigation into the potential circadian mechanisms underlying these diseases in animal models must contend with the fact that the human PFC is highly evolved and specialized relative to that of rodents. Here, we use RNA sequencing to lay the groundwork for translational studies of molecular rhythms through a sex-specific, cross species comparison of transcriptomic rhythms between the mouse medial PFC (mPFC) and two subregions of the human PFC, the anterior cingulate cortex (ACC) and the dorsolateral PFC (DLPFC). We find that while circadian rhythm signaling is conserved across species and subregions, there is a phase shift in the expression of core clock genes between the mouse mPFC and human PFC subregions that differs by sex. Furthermore, we find that the identity of rhythmic transcripts is largely unique between the mouse mPFC and human PFC subregions, with the most overlap (20%, 236 transcripts) between the mouse mPFC and the human ACC in females. Nevertheless, we find that basic biological processes are enriched for rhythmic transcripts across species, with key differences between regions and sexes. Together, this work highlights both the evolutionary conservation of transcriptomic rhythms and the advancement of the human PFC, underscoring the importance of considering cross-species differences when using animal models., Competing Interests: Competing interesting The authors have nothing to disclose.

Previous studies have shown that there are rhythms in gene expression in the mouse prefrontal cortex (PFC); however, the contribution of different cell types and potential variation by sex has not yet been determined. Of particular interest are excitatory pyramidal cells and inhibitory parvalbumin (PV) interneurons, as interactions between these cell types are essential for regulating the excitation/inhibition balance and controlling many of the cognitive functions regulated by the PFC. In this study, we identify cell-type specific rhythms in the translatome of PV and pyramidal cells in the mouse PFC and assess diurnal rhythms in PV cell electrophysiological properties. We find that while core molecular clock genes are conserved and synchronized between cell types, pyramidal cells have nearly twice as many rhythmic transcripts as PV cells (35% vs. 18%). Rhythmic transcripts in pyramidal cells also show a high degree of overlap between sexes, both in terms of which transcripts are rhythmic and in the biological processes associated with them. Conversely, in PV cells, rhythmic transcripts from males and females are largely distinct. Moreover, we find sex-specific effects of phase on action potential properties in PV cells that are eliminated by environmental circadian disruption. Together, this study demonstrates that rhythms in gene expression and electrophysiological properties in the mouse PFC vary by both cell type and sex. Moreover, the biological processes associated with these rhythmic transcripts may provide insight into the unique functions of rhythms in these cells, as well as their selective vulnerabilities to circadian disruption., Competing Interests: The authors declare no competing financial interests.

Context: Contributing to the evidence base, by disseminating findings through written products such as journal articles, is a core competency for public health practitioners. Disseminating practice-based evidence that supports improving cardiovascular health is necessary for filling literature gaps, generating health policies and laws, and translating evidence-based strategies into practice. However, a gap exists in the dissemination of practice-based evidence in public health. Public health practitioners face various dissemination barriers (eg, lack of time and resources, staff turnover) which, more recently, were compounded by the COVID-19 pandemic., Program: The Centers for Disease Control and Prevention's Division for Heart Disease and Stroke Prevention (DHDSP) partnered with the National Network of Public Health Institutes to implement a multimodal approach to build writing capacity among recipients funded by three DHDSP cooperative agreements. This project aimed to enhance public health practitioners' capacity to translate and disseminate their evaluation findings., Implementation: Internal evaluation technical assistance expertise and external subject matter experts helped to implement this project and to develop tailored multimodal capacity-building activities. These activities included online peer-to-peer discussion posts, virtual writing workshops, resource documents, one-to-one writing coaching sessions, an online toolkit, and a supplemental issue in a peer-reviewed journal., Evaluation: Findings from an informal process evaluation demonstrate positive results. Most participants were engaged and satisfied with the project's activities. Across eight workshops, participants reported increased knowledge (≥94%) and enhanced confidence in writing (≥98%). The majority of participants (83%) reported that disseminating evaluation findings improved program implementation. Notably, 30 abstracts were submitted for a journal supplement and 23 articles were submitted for consideration., Discussion: This multimodal approach serves as a promising model that enhances public health practitioners' capacity to disseminate evaluation findings during times of evolving health needs., Competing Interests: The authors declare no potential conflicts of interests with respect to the authorship and/or publication of this article. The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc.)

The human striatum can be subdivided into the caudate, putamen, and nucleus accumbens (NAc). In mice, this roughly corresponds to the dorsal medial striatum (DMS), dorsal lateral striatum (DLS), and ventral striatum (NAc). Each of these structures have some overlapping and distinct functions related to motor control, cognitive processing, motivation, and reward. Previously, we used a "time-of-death" approach to identify diurnal rhythms in RNA transcripts in these three human striatal subregions. Here, we identify molecular rhythms across similar striatal subregions collected from C57BL/6J mice across 6 times of day and compare results to the human striatum. Pathway analysis indicates a large degree of overlap between species in rhythmic transcripts involved in processes like cellular stress, energy metabolism, and translation. Notably, a striking finding in humans is that small nucleolar RNAs (snoRNAs) and long non-coding RNAs (lncRNAs) are among the most highly rhythmic transcripts in the NAc and this is not conserved in mice, suggesting the rhythmicity of RNA processing in this region could be uniquely human. Furthermore, the peak timing of overlapping rhythmic genes is altered between species, but not consistently in one direction. Taken together, these studies reveal conserved as well as distinct transcriptome rhythms across the human and mouse striatum and are an important step in understanding the normal function of diurnal rhythms in humans and model organisms in these regions and how disruption could lead to pathology., (© 2024. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.)

Background: The Patient Cloud ePRO app was adopted by the National Cancer Institute National Clinical Trials Network (NCTN) to facilitate capturing electronic patient-reported (ePRO) outcome data, but use has been low. The study objectives were to test whether a patient-targeted ePRO educational resource (ePRO-E) would increase ePRO intent (number of users) and improve data quality (high quality: ≥80% of the required surveys submitted) within an ongoing NCTN study., Methods: The ePRO-E intervention, a patient-targeted educational resource (written material and 6-minute animated YouTube video), was designed to address ePRO barriers. ePRO intent and data quality were compared between 2 groups (N = 69): a historical control group and a prospectively recruited intervention group exposed to ePRO-E. Covariates included technology attitudes, age, sex, education, socioeconomic status, and comorbidity., Results: Intervention group ePRO intent (78.8%) was statistically significantly higher than historical control group intent (47.1%) (P = .03). Patients choosing ePRO versus paper surveys had more positive and higher technology attitudes scores (P = .03). The odds of choosing ePRO were 4.7 times higher (95% Confidence Interval [CI] = 1.2 to 17.8) (P = .02) among intervention group patients and 5.2 times higher (95% CI = 1.3 to 21.6) (P = .02) among patients with high technology attitudes scores, after controlling for covariates. However, the 80% submission rate (percentage submitting ≥80% of required surveys) in the ePRO group (30.6%) was statistically significantly lower than in the paper group (57.9%) (P = .05)., Conclusions: ePRO-E exposure increased ePRO intent. High technology attitudes scores were associated with ePRO selection. Since the ePRO survey submission rate was low, additional strategies are needed to promote high-quality data submission., (© The Author(s) 2024. Published by Oxford University Press.)

Clinically normal females exhibit higher 18 F-flortaucipir (FTP)-PET signal than males across the cortex. However, these sex differences may be explained by neuroimaging idiosyncrasies such as off-target extracerebral tracer retention or partial volume effects (PVEs). 343 clinically normal participants (female = 58%; mean[SD]=73.8[8.5] years) and 55 patients with mild cognitive impairment (female = 38%; mean[SD] = 76.9[7.3] years) underwent cross-sectional FTP-PET. We parcellated extracerebral FreeSurfer areas based on proximity to cortical ROIs. Sex differences in cortical tau were then estimated after accounting for local extracerebral retention. We simulated PVE by convolving group-level standardized uptake value ratio means in each ROI with 6 mm Gaussian kernels and compared the sexes across ROIs post-smoothing. Widespread sex differences in extracerebral retention were observed. Although attenuating sex differences in cortical tau-PET signal, covarying for extracerebral retention did not impact the largest sex differences in tau-PET signal. Differences in PVE were observed in both female and male directions with no clear sex-specific bias. Our findings suggest that sex differences in FTP are not solely attributed to off-target extracerebral retention or PVE, consistent with the notion that sex differences in medial temporal and neocortical tau are biologically driven. Future work should investigate sex differences in regional cerebral blood flow kinetics and longitudinal tau-PET., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Associations of plasma total tau levels with future risk of AD have been described., Objective: To examine the extent to which plasma tau reflects underlying AD brain pathology in cognitively healthy individuals., Methods: We examined cross-sectional associations of plasma total tau with 11C-Pittsburgh Compound-B (PiB)-PET and 18F-Flortaucipir (FTP)-PET in middle-aged participants at the community-based Framingham Heart Study., Results: Our final sample included 425 participants (mean age 57.6± 9.9, 50% F). Plasma total tau levels were positively associated with amyloid-β deposition in the precuneus region (β±SE, 0.11±0.05; p = 0.025). A positive association between plasma total tau and tau PET in the rhinal cortex was suggested in participants with higher amyloid-PET burden and in APOEɛ4 carriers., Conclusions: Our study highlights that plasma total tau is a marker of amyloid deposition as early as in middle-age.

This review focuses on recent advances made towards understanding the neurobiology of bipolar disorder (BD), a chronic neuropsychiatric illness characterized by altered mood and energy states. The past few years have seen the completion of the largest genetic studies by far, which have emphasized the polygenic nature of BD as well as it's connection to other psychiatric illnesses. Furthermore, the use of inducible pluripotent stem cells has rapidly expanded. These studies support previous work that implicates dysregulation of neurodevelopment, mitochondria, and calcium homeostasis, while also allowing for investigation into the underlying mechanisms of individual responsivity to lithium. Sleep and circadian rhythms have also been heavily implicated in BD, from disruptions in activity patterns to molecular abnormalities., Competing Interests: Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Introduction: With the increasing use of the internet for health information, it is essential to prioritize resources that match the reading level of patients and parents. Limited health literacy is a notable issue in the United States, creating a financial burden and negatively affecting patient outcomes. This study aimed to assess the availability and readability of pediatric hospital web pages concerning two prevalent spine conditions in children, spondylolisthesis and spondylolysis, specifically examining whether the available resources meet the recommended sixth grade reading level., Methods: A total of 179 pediatric hospital web pages were assessed for their availability and readability of spondylolisthesis and spondylolysis patient information. The web pages' readability was assessed using five readability formulae. Descriptive statistics and Student t-tests were performed on the collected scores with significance set at P < 0.05., Results: Among the analyzed hospitals, 40.2% had no information on spondylolisthesis or spondylolysis, 20.1% mentioned treating these conditions, 7.8% had < 100 dedicated words, and only 31.8% had dedicated web pages with more than 100 words on these conditions. The average reading grade level for the evaluated web pages was 12.0, indicating a high school education level is required for comprehension. None of the web pages were written below the recommended sixth grade reading level., Discussion: The readability of the limited resources was markedly higher than the recommended reading level. In addition, this study emphasizes the need for enhanced accessibility and readability of online patient information from pediatric hospitals to improve parental comprehension and informed decision-making. Physicians should consider identifying online resources that they consider of high quality and acceptable readability to support better patient understanding and outcomes., (Copyright © 2023 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.)

Background: Preclinical studies highlight the importance of endogenous cannabinoids (endocannabinoids; eCBs) in neurodegeneration. Yet, prior observational studies focused on limited outcome measures and assessed only few eCB compounds while largely ignoring the complexity of the eCB system. We examined the associations of multiple circulating eCBs and eCB-like molecules with early markers of neurodegeneration and neuro-injury and tested for effect modification by sex., Methods: This exploratory cross-sectional study included a random sample of 237 dementia-free older participants from the Framingham Heart Study Offspring cohort who attended examination cycle 9 (2011-2014), were 65 years or older, and cognitively healthy. Forty-four eCB compounds were quantified in serum, via liquid chromatography high-resolution mass spectrometry. Linear regression models were used to examine the associations of eCB levels with brain MRI measures (i.e., total cerebral brain volume, gray matter volume, hippocampal volume, and white matter hyperintensities volume) and blood biomarkers of Alzheimer's disease and neuro-injury (i.e., total tau, neurofilament light, glial fibrillary acidic protein and Ubiquitin C-terminal hydrolase L1). All models were adjusted for potential confounders and effect modification by sex was examined., Results: Participants mean age was 73.3 ± 6.2 years, and 40% were men. After adjustment for potential confounders and correction for multiple comparisons, no statistically significant associations were observed between eCB levels and the study outcomes. However, we identified multiple sex-specific associations between eCB levels and the various study outcomes. For example, high linoleoyl ethanolamide (LEA) levels were related to decreased hippocampal volume among men and to increased hippocampal volume among women (β ± SE =  - 0.12 ± 0.06, p = 0.034 and β ± SE = 0.08 ± 0.04, p = 0.026, respectively)., Conclusions: Circulating eCBs may play a role in neuro-injury and may explain sex differences in susceptibility to accelerated brain aging. Particularly, our results highlight the possible involvement of eCBs from the N-acyl amino acids and fatty acid ethanolamide classes and suggest specific novel fatty acid compounds that may be implicated in brain aging. Furthermore, investigation of the eCBs contribution to neurodegenerative disease such as Alzheimer's disease in humans is warranted, especially with prospective study designs and among diverse populations, including premenopausal women., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Population-based autopsy studies provide valuable insights into the causes of dementia but are limited by sample size and restriction to specific populations. Harmonisation across studies increases statistical power and allows meaningful comparisons between studies. We aimed to harmonise neuropathology measures across studies and assess the prevalence, correlation, and co-occurrence of neuropathologies in the ageing population., Methods: We combined data from six community-based autopsy cohorts in the US and the UK in a coordinated cross-sectional analysis. Among all decedents aged 80 years or older, we assessed 12 neuropathologies known to be associated with dementia: arteriolosclerosis, atherosclerosis, macroinfarcts, microinfarcts, lacunes, cerebral amyloid angiopathy, Braak neurofibrillary tangle stage, Consortium to Establish a Registry for Alzheimer's disease (CERAD) diffuse plaque score, CERAD neuritic plaque score, hippocampal sclerosis, limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and Lewy body pathology. We divided measures into three groups describing level of confidence (low, moderate, and high) in harmonisation. We described the prevalence, correlations, and co-occurrence of neuropathologies., Findings: The cohorts included 4354 decedents aged 80 years or older with autopsy data. All cohorts included more women than men, with the exception of one study that only included men, and all cohorts included decedents at older ages (range of mean age at death across cohorts 88·0-91·6 years). Measures of Alzheimer's disease neuropathological change, Braak stage and CERAD scores, were in the high confidence category, whereas measures of vascular neuropathologies were in the low (arterioloscerosis, atherosclerosis, cerebral amyloid angiopathy, and lacunes) or moderate (macroinfarcts and microinfarcts) categories. Neuropathology prevalence and co-occurrence was high (2443 [91%] of 2695 participants had more than one of six key neuropathologies and 1106 [41%] of 2695 had three or more). Co-occurrence was strongly but not deterministically associated with dementia status. Vascular and Alzheimer's disease features clustered separately in correlation analyses, and LATE-NC had moderate associations with Alzheimer's disease measures (eg, Braak stage ρ=0·31 [95% CI 0·20-0·42])., Interpretation: Higher variability and more inconsistency in the measurement of vascular neuropathologies compared with the measurement of Alzheimer's disease neuropathological change suggests the development of new frameworks for the measurement of vascular neuropathologies might be helpful. Results highlight the complexity and multi-morbidity of the brain pathologies that underlie dementia in older adults and suggest that prevention efforts and treatments should be multifaceted., Funding: Gates Ventures., Competing Interests: Declaration of interests SS reports consulting fees from Biogen and Eisai. JS reports consulting fees from AVID, Alnylam Pharmaceuticals, and Cerveau Technologies. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Twelve-hour (12 h) ultradian rhythms are a well-known phenomenon in coastal marine organisms. While 12 h cycles are observed in human behavior and physiology, no study has measured 12 h rhythms in the human brain. Here, we identify 12 h rhythms in transcripts that either peak at sleep/wake transitions (approximately 9 AM/PM) or static times (approximately 3 PM/AM) in the dorsolateral prefrontal cortex, a region involved in cognition. Subjects with schizophrenia (SZ) lose 12 h rhythms in genes associated with the unfolded protein response and neuronal structural maintenance. Moreover, genes involved in mitochondrial function and protein translation, which normally peak at sleep/wake transitions, peak instead at static times in SZ, suggesting suboptimal timing of these essential processes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Scott et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Psychosis is a defining feature of schizophrenia and highly prevalent in bipolar disorder. Notably, individuals with these illnesses also have major disruptions in sleep and circadian rhythms, and disturbances of sleep and circadian rhythms can precipitate or exacerbate psychotic symptoms. Psychosis is associated with the striatum, though to our knowledge, no study to date has directly measured molecular rhythms and determined how they are altered in the striatum of subjects with psychosis., Methods: We performed RNA sequencing and both differential expression and rhythmicity analyses to investigate diurnal alterations in gene expression in human postmortem striatal subregions (nucleus accumbens, caudate, and putamen) in subjects with psychosis (n = 36) relative to unaffected comparison subjects (n = 36)., Results: Across regions, we found differential expression of immune-related transcripts and a substantial loss of rhythmicity in core circadian clock genes in subjects with psychosis. In the nucleus accumbens, mitochondrial-related transcripts had decreased expression in subjects with psychosis, but only in those who died at night. Additionally, we found a loss of rhythmicity in small nucleolar RNAs and a gain of rhythmicity in glutamatergic signaling in the nucleus accumbens of subjects with psychosis. Between-region comparisons indicated that rhythmicity in the caudate and putamen was far more similar in subjects with psychosis than in matched comparison subjects., Conclusions: Together, these findings reveal differential and rhythmic gene expression differences across the striatum that may contribute to striatal dysfunction and psychosis in psychotic disorders., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Summary: Circadian oscillations of gene expression regulate daily physiological processes, and their disruption is linked to many diseases. Circadian rhythms can be disrupted in a variety of ways, including differential phase, amplitude and rhythm fitness. Although many differential circadian biomarker detection methods have been proposed, a workflow for systematic detection of multifaceted differential circadian characteristics with accurate false positive control is not currently available. We propose a comprehensive and interactive pipeline to capture the multifaceted characteristics of differentially rhythmic biomarkers. Analysis outputs are accompanied by informative visualization and interactive exploration. The workflow is demonstrated in multiple case studies and is extensible to general omics applications., Availability and Implementation: R package, Shiny app and source code are available in GitHub (https://github.com/DiffCircaPipeline) and Zenodo (https://doi.org/10.5281/zenodo.7507989)., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author(s) 2023. Published by Oxford University Press.)

Autosomal-dominant, Dutch-type cerebral amyloid angiopathy (D-CAA) offers a unique opportunity to develop biomarkers for pre-symptomatic cerebral amyloid angiopathy (CAA). We hypothesized that neuroimaging measures of white matter injury would be present and progressive in D-CAA prior to hemorrhagic lesions or symptomatic hemorrhage. In a longitudinal cohort of D-CAA carriers and non-carriers, we observed divergence of white matter injury measures between D-CAA carriers and non-carriers prior to the appearance of cerebral microbleeds and >14 years before the average age of first symptomatic hemorrhage. These results indicate that white matter disruption measures may be valuable cross-sectional and longitudinal biomarkers of D-CAA progression. ANN NEUROL 2022;92:358-363., (© 2022 American Neurological Association.)

Introduction: Physical activity (PA) promotes resilience with respect to cognitive decline, although the underlying mechanisms are not well understood. We examined the associations between objectively measured PA and resting-state functional connectivity magnetic resonance imaging (rs-fcMRI) across seven anatomically distributed neural networks., Methods: rs-fcMRI, amyloid beta (Aβ) positron emission tomography (PET), PA (steps/day × 1 week), and longitudinal cognitive (Preclinical Alzheimer's Cognitive Composite) data from 167 cognitively unimpaired adults (ages 63 to 90) were used. We used linear and linear mixed-effects regression models to examine the associations between baseline PA and baseline network connectivity and between PA, network connectivity, and longitudinal cognitive performance., Results: Higher PA was associated selectively with greater connectivity in three networks previously associated with cognitive decline (default, salience, left control). This association with network connectivity accounted for a modest portion of PA's effects on Aβ-related cognitive decline., Discussion: Although other mechanisms are likely present, PA may promote resilience with respect to Aß-related cognitive decline, partly by increasing connectivity in a subset of cognitive networks., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

We propose a Dual-stream Pyramid Registration Network (referred as Dual-PRNet) for unsupervised 3D brain image registration. Unlike recent CNN-based registration approaches, such as VoxelMorph, which computes a registration field from a pair of 3D volumes using a single-stream network, we design a two-stream architecture able to estimate multi-level registration fields sequentially from a pair of feature pyramids. Our main contributions are: (i) we design a two-stream 3D encoder-decoder network that computes two convolutional feature pyramids separately from two input volumes; (ii) we propose sequential pyramid registration where a sequence of pyramid registration (PR) modules is designed to predict multi-level registration fields directly from the decoding feature pyramids. The registration fields are refined gradually in a coarse-to-fine manner via sequential warping, which equips the model with a strong capability for handling large deformations; (iii) the PR modules can be further enhanced by computing local 3D correlations between the feature pyramids, resulting in the improved Dual-PRNet ++ able to aggregate rich detailed anatomical structure of the brain; (iv) our Dual-PRNet ++ can be integrated into a 3D segmentation framework for joint registration and segmentation, by precisely warping voxel-level annotations. Our methods are evaluated on two standard benchmarks for brain MRI registration, where Dual-PRNet ++ outperforms the state-of-the-art approaches by a large margin, i.e., improving recent VoxelMorph from 0.511 to 0.748 (Dice score) on the Mindboggle101 dataset. In addition, we further demonstrate that our methods can greatly facilitate the segmentation task in a joint learning framework, by leveraging limited annotations., Competing Interests: Declaration of Competing Interest The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript., (Copyright © 2022. Published by Elsevier B.V.)

Animal and human imaging research reported that the presence of cortical Alzheimer's Disease's (AD) neuropathology, beta-amyloid and neurofibrillary tau, is associated with altered neuronal activity and circuitry failure, together facilitating clinical progression. The locus coeruleus (LC), one of the initial subcortical regions harboring pretangle hyperphosphorylated tau, has widespread connections to the cortex modulating cognition. Here we investigate whether LC's in-vivo neuronal activity and functional connectivity (FC) are associated with cognitive decline in conjunction with beta-amyloid. We combined functional MRI of a novel versus repeated face-name paradigm, beta-amyloid-PET and longitudinal cognitive data of 128 cognitively unimpaired older individuals. We show that LC activity and LC-FC with amygdala and hippocampus was higher during novelty. We also demonstrated that lower novelty-related LC activity and LC-FC with hippocampus and parahippocampus were associated with steeper beta-amyloid-related cognitive decline. Our results demonstrate the potential of LC's functional properties as a gauge to identify individuals at-risk for AD-related cognitive decline., (© 2022. The Author(s).)

Noninvasive biomarkers of early neuronal injury may help identify cognitively normal individuals at risk of developing Alzheimer's disease (AD). A recent diffusion-weighted imaging (DWI) method allows assessing cortical microstructure via cortical mean diffusivity (cMD), suggested to be more sensitive than macrostructural neurodegeneration. Here, we aimed to investigate the association of cMD with amyloid-β and tau pathology in older adults, and whether cMD predicts longitudinal cognitive decline, neurodegeneration and clinical progression. The study sample comprised n = 196 cognitively normal older adults (mean[SD] 72.5 [9.4] years; 114 women [58.2%]) from the Harvard Aging Brain Study. At baseline, all participants underwent structural MRI, DWI, 11 C-Pittsburgh compound-B-PET, 18 F-flortaucipir-PET imaging, and cognitive assessments. Longitudinal measures of Preclinical Alzheimer Cognitive Composite-5 were available for n = 186 individuals over 3.72 (1.96)-year follow-up. Prospective clinical follow-up was available for n = 163 individuals over 3.2 (1.7) years. Surface-based image analysis assessed vertex-wise relationships between cMD, global amyloid-β, and entorhinal and inferior-temporal tau. Multivariable regression, mixed effects models and Cox proportional hazards regression assessed longitudinal cognition, brain structural changes and clinical progression. Tau, but not amyloid-β, was positively associated with cMD in AD-vulnerable regions. Correcting for baseline demographics and cognition, increased cMD predicted steeper cognitive decline, which remained significant after correcting for amyloid-β, thickness, and entorhinal tau; there was a synergistic interaction between cMD and both amyloid-β and tau on cognitive slope. Regional cMD predicted hippocampal atrophy rate, independently from amyloid-β, tau, and thickness. Elevated cMD predicted progression to mild cognitive impairment. Cortical microstructure is a noninvasive biomarker that independently predicts subsequent cognitive decline, neurodegeneration and clinical progression, suggesting utility in clinical trials., (© 2021. The Author(s).)

Abnormalities in protein localization, function, and posttranslational modifications are targets of schizophrenia (SCZ) research. As a major contributor to the synthesis, folding, trafficking, and modification of proteins, the endoplasmic reticulum (ER) is well-positioned to sense cellular stress. The unfolded protein response (UPR) is an evolutionarily conserved adaptive reaction to environmental and pathological perturbation in ER function. The UPR is a highly orchestrated and complex cellular response, which is mediated through the ER chaperone protein, BiP, three known ER transmembrane stress sensors, protein kinase RNA-like ER kinase (PERK), activating transcription factor-6 (ATF6), inositol requiring enzyme 1α (IRE1α), and their downstream effectors. In this study, we measured protein expression and phosphorylation states of UPR sensor pathway proteins in the dorsolateral prefrontal cortex (DLPFC) of 22 matched pairs of elderly SCZ and comparison subjects. We observed increased protein expression of BiP, decreased PERK, and decreased phosphorylation of IRE1α. We also observed decreased p-JNK2 and increased sXBP1, downstream targets of the IRE1α arm of the UPR. The disconnect between decreased p-IRE1α and increased sXBP1 protein expression led us to measure sXbp1 mRNA. We observed increased expression of the ratio of sXbp1/uXbp1 transcripts, suggesting that splicing of Xbp1 mRNA by IRE1α is increased and drives upregulation of sXBP1 protein expression. These findings suggest an abnormal pattern of UPR activity in SCZ, with specific dysregulation of the IRE1α arm. Dysfunction of this system may lead to abnormal responses to cellular stressors and contribute to protein processing abnormalities previously observed in SCZ.

The human striatum can be subdivided into the caudate, putamen, and nucleus accumbens (NAc). Each of these structures have some overlapping and some distinct functions related to motor control, cognitive processing, motivation, and reward. Previously, we used a "time-of-death" approach to identify diurnal rhythms in RNA transcripts in human cortical regions. Here, we identify molecular rhythms across the three striatal subregions collected from postmortem human brain tissue in subjects without psychiatric or neurological disorders. Core circadian clock genes are rhythmic across all three regions and show strong phase concordance across regions. However, the putamen contains a much larger number of significantly rhythmic transcripts than the other two regions. Moreover, there are many differences in pathways that are rhythmic across regions. Strikingly, the top rhythmic transcripts in NAc (but not the other regions) are predominantly small nucleolar RNAs and long noncoding RNAs, suggesting that a completely different mechanism might be used for the regulation of diurnal rhythms in translation and/or RNA processing in the NAc versus the other regions. Further, although the NAc and putamen are generally in phase with regard to timing of expression rhythms, the NAc and caudate, and caudate and putamen, have several clusters of discordant rhythmic transcripts, suggesting a temporal wave of specific cellular processes across the striatum. Taken together, these studies reveal distinct transcriptome rhythms across the human striatum and are an important step in helping to understand the normal function of diurnal rhythms in these regions and how disruption could lead to pathology., Competing Interests: The authors declare no competing interest.

Altered behavioral rhythms are a fundamental diagnostic feature of mood disorders. Patients report worse subjective sleep and objective measures confirm this, implicating a role for circadian rhythm disruptions in mood disorder pathophysiology. Molecular clock gene mutations are associated with increased risk of mood disorder diagnosis and/or severity of symptoms, and mouse models of clock gene mutations have abnormal mood-related behaviors. The mechanism by which circadian rhythms contribute to mood disorders remains unknown, however, circadian rhythms regulate and are regulated by various biological systems that are abnormal in mood disorders and this interaction is theorized to be a key component of mood disorder pathophysiology. A growing body of evidence has begun defining how the interaction of circadian and neurotransmitter systems influences mood and behavior, including the role of current antidepressants and mood stabilizers. Additionally, the hypothalamus-pituitary-adrenal (HPA) axis interacts with both circadian and monoaminergic systems and may facilitate the contribution of environmental stressors to mood disorder pathophysiology. The central role of circadian rhythms in mood disorders has led to the development of chronotherapeutics, which are treatments designed specifically to target circadian rhythm regulators, such as sleep, light, and melatonin, to produce an antidepressant response., (© 2021. Springer Nature Switzerland AG.)

This systematic review provides a high-quality synthesis of the empirical evidence regarding chemotherapy-induced peripheral neuropathy (CIPN) characteristics and patterns described in studies of children who received neurotoxic chemotherapy to treat cancer. PubMed, CINAHL, PsycINFO, and Embase were searched for articles published 2009 - 2019, yielding 861. Forty-two papers met the eligibility criteria, including 31 that described characteristics and patterns of vincristine-induced CIPN. Fifty-seven percent of articles were of low to moderate quality; measurement flaws were the most common limitations. The reported CIPN incidence varies widely (2.8%-100%) depending on risk factors (e.g., race) and the measurement approach. Incidence rates of sensory, motor, autonomic CIPN, and pain were 12-28%, 50-72%, 0.8-83% and 5.7-44%, respectively. The evidence suggests that sensory and motor neuropathy, pain, and functional deficits are common and can persist into adulthood. Caucasian race is a risk factor and, contrary to prior thinking, cumulative chemotherapy dosage alone does not predict CIPN severity. The influence of other risk factors is less clear, and studies to date have not explored potential interactions among race, genetics, age, sex, drug metabolism, and nutritional status, among other factors., (Copyright © 2021. Published by Elsevier Ltd.)

Objective: The goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories., Methods: Participants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined 18 F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*Aβ-PET positive / negative (+ / -) and sex*apolipoprotein ε4 (APOEε4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline., Results: Women showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p < 0.007). β-amyloid (Aβ)-moderated sex differences in tau signal were localized to medial and inferio-lateral temporal regions (p < 0.007); Aβ + women exhibited greater FTP-signal than other groups. APOEε4-moderated sex differences in FTP-signal were only found in the lateral occipital lobe. Women with higher FTP-signals in composite ROI exhibited faster cognitive decline than men (p = 0.04)., Interpretation: Tau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and Aβ were predominantly localized in the temporal lobe, however, sex differences in extra-temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020;88:921-932., (© 2020 American Neurological Association.)

Neurofibrillary tau tangles are a hallmark pathology of Alzheimer's disease (AD) and are more closely associated with AD-related cortical atrophy and symptom severity than amyloid-beta (Aβ). However, studies regarding the effect of tau on longitudinal cortical thinning, particularly in healthy aging and preclinical AD, have been limited in number due to the relatively recent introduction of in vivo PET tracers for imaging tau pathology. Here, we investigate [18F]-flortaucipir (FTP, a marker of paired helical filament tau) PET as a predictor of atrophy in healthy aging and preclinical AD. We examine longitudinal structural MRI brain imaging data, retrospectively and prospectively relative to FTP imaging, using piecewise linear mixed-effect models with time centered at each participant's FTP-PET session. Participants include 111 individuals from the Harvard Aging Brain Study who underwent at least three MRI sessions over an average of 4.46 years and one FTP-PET at the approximate midpoint of the observation period. Our primary analyses focus on inferior temporal (IT) FTP standardized uptake value ratios and longitudinal FreeSurfer defined cortical regions of interest. Relationships were also explored using other regional FTP measures (entorhinal, composite, and local), within high and low Pittsburgh compound-B (PiB) PET groups, and with longitudinal subcortical volume. Strong associations between IT FTP and cortical thinning were found, most notably in temporal, midline, and prefrontal regions, with stronger effects generally observed in the prospective as compared to retrospective time frame. Significant differences between prospective and retrospective rates of thinning were found in the inferior and middle temporal gyri, cingulate areas, as well as pars orbitalis such that higher IT FTP was associated with greater prospective rates of thinning. Within the high PiB group, significant differences between prospective and retrospective rates of thinning were similarly observed. However, no consistent pattern of tau-related change in cortical thickness within the low PiB group was discerned. These results provide support for the hypothesis that tau pathology is a driver of future atrophy as well as provide additional evidence for tau-PET as an effective AD biomarker for interventional clinical trials., Competing Interests: Declaration of competing interest Dr. Schultz has received grants from the National Institute on Aging and served on paid advisory boards for Janssen Pharmaceuticals (2013) and Biogen (2016). Dr. Hanseeuw is funded by the Belgian National Fund for Scientific Research (FNRS) #SPD28094292. Dr. Jacobs reported funding from the European Union's Horizon 2020 Research and Innovation Programme under the Marie Sklodowska-Curie Grant agreement (IF-2015-GF, 706714). Dr. Johnson has served as a paid consultant for Bayer, GE Healthcare, Janssen, Siemens Medical Solutions, Genzyme, Novartis, Biogen, Roche, AZTherapy, GEHC, Lundbeck, Genentech, Lilly/Avid, AC Immune, and Abbvie. Dr. Sperling has received grants from National Institute on Aging, Alzheimer's Association, Eli Lilly and Co., and Janssen Pharmaceuticals. She has consulted for AC Immune, Eisai, Janssen, Roche, and Takeda. There are no other conflicts of interest to be reported., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

The ability to synthesize multi-modality data is highly desirable for many computer-aided medical applications, e.g. clinical diagnosis and neuroscience research, since rich imaging cohorts offer diverse and complementary information unraveling human tissues. However, collecting acquisitions can be limited by adversary factors such as patient discomfort, expensive cost and scanner unavailability. In this paper, we propose a multi-task coherent modality transferable GAN (MCMT-GAN) to address this issue for brain MRI synthesis in an unsupervised manner. Through combining the bidirectional adversarial loss, cycle-consistency loss, domain adapted loss and manifold regularization in a volumetric space, MCMT-GAN is robust for multi-modality brain image synthesis with visually high fidelity. In addition, we complement discriminators collaboratively working with segmentors which ensure the usefulness of our results to segmentation task. Experiments evaluated on various cross-modality synthesis show that our method produces visually impressive results with substitutability for clinical post-processing and also exceeds the state-of-the-art methods.

Background: By participating in priority-setting activities in research, patients and members of the public help ensure that important questions are incorporated into future research agendas. Surveys, focus groups, and online crowdsourcing are increasingly used to obtain input, yet little is known about how they compare for prioritizing research topics. To address this gap, the Study of Methods for Assessing Research Topic Elicitation and pRioritization (SMARTER) evaluated participant satisfaction with the engagement experience across three prioritization activities., Methods: Respondents from Back pain Outcomes using Longitudinal Data (BOLD), a registry of patients 65 years and older with low back pain (LBP), were randomly assigned to one of three interactive prioritization activities: online crowd-voting, in-person focus groups using nominal group technique, and two rounds of a mailed survey (Delphi). To assess quality of experience, participants completed a brief survey; a subset were subsequently interviewed. We used descriptive statistics to characterize participants, and we analyzed responses to the evaluation using a mixed-methods approach, tabulating responses to Likert-scale questions and using thematic analysis of interviews to explore participant understanding of the activity and perceptions of experience., Results: The crowd-voting activity had 38 participants, focus groups 39, and the Delphi survey 74. Women outnumbered men in the focus groups and Delphi survey; otherwise, demographics among groups were similar, with participants being predominantly white, non-Hispanic, and college educated. Activities generated similar lists of research priorities, including causes of LBP, improving physician-patient communication, and self-care strategies. The evaluation survey was completed by 123 participants. Of these, 31 across all activities were interviewed about motivations to participate, understanding of activity goals, logistics, clarity of instructions, and the role of patients in research. Focus group participants rated their experience highest, in both the evaluation and interviews., Conclusion: Common methods for research prioritization yielded similar priorities but differing perceptions of experience. Such comparative studies are rare but important in understanding methods to involve patients and the public in research. Preferences for different methods may vary across stakeholder groups; this warrants future study., Trial Registration: NICHSR, HSRP20152274. Registered 19 February 2015., Competing Interests: Competing interestsART, SEM, ALA, DRN, SOL, ZB, TCE, DLP, and DCL have no conflicts to disclose. JGJ receives royalties from Springer Publishing as a book co-editor; travel reimbursement for the Faculty Board of Review from the GE-Association of University Radiologists Radiology Research Academic Fellowship (GERRAF); and royalties from Wolters Kluwer/UpToDate: as a chapter author., (© The Author(s) 2020.)

Protein homeostasis is an emerging component of schizophrenia (SZ) pathophysiology. Proteomic alterations in SZ are well-documented and changes in transcript expression are frequently not associated with changes in protein expression in SZ brain. The underlying mechanism driving these changes remains unknown, though altered expression of ubiquitin proteasome system (UPS) components have implicated protein degradation. Previous studies have been limited to protein and transcript expression, however, and do not directly test the function of the proteasome. To address this gap in knowledge, we measured enzymatic activity associated with the proteasome (chymotrypsin-, trypsin-, and caspase-like) in the superior temporal gyrus (STG) of 25 SZ and 25 comparison subjects using flourogenic substrates. As localization regulates which cellular processes the proteasome contributes to, we measured proteasome activity and subunit expression in fractions enriched for nucleus, cytosolic, and membrane compartments. SZ subjects had decreased trypsin-like activity in total homogenate. This finding was specific to the nucleus-enriched fraction and was not associated with changes in proteasome subunit expression. Interestingly, both chymotrypsin-like activity and protein expression of 19S RP subunits, which facilitate ubiquitin-dependent degradation, were decreased in the cytosol-enriched fraction of SZ subjects. Intracellular compartment-specific proteasome dysfunction implicates dysregulation of protein expression both through altered ubiquitin-dependent degradation of cytosolic proteins and regulation of protein synthesis due to degradation of transcription factors and transcription machinery in the nucleus. Together, these findings implicate proteasome dysfunction in SZ, which likely has a broad impact on the proteomic landscape and cellular function in the pathophysiology of this illness.

MR images (MRIs) accurate segmentation of brain lesions is important for improving cancer diagnosis, surgical planning, and prediction of outcome. However, manual and accurate segmentation of brain lesions from 3D MRIs is highly expensive, time-consuming, and prone to user biases. We present an efficient yet conceptually simple brain segmentation network (referred as Brain SegNet), which is a 3D residual framework for automatic voxel-wise segmentation of brain lesion. Our model is able to directly predict dense voxel segmentation of brain tumor or ischemic stroke regions in 3D brain MRIs. The proposed 3D segmentation network can run at about 0.5s per MRIs - about 50 times faster than previous approaches Med Image Anal 43: 98-111, 2018, Med Image Anal 36:61-78, 2017. Our model is evaluated on the BRATS 2015 benchmark for brain tumor segmentation, where it obtains state-of-the-art results, by surpassing recently published results reported in Med Image Anal 43: 98-111, 2018, Med Image Anal 36:61-78, 2017. We further applied the proposed Brain SegNet for ischemic stroke lesion outcome prediction, with impressive results achieved on the Ischemic Stroke Lesion Segmentation (ISLES) 2017 database.

Objective: Unawareness, or anosognosia, of memory deficits is a challenging manifestation of Alzheimer's disease (AD) that adversely affects a patient's safety and decision-making. However, there is a lack of consensus regarding the presence, as well as the evolution, of altered awareness of memory function across the preclinical and prodromal stages of AD. Here, we aimed to characterize change in awareness of memory abilities and its relationship to beta-amyloid (Aβ) burden in a large cohort (N = 1,070) of individuals across the disease spectrum., Methods: Memory awareness was longitudinally assessed (average number of visits = 4.3) and operationalized using the discrepancy between mean participant and partner report on the Everyday Cognition scale (memory domain). Aβ deposition was measured at baseline using [18F]florbetapir positron emission tomographic imaging., Results: Aβ predicted longitudinal changes in memory awareness, such that awareness decreased faster in participants with increased Aβ burden. Aβ and clinical group interacted to predict change in memory awareness, demonstrating the strongest effect in dementia participants, but could also be found in the cognitively normal (CN) participants. In a subset of CN participants who progressed to mild cognitive impairment (MCI), heightened memory awareness was observed up to 1.6 years before MCI diagnosis, with memory awareness declining until the time of progression to MCI (-0.08 discrepant-points/yr). In a subset of MCI participants who progressed to dementia, awareness was low initially and continued to decline (-0.23 discrepant-points/yr), reaching anosognosia 3.2 years before dementia onset., Interpretation: Aβ burden is associated with a progressive decrease in self-awareness of memory deficits, reaching anosognosia approximately 3 years before dementia diagnosis. ANN NEUROL 2020;87:267-280., (© 2019 American Neurological Association.)

Proteinopathies are key elements in the pathogenesis of age-related neurodegenerative diseases, particularly Alzheimer's disease (AD), with the nature and location of the proteinopathy characterizing much of the disease phenotype. Susceptibility of brain regions to pathology may partly be determined by intrinsic network structure and connectivity. It remains unknown, however, how these networks inform the disease cascade in the context of AD biomarkers, such as beta-amyloid (Aβ), in clinically-normal older adults.The default-mode network (DMN), a prominent intrinsic network, is heavily implicated in AD due to its spatial overlap with AD atrophy patterns and tau deposition. We investigated the influence of baseline Aβ positron emission tomography (PET) signal and intrinsic DMN connectivity on DMN-specific cortical thinning in 120 clinically-normal older adults from the Harvard Aging Brain Study (73 ± 6 years, 58% Female, CDR = 0). Participants underwent 11 C Pittsburgh Compound-B (PiB) PET, 18 F flortaucipir (FTP) PET, and resting-state MRI scans at baselineand longitudinal MRI (3.6 ± 0.96 scans; 5.04 ± 0.8 years). Linear mixed models tested relationships between baseline PiB and DMN connectivity on cortical thinning in a composite of DMN regions. Lower DMN connectivity was associated with faster cortical thinning, but only in those with elevated baseline PiB-PET signal. This relationship was network specific, in that the frontoparietal control network did not account for the observed association. Additionally, the relationship was independent of inferior temporal lobe FTP-PET signal. Our findings provide evidence that compromised DMN connectivity, in the context of preclinical AD, foreshadows neurodegeneration in DMN regions., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Resting-state functional connectivity MRI (rs-fcMRI) is a non-invasive imaging technique that has come into increasing use to understand disrupted neural network function in neuropsychiatric disease. However, despite extensive study over the past 15 years, the development of rs-fcMRI as a biomarker has been impeded by a lack of reliable longitudinal rs-fcMRI measures. Here we focus on longitudinal change along the Alzheimer's disease (AD) trajectory and demonstrate the utility of Template Based Rotation (TBR) in detecting differential longitudinal rs-fcMRI change between higher and lower amyloid burden individuals with mildly impaired cognition. Specifically, we examine a small (N = 24), but densely sampled (~5 observations over ~3 years), cohort of symptomatic individuals with serial rs-fcMRI imaging and PiB-PET imaging for β-amyloid pathology. We observed longitudinal decline of the Default Mode and Salience network axis (DMN/SAL) among impaired individuals with high amyloid burden. No other networks showed differential change in high vs. low amyloid individuals over time. The standardized effect size of AD related DMN/SAL change is comparable to the standardized effect size of amyloid-related change on the mini-mental state exam (MMSE) and hippocampal volume (HV). Last, we show that the AD-related change in DMN/SAL connectivity is almost completely independent of change on MMSE or HV, suggesting that rs-fcMRI is sensitive to an aspect of AD progression that is not captured by these other measures. Together these analyses demonstrate that longitudinal rs-fcMRI using TBR can capture disease-relevant network disruption in a clinical population., (Copyright © 2019. Published by Elsevier Inc.)

Objective: The aim of this study was to conduct a cross-sectional assessment of the adoption of Total Worker Health (TWH) policies and practices by business size and evaluate extent and alignment of their safety and health., Methods: We conducted an analysis of 382 businesses that completed the Health Links Assessment. We measured organizational adoption of TWH across six benchmarks: organizational supports, workplace assessments, health policies and programs, safety, engagement, and evaluation., Results: Benchmark scores were significantly associated with business size. Larger businesses were more likely to score higher across each benchmark., Conclusion: Small businesses are implementing TWH in a variety of ways and the level of implementation differs by business size. Practical interventions as well as dissemination and implementation research should take business size into account to ensure that TWH is both effective and sustainable in meeting the needs of employees.

Importance: Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals., Objective: To examine sex differences in the cross-sectional association between Aβ and regional tau deposition as measured with positron emission tomography (PET)., Design, Setting and Participants: This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and Aβ PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women [61%]) who underwent carbon 11-labeled Pittsburgh Compound B and flortaucipir F18 PET and 103 clinically normal individuals from the Alzheimer's Disease Neuroimaging Initiative (age range, 63-94 years; 55 women [51%]) who underwent florbetapir and flortaucipir F 18 PET., Main Outcomes and Measures: A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global Aβ as well as sex and APOE ε4 on these regions after controlling for age were also examined., Results: The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE ε4 carriers [31%]; 89 individuals [30%] with high Aβ). There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: β [male] = -0.11 [0.05]; 95% CI, -0.21 to -0.02; P = .02), which was associated with individuals with higher Aβ burden. A sex by APOE ε4 interaction was not associated with regional tau (meta-analytic estimate: β [male, APOE ε4+] = -0.15 [0.09]; 95% CI, -0.32 to 0.01; P = .07)., Conclusions and Relevance: Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.

Context: Sexually transmitted infections (STI) and mental health and substance use (MHSU) disorders all occur at elevated rates in sexual and gender minorities. These overlapping epidemics, or syndemics, are exacerbated by challenges these same populations face in accessing sexual/gender minority-affirming services. Many publicly funded STI clinics are a low barrier and provide sexual minority-competent care. These sites therefore may be uniquely situated to address clients' MHSU-related needs., Objective: We characterize the need and desire for MHSU services among STI clinic clients., Design, Setting, Participants: We conducted a waiting room survey at 6 STI clinics in Metro Vancouver, Canada., Main Outcome Measures: We calculated the proportion of clients with self-reported unmet MHSU needs in the previous 12 months and, among these clients, barriers to accessing MHSU services and desire for MHSU services within the STI clinic. We also examined social disparities in barriers to accessing MHSU services., Results: Among 1115 respondents-65% of whom were sexual minorities-39% reported a recent need for MHSU-related care, most frequently in relation to anxiety (29%), depression (26%), substance use (10%), or suicide ideation (7%). Seventy-two percent of this group had not yet talked to a provider about their concern. Common barriers included shame (26%) and inability to afford the service (24%). Eighty-three percent of clients with unmet MHSU needs indicated that they were comfortable discussing MHSU concerns with an STI clinic provider, and 94% expressed desire to receive MHSU assessments, referrals, or counseling in the STI clinic. Sexual and gender minorities and those attending a suburban clinic were more likely to report barriers to accessing MHSU services., Conclusions: More than a quarter of STI clinic clients report unmet MHSU health care needs; moreover, these clients report high levels of comfort with and desire to discuss MHSU concerns with STI clinic providers. Sexually transmitted infections clinics are thus opportune sites for syndemic service integration.

Abnormalities of posttranslational protein modifications (PTMs) have recently been implicated in the pathophysiology of schizophrenia. Glycosylphosphatidylinositols (GPIs) are a class of complex glycolipids, which anchor surface proteins and glycoproteins to the cell membrane. GPI attachment to proteins represents one of the most common PTMs and GPI-associated proteins (GPI-APs) facilitate many cell surface processes, including synapse development and maintenance. Mutations in the GPI processing pathway are associated with intellectual disability, emphasizing the potential role of GPI-APs in cognition and schizophrenia-associated cognitive dysfunction. As initial endoplasmic reticulum (ER)-associated protein processing is essential for GPI-AP function, we measured protein expression of molecules involved in attachment (GPAA1), modification (PGAP1), and ER export (Tmp21) of GPI-APs, in homogenates and in an ER enriched fraction derived from dorsolateral prefrontal cortex (DLPFC) of 15 matched pairs of schizophrenia and comparison subjects. In total homogenate we found a significant decrease in transmembrane protein 21 (Tmp21) and in the ER-enriched fraction we found reduced expression of post-GPI attachment protein (PGAP1). PGAP1 modifies GPI-anchors through inositol deacylation, allowing it to be recognized by Tmp21. Tmp21 is a component of the p24 complex that recognizes GPI-anchored proteins, senses the status of the GPI-anchor, and regulates incorporation into COPII vesicles for export to the Golgi apparatus. Together, these proteins are the molecular mechanisms underlying GPI-AP quality control and ER export. To investigate the potential consequences of a deficit in export and/or quality control, we measured cell membrane-associated expression of known GPI-APs that have been previously implicated in schizophrenia, including GPC1, NCAM, MDGA2, and EPHA1, using Triton X-114 phase separation. Additionally, we tested the sensitivity of those candidate proteins to phosphatidylinositol-specific phospholipase C (PI-PLC), an enzyme that cleaves GPI from GPI-APs. While we did not observe a difference in the amount of these GPI-APs in Triton X-114 phase separated membrane fractions, we found decreased NCAM and GPC1 within the PI-PLC sensitive fraction. These findings suggest dysregulation of ER-associated GPI-AP protein processing, with impacts on post-translational modifications of proteins previously implicated in schizophrenia such as NCAM and GPC1. These findings provide evidence for a deficit in ER protein processing pathways in this illness.

Education scholars grappling with policy issues related to community and identity issues may pay attention to the work of emotion. Rationalist, psychological frameworks that bound many educational researchers' policy analyses are limited in scope: the policy process is seen as a linear cause-and-effect process. A feminist geographic attention to this research offers a more complex understanding of the experiences of policy. Using children's displacement by gentrification as an example, this commentary will show how a feminist geographic understanding of place attachment offers a more complete understanding of the effects of gentrification. Specifically, using the concept of the 'intimate city' (Datta 2016), I show how the global process of gentrification is entangled with the intimate embodiment of emotions. And in order to effectively study education policy, we must be attuned to how children embody their emotions.

This paper explores the importance of considering transportation mode when calculating commute time for a child's school choice options. While proponents of school choice argue that students can attend any school that will provide them the best education, several have argued that commute time is as important for families as a school's characteristics. However, research to date models commute time using either distance as a proxy or minutes driving. In Philadelphia, a context where most people use public transportation to work and school, the authors argue that commute time to school must be calculated using this mode of transit. Using geospatial network analyses, the authors create choice sets for each neighborhood public high school. They first calculate the commute time between each zoned public high school and each public high school choice in the city by driving and by using public transportation. These two sets of commute times are then evaluated for the differences. The authors then calculate choice sets based on the average commute time in the city based on both modes of transportation. Finally, they compare the choice sets for each service area for spatial equity of public school quality. Findings indicate that the commute times between driving and public transportation are statistically different. Furthermore, public school choice sets within Philadelphia are spatially equitable, although the overall school quality needs improvement. The paper concludes with policy implications and recommendations for future research.

Abnormalities in posttranslational protein modifications (PTMs) that regulate protein targeting, trafficking, synthesis, and function have been implicated in the pathophysiology of schizophrenia. The endoplasmic reticulum (ER) contains specialized machinery that facilitate protein synthesis, ER entry and exit, quality control, and post-translational processing, steps required for protein maturation. Dysregulation of these systems could represent potential mechanisms for abnormalities of neurotransmitter associated proteins in schizophrenia. We hypothesized that expression of ER processing pathways is dysregulated in schizophrenia. We characterized protein and complex expression of essential components from protein folding, ER quality control (ERQC), and ER associated degradation (ERAD) processes in the dorsolateral prefrontal cortex of 12 matched pairs of elderly schizophrenia and comparison subjects. We found increased expression of proteins associated with recognizing and modifying misfolded proteins, including UDP-glucose/glycoprotein glucosyltransferase 2 (UGGT2), ER degradation enhancing alpha-mannosidase like protein 2 (EDEM2), and synoviolin (SYVN1)/HRD1. As SYVN1/HRD1 is a component of the ubiquitin ligase HRD1-SEL1L complex that facilitates ERAD, we immunoprecipitated SEL1L and measured expression of other proteins in this complex. In schizophrenia, SYVN1/HRD1 and OS-9, ERAD promoters, have increased association with SEL1L, while XTP3-B, which can prevent ERAD of substrates, has decreased association. Abnormal expression of proteins associated with ERQC and ERAD suggests dysregulation in ER localized protein processing pathways in schizophrenia. Interestingly, the deficits we found are not in the protein processing machinery itself, but in proteins that recognize and target incompletely or misfolded proteins. These changes may reflect potential mechanisms of abnormal neurotransmitter associated protein expression previously observed in schizophrenia., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Involving patients as partners in research is a defining characteristic of patient-centered outcomes research (PCOR). While patients' experiential knowledge of a health condition or treatment may yield research priorities not reflected by researchers and policy makers, the methods for identifying and effectively collaborating with patients are still evolving. Patient registries and crowdsourcing may offer ease of access and convenience to both researchers and patients. Surveys and focus groups, including online modalities, have been described for prioritizing research topics. However, little is known about how these different methods compare in producing consistent priorities and similar perceptions of engagement quality among participants., Objective: The aims of this study are (1) to compare how different engagement methods used to elicit patient priorities for research perform as measured by rankings for priorities generated and participant satisfaction; and (2) to determine characteristics of individuals choosing to participate in research prioritization activities., Methods: Participants in the Back pain Outcomes using Longitudinal Data (BOLD) patient registry, established to evaluate the natural history of back pain among individuals 65 years and older, and participants on the Amazon Mechanical Turk (MTurk) crowdsourcing platform, to provide input on priorities for research via a questionnaire, are invited. For BOLD participants, we subsequently randomize interested respondents to 1 of 3 interactive prioritization activities to further develop priorities: a Delphi panel, an online crowd voting activity, or an in-person facilitated prioritization activity using nominal group technique (NGT). Participants involved in each activity complete a survey to evaluate the quality of the experience and a subset of these participants discuss their experience further in an interview. Descriptive statistics are used to characterize the rankings produced by each method and compare the top 5 rated topics resulting from each prioritization activity. We use rank-ordered logistic regression models to identify associations of the ranked priority topics with baseline patient characteristics. We analyze responses to the evaluation using a mixed-methods approach wherein we tabulate responses to Likert-scale questions and use content analysis to enumerate themes emerging from interviews for the 3 activities., Results: In Phase I, we invite approximately 3000 BOLD participants and 500 Amazon MTurk workers to complete a research topic prioritization survey. Based on these results, we include additional topics into a subsequent prioritization survey. In Phase II, we invite BOLD participants to join 1 of 3 activities: 90 participants for Delphi panel, 100 participants for crowd voting, and 60 participants for focus groups. Of the Phase II participants, 30 will be interviewed to evaluate the activities., Conclusions: This study informs decisions about how to conduct outreach to patient registry participants for providing input on research priorities, how individuals 65 years and older wish to participate in engagement activities, and how different research prioritization methods compare in terms of rankings generated and participant satisfaction., (©Danielle C Lavallee, Bryan Comstock, Mary R Scott, Andrew L Avins, David R Nerenz, Todd C Edwards, Donald L Patrick, Sarah O Lawrence, Zoya Bauer, Anjali R Truitt, Jeffrey G Jarvik. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 07.09.2017.)

Macromolecules derived from 1,3-dienes, such as polyisoprene (or natural rubber), are of considerable importance in polymer science. Given the parallels between P=C and C=C bonds, the prospect of polymerizing P-containing 1,3-dienes, such as 1-phosphaisoprene, is intriguing due to the unique chemical functionality imparted by the heavier element combined with their structural relationship to natural rubber. Herein, we report the synthesis, characterization and coordination chemistry of the first polymers derived from Mes*P=CR-CH=CH 2 (Mes*=2,4,6-t-Bu 3 C 6 H 2 ; R=H, Me). In the case of 1-phosphaisoprene (R=Me), the monomer is isolable and its anionic polymerization affords a polymer that retains P=C bonds in its microstructure. The chemical functionality of these novel materials is demonstrated by forming the macromolecular gold(I) complex where the P=C bond is retained for further chemical elaboration., (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: The rate of feeding advancement following surgery for hypertrophic pyloric stenosis (HPS) affects length of stay. We hypothesized that: 1) a relaxed feeding regimen following pyloromyotomy would allow infants to achieve feeding goals more quickly without affecting postoperative emesis, and 2) preoperative metabolic derangements would impair the ability to advance feedings following pyloromyotomy., Methods: A prospective, randomized trial compared two postoperative feeding methods. The primary outcome was length of time to tolerate two consecutive goal feeds (GFs). Infants were randomized into the Incremental-arm (N=74), in which infants were gradually advanced on enteral formula, or the Relaxed-arm (N=69), in which infants were allowed to consume up to GF immediately. Preoperative variables, time to GF, preoperative laboratory values, and postoperative emesis were recorded. A p-value less than 0.05 was significant., Results: Patient demographics, pyloric ultrasound measurements, and episodes of postoperative emesis were similar between groups. Infants in the Relaxed-arm reached GF more quickly than those in the Incremental-arm and had a shorter length of stay (p<0.001). Infants with preoperative serum chloride less than 100mmol/L reached GF more slowly than those with normal labs (p<0.03)., Conclusion: Following surgery for HPS, surgeons can safely utilize a relaxed, nonstructured feeding regimen, which may allow infants to reach feeding goals more quickly without untoward vomiting., Level of Evidence: Level 1-therapeutic., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The ubiquitin proteasome system (UPS) is a major regulator of protein processing, trafficking, and degradation. While protein ubiquitination is utilized for many cellular processes, one major function of this system is to target proteins to the proteasome for degradation. In schizophrenia, studies have found UPS transcript abnormalities in both blood and brain, and we have previously reported decreased protein expression of ubiquitin-associated proteins in brain. To test whether the proteasome is similarly dysregulated, we measured the protein expression of proteasome catalytic subunits as well as essential subunits from proteasome regulatory complexes in 14 pair-matched schizophrenia and comparison subjects in superior temporal cortex. We found decreased expression of Rpt1, Rpt3, and Rpt6, subunits of the 19S regulatory particle essential for ubiquitin-dependent degradation by the proteasome. Additionally, the α subunit of the 11S αβ regulatory particle, which enhances proteasomal degradation of small peptides and unfolded proteins, was also decreased. Haloperidol-treated rats did not have altered expression of these subunits, suggesting the changes we observed in schizophrenia are likely not due to chronic antipsychotic treatment. Interestingly, expression of the catalytic subunits of both the standard and immunoproteasome were unchanged, suggesting the abnormalities we observed may be specific to the complexed state of the proteasome. Aging has significant effects on the proteasome, and several subunits (20S β2, Rpn10, Rpn13, 11Sβ, and 11Sγ) were significantly correlated with subject age. These data provide further evidence of dysfunction of the ubiquitin-proteasome system in schizophrenia, and suggest that altered proteasome activity may be associated with the pathophysiology of this illness.

Background: The authors describe the preclinical pharmacological properties of GAL-021, a novel peripheral chemoreceptor modulator., Methods: The ventilatory effects of GAL-021 were characterized using tracheal pneumotachometry (n = 4 to 6), plethysmography (n = 5 to 6), arterial blood gas analyses (n = 6 to 11), and nasal capnography (n = 3 to 4) in naive animals and those subjected to morphine-induced respiratory depression. Morphine analgesia in rats was evaluated by tail-flick test (n = 6). Carotid body involvement in GAL-021 ventilatory effects was assessed by comparing responses in intact and carotid sinus nerve-transected rats. Hemodynamic effects of GAL-021 were evaluated in urethane-anesthetized rats (n = 7). The pharmacological profile of GAL-021 in vitro was investigated using radioligand binding, enzyme inhibition, and cellular electrophysiology assays., Results: GAL-021 given intravenously stimulated ventilation and/or attenuated opiate-induced respiratory depression in rats, mice, and nonhuman primates, without decreasing morphine analgesia in rats. GAL-021 did not alter mean arterial pressure but produced a modest increase in heart rate. Ventilatory stimulation in rats was attenuated by carotid sinus nerve transection. GAL-021 inhibited KCa1.1 in GH3 cells, and the evoked ventilatory stimulation was attenuated in Slo1 mice lacking the pore-forming α-subunit of the KCa1.1 channel., Conclusions: GAL-021 behaved as a breathing control modulator in rodents and nonhuman primates and diminished opioid-induced respiratory depression without compromising opioid analgesia. It acted predominantly at the carotid body, in part by inhibiting KCa1.1 channels. Its preclinical profile qualified the compound to enter clinical trials to assess effects on breathing control disorders such as drug (opioid)-induced respiratory depression and sleep apnea.

Atypical models of experimental autoimmune encephalomyelitis (EAE) are advantageous in that the heterogeneity of clinical signs appears more reflective of those in multiple sclerosis (MS). Conversely, models of classical EAE feature stereotypic progression of an ascending flaccid paralysis that is not a characteristic of MS. The study of atypical EAE however has been limited due to the relative lack of suitable models that feature reliable disease incidence and severity, excepting mice deficient in gamma-interferon signaling pathways. In this study, atypical EAE was induced in Lewis rats, and a related approach was effective for induction of an unusual neurologic syndrome in a cynomolgus macaque. Lewis rats were immunized with the rat immunoglobulin variable (IgV)-related extracellular domain of myelin oligodendrocyte glycoprotein (IgV-MOG) in complete Freund's adjuvant (CFA) followed by one or more injections of rat IgV-MOG in incomplete Freund's adjuvant (IFA). The resulting disease was marked by torticollis, unilateral rigid paralysis, forelimb weakness, and high titers of anti-MOG antibody against conformational epitopes of MOG, as well as other signs of atypical EAE. A similar strategy elicited a distinct atypical form of EAE in a cynomolgus macaque. By day 36 in the monkey, titers of IgG against conformational epitopes of extracellular MOG were evident, and on day 201, the macaque had an abrupt onset of an unusual form of EAE that included a pronounced arousal-dependent, transient myotonia. The disease persisted for 6-7 weeks and was marked by a gradual, consistent improvement and an eventual full recovery without recurrence. These data indicate that one or more boosters of IgV-MOG in IFA represent a key variable for induction of atypical or unusual forms of EAE in rat and Macaca species. These studies also reveal a close correlation between humoral immunity against conformational epitopes of MOG, extended confluent demyelinating plaques in spinal cord and brainstem, and atypical disease induction.

Social behaviors in vertebrates are modulated by catecholamine (CA; dopamine, norepinephrine, epinephrine) release within the social behavior neural network. Few studies have examined activity across CA populations in relation to social behaviors. The involvement of CAs in social behavior regulation is especially underexplored in reptiles, relative to other amniotes. In this study, we mapped CA populations throughout the brain (excluding retina and olfactory bulb) of the male brown anole lizard, Anolis sagrei, via immunofluorescent visualization of the rate-limiting enzyme for CA synthesis, tyrosine hydroxylase (TH). Colocalization of TH with the immediate early gene product Fos, an indirect marker of neural activity, also enabled us to relate activity in TH-immunoreactive (TH-ir) neurons to appetitive and consummatory sexual and aggressive behaviors. We detected most major TH-ir cell populations that are present in other amniotes (within the hypothalamus, midbrain, and hindbrain), although the A15 population was entirely absent. We also detected a few novel or rare cell clusters within the amygdala, medial septum, and inferior raphe. Many CA populations, especially dopaminergic groups, showed increased TH-Fos colocalization in association with appetitive and consummatory sexual behavior expression, while a small number of regions showed increased colocalization in relation to solely consummatory aggression (biting of an opponent). In conclusion, we here map CA populations throughout the brown anole brain and demonstrate evidence for catecholaminergic involvement in appetitive and consummatory sexual behaviors and consummatory aggressive behaviors in this species., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Current husbandry and care guidelines for laboratory animals recommend social housing for nonhuman primates and all other social species. However, not all individuals of a social species are compatible, which can lead to psychosocial stress on certain members. Because stress affects immune responses, we undertook the present study to determine whether psychosocial stress associated with changes in the group housing of nonhuman primates affected allergic responses in a nonhuman primate model of allergic asthma. Historic records from 35 cynomolgus macaques (Macaca fascicularis) sensitive to house dust mites (HDM) and enrolled in asthma studies from 2007 to 2011 were reviewed for variations in response to aerosolized HDM that could not be explained by clinical or experimental interventions. We then compared these variations with husbandry and clinical records to determine whether the unexplained variations in responses were associated with events known to induce psychosocial stress in this species, including restructuring of social groups, temporary isolation of group members, and changes in cage or room configurations. Adult macaques in stable social groups exhibited little variation in responses to aerosolized antigen. Changes in group membership (conspecifics), cage configurations, and temporary isolation of a group member were associated with decreased responses to HDM. This attenuation lasted 2 to 3 mo on average, although some macaques showed prolonged responses. No evidence for a stress-induced increase in allergic responses was noted. These results demonstrate that acute stress in HDM-sensitive cynomolgus macaques diminishes the physiologic response to inhaled allergen.

Development of cancer survivor resources has been hampered by lack of knowledge regarding survivors' needs. The main study aim was to pilot test a Web-based cancer survivor needs assessment survey. The second aim was to pilot three sampling approaches. This cross-sectional study was conducted at the Norris Cotton Cancer Center and nine community-based clinics serving urban and rural populations. Population-based and convenience sampling approaches were used to recruit 547 participants over 4 months. Participants completed a Web-based cancer survivor needs assessment survey. Respondents were mainly white (98%), married (71%) women (80%) with a college education (96%). Although most (66%) (n = 362) had been diagnosed with breast cancer, other cancer diagnoses were represented. Participants reported fatigue (47%), forgetfulness (39%), joint pain (34%), anxiety (31%), trouble sleeping (28%), peripheral neuropathy (27%), inflexibility (23%), and weight gain (23%). Survivors with nonbreast solid tumor malignancies reported more problems than those with breast or hematologic malignancies (P range = .037 to <.0001). Most survivors requested assistance for losing weight (74.2%), decreasing fatigue (50%), and improving flexibility (69.3%), sleep (68.5%), and memory (60.2%). Results supported that cancer survivors struggle with many enduring problems. Web-based technology will facilitate future exploration of unmet needs.

Background: Biomarkers facilitate early detection of disease and measurement of therapeutic efficacy, both at clinical and experimental levels. Recent advances in analytics and disease models allow comprehensive screening for biomarkers in complex diseases, such as asthma, that was previously not feasible., Objective: Using murine and nonhuman primate (NHP) models of asthma, identify biomarkers associated with early and chronic stages of asthma and responses to steroid treatment., Methods: The total protein content from thymic stromal lymphopoietin transgenic (TSLP Tg) mouse BAL fluid was ascertained by shotgun proteomics analysis. A subset of these potential markers was further analyzed in BAL fluid, BAL cell mRNA, and lung tissue mRNA during the stages of asthma and following corticosteroid treatment. Validation was conducted in murine and NHP models of allergic asthma., Results: Over 40 proteins were increased in the BAL fluid of TSLP Tg mice that were also detected by qRT-PCR in lung tissue and BAL cells, as well as in OVA-sensitive mice and house dust mite-sensitive NHP. Previously undescribed as asthma biomarkers, KLK1, Reg3γ, ITLN2, and LTF were modulated in asthmatic mice, and Clca3, Chi3l4 (YM2), and Ear11 were the first lung biomarkers to increase during disease and the last biomarkers to decline in response to therapy. In contrast, GP-39, LCN2, sICAM-1, YM1, Epx, Mmp12, and Klk1 were good indicators of early therapeutic intervention. In NHP, AMCase, sICAM-1, CLCA1, and GP-39 were reduced upon treatment with corticosteroids., Conclusions and Clinical Relevance: These results significantly advance our understanding of the biomarkers present in various tissue compartments in animal models of asthma, including those induced early during asthma and modulated with therapeutic intervention, and show that BAL cells (or their surrogate, induced sputum cells) are a viable choice for biomarker examination.