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Objective: The quality of alcohol-related prevention and treatment in US primary care is poor. The purpose of this study was to describe the extent to which Electronic Health Records (EHRs) used by 167 primary care practices across 7 states currently include the necessary prompts, clinical support, and performance reporting essential for improving alcohol-related prevention and treatment in primary care., Materials and Methods: Experts from five regional quality improvement programs identified basic EHR features needed to support evidence-based alcohol-related prevention (ie, screening and brief intervention) and treatment of alcohol use disorders (AUD). Data were collected regarding whether EHRs included these features., Results: EHRs from 21 vendors were used by the primary care practices. For prevention, 62% of the 167 practices' EHRs included a validated screening questionnaire, 46% automatically scored the screening instrument, 62% could report the percent screened, and 37% could report the percent screening positive. Only 7% could report the percent offered brief intervention. For alcohol treatment, 49% of practices could report the percent diagnosed with AUD, 58% and 91% allowed documentation of referral and treatment with AUD medication, respectively. Only 3% could report the percent of patients diagnosed with AUD who received treatment., Discussion: Most EHRs observed across 167 primary care practices across 7 US states lacked basic functionality necessary to support evidence-based alcohol-related prevention and AUD treatment. Only 3% and 7% of EHRs, respectively, included the ability to report widely recommended quality measures needed to improve the quality of recommended alcohol-related prevention and treatment in primary care., Conclusion: Improving EHR functionality is likely necessary before alcohol-related primary care can be improved., Competing Interests: The authors have no competing interests to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Background: Valid, single-item cannabis screens for the frequency of past-year use (SIS-C) can identify patients at risk for cannabis use disorder (CUD); however, the prevalence of CUD for patients who report varying frequencies of use in the clinical setting remains unexplored., Objective: Compare clinical responses about the frequency of past-year cannabis use to typical use and CUD severity reported on a confidential survey., Participants: Among adult patients in an integrated health system who completed the SIS-C as part of routine care (3/28/2019-9/12/2019; n = 108,950), 5000 were selected for a confidential survey using stratified random sampling. Among 1688 respondents (34% response rate), 1589 who reported past-year cannabis use on the SIS-C were included., Main Measures: We compared patients with varying frequency of cannabis use on the SIS-C (< monthly, monthly, weekly, daily) to survey responses on the Composite International Diagnostic Interview Substance Abuse Module for CUD (any and moderate-severe CUD) and cannabis exposure measures (typical use per-week, per-day). Adjusted multinomial (categorical) and logistic regression (binary), weighted for population estimates, estimated the prevalence of outcomes across frequencies., Key Results: Patients were predominantly middle-aged (mean = 43.3 years [SD = 16.9]), male (51.8%), white (78.2%), non-Hispanic (94.0%), and commercially insured (68.9%). The prevalence of any and moderate-severe CUD increased with greater frequency of past-year cannabis use reported on the SIS-C (p-values < 0.001) and ranged from 12.7% (6.3-19.2%) and 0.9% (0.0-2.7%) for < monthly to 44.6% (41.4-47.7%) and 20.3% (17.8-22.9%) for daily use, respectively. Greater frequency of use on the SIS-C in the clinical setting corresponded with greater per-week and per-day use on the confidential survey., Conclusions: Among patients who reported past-year cannabis use as part of routine screening, the prevalence of CUD and other cannabis exposure measures increased with greater frequency of cannabis use, underscoring the utility of brief cannabis screens for identifying patients at risk for CUD., (© 2024. The Author(s), under exclusive licence to Society of General Internal Medicine.)

Background: The prevalence of cannabis use disorder (CUD) is increasing in the US and primary care providers need tools to identify patients with moderate-severe CUD to facilitate treatment. A single-item screen for cannabis (SIS-C) has outstanding discriminative validity for CUD. However, because the prevalence of moderate-severe CUD is typically low, the probability that an average patient who screens positive for daily cannabis has moderate-severe cannabis use disorder is low, making follow-up assessment important., Methods: This study reports the discriminative validity of a DSM-5 Substance Use Symptom Checklist ("Checklist") for moderate-severe CUD among 498 primary care patients who reported daily cannabis use on the SIS-C. We evaluated the performance of the Checklist (score 0-11) completed during routine care, compared to ≥4 DSM-5 CUD symptoms (moderate-severe CUD) on the Composite International Diagnostic Interview Substance Abuse Module from a confidential survey (reference standard). We estimated areas under receiver operating curve (AUROC), sensitivities, specificities, and post-test probabilities., Results: Of 498 eligible patients, 17 % met diagnostic criteria for moderate-severe CUD. The Checklist's AUROC for moderate-severe CUD was 0.77 (95 % CI: 0.71-0.83), and Checklist scores of 1-2 balanced sensitivity and specificity. Among patients from a population with average prevalence of CUD before screening (~6 % prevalence) and daily use on the SIS-C, a Checklist score of 3 indicated a post-test probability of 82.1 %., Conclusion: Overall performance of the Checklist was good and the high specificity made it useful for identifying patients likely to have moderate-severe CUD among those at average risk., Competing Interests: none, (© 2024 Published by Elsevier B.V.)

Evidence from genetic and epidemiological studies point to lipid metabolism defects in both the brain and periphery being at the core of Alzheimer's disease (AD) pathogenesis. Previously, we reported that central inhibition of the rate-limiting enzyme in monounsaturated fatty acid synthesis, stearoyl-CoA desaturase (SCD), improves brain structure and function in the 3xTg mouse model of AD (3xTg-AD). Here, we tested whether these beneficial central effects involve recovery of peripheral metabolic defects, such as fat accumulation and glucose and insulin handling. As early as 3 months of age, 3xTg-AD mice exhibited peripheral phenotypes including increased body weight and visceral and subcutaneous white adipose tissue as well as diabetic-like peripheral gluco-regulatory abnormalities. We found that intracerebral infusion of an SCD inhibitor that normalizes brain fatty acid desaturation, synapse loss and learning and memory deficits in middle-aged memory-impaired 3xTg-AD mice did not affect these peripheral phenotypes. This suggests that the beneficial effects of central SCD inhibition on cognitive function are not mediated by recovery of peripheral metabolic abnormalities. Given the widespread side-effects of systemically administered SCD inhibitors, these data suggest that selective inhibition of SCD in the brain may represent a clinically safer and more effective strategy for AD., (© 2024. The Author(s).)

Preserving the in vivo cell transcriptome is essential for accurate profiling, yet factors during cell isolation including time ex vivo and temperature induce artifactual gene expression, particularly in stress-responsive immune cells. In this study, we investigated two methods to mitigate ex vivo activation signature gene (ASG) expression in peripheral blood mononuclear cells (PBMCs): transcription and translation inhibitors (TTis) and cold temperatures during isolation. Comparative analysis of PBMCs isolated with TTis revealed reduced ASG expression. However, TTi treatment impaired responsiveness to LPS stimulation in subsequent in vitro experiments. In contrast, cold isolation methods also prevented ASG expression; up to a point where the addition of TTis during cold isolation offered minimal additional advantage. These findings highlight the importance of considering the advantages and drawbacks of different isolation methods to ensure accurate interpretation of PBMC transcriptomic profiles., (© 2023. The Author(s).)

Importance: Few primary care (PC) practices treat patients with medications for opioid use disorder (OUD) despite availability of effective treatments., Objective: To assess whether implementation of the Massachusetts model of nurse care management for OUD in PC increases OUD treatment with buprenorphine or extended-release injectable naltrexone and secondarily decreases acute care utilization., Design, Setting, and Participants: The Primary Care Opioid Use Disorders Treatment (PROUD) trial was a mixed-methods, implementation-effectiveness cluster randomized clinical trial conducted in 6 diverse health systems across 5 US states (New York, Florida, Michigan, Texas, and Washington). Two PC clinics in each system were randomized to intervention or usual care (UC) stratified by system (5 systems were notified on February 28, 2018, and 1 system with delayed data use agreement on August 31, 2018). Data were obtained from electronic health records and insurance claims. An implementation monitoring team collected qualitative data. Primary care patients were included if they were 16 to 90 years old and visited a participating clinic from up to 3 years before a system's randomization date through 2 years after., Intervention: The PROUD intervention included 3 components: (1) salary for a full-time OUD nurse care manager; (2) training and technical assistance for nurse care managers; and (3) 3 or more PC clinicians agreeing to prescribe buprenorphine., Main Outcomes and Measures: The primary outcome was a clinic-level measure of patient-years of OUD treatment (buprenorphine or extended-release injectable naltrexone) per 10 000 PC patients during the 2 years postrandomization (follow-up). The secondary outcome, among patients with OUD prerandomization, was a patient-level measure of the number of days of acute care utilization during follow-up., Results: During the baseline period, a total of 130 623 patients were seen in intervention clinics (mean [SD] age, 48.6 [17.7] years; 59.7% female), and 159 459 patients were seen in UC clinics (mean [SD] age, 47.2 [17.5] years; 63.0% female). Intervention clinics provided 8.2 (95% CI, 5.4-∞) more patient-years of OUD treatment per 10 000 PC patients compared with UC clinics (P = .002). Most of the benefit accrued in 2 health systems and in patients new to clinics (5.8 [95% CI, 1.3-∞] more patient-years) or newly treated for OUD postrandomization (8.3 [95% CI, 4.3-∞] more patient-years). Qualitative data indicated that keys to successful implementation included broad commitment to treat OUD in PC from system leaders and PC teams, full financial coverage for OUD treatment, and straightforward pathways for patients to access nurse care managers. Acute care utilization did not differ between intervention and UC clinics (relative rate, 1.16; 95% CI, 0.47-2.92; P = .70)., Conclusions and Relevance: The PROUD cluster randomized clinical trial intervention meaningfully increased PC OUD treatment, albeit unevenly across health systems; however, it did not decrease acute care utilization among patients with OUD., Trial Registration: ClinicalTrials.gov Identifier: NCT03407638.

Importance: Medical and nonmedical cannabis use and cannabis use disorders (CUD) have increased with increasing cannabis legalization. However, the prevalence of CUD among primary care patients who use cannabis for medical or nonmedical reasons is unknown for patients in states with legal recreational use., Objective: To estimate the prevalence and severity of CUD among patients who report medical use only, nonmedical use only, and both reasons for cannabis use in a state with legal recreational use., Design, Setting, and Participants: This cross-sectional survey study took place at an integrated health system in Washington State. Among 108 950 adult patients who completed routine cannabis screening from March 2019 to September 2019, 5000 were selected for a confidential cannabis survey using stratified random sampling for frequency of past-year cannabis use and race and ethnicity. Among 1688 respondents, 1463 reporting past 30-day cannabis use were included in the study., Exposure: Patient survey-reported reason for cannabis use in the past 30 days: medical use only, nonmedical use only, and both reasons., Main Outcomes and Measures: Patient responses to the Composite International Diagnostic Interview-Substance Abuse Module for CUD, corresponding to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition CUD severity (0-11 symptoms) were categorized as any CUD (≥2 symptoms) and moderate to severe CUD (≥4 symptoms). Adjusted analyses were weighted for survey stratification and nonresponse for primary care population estimates and compared prevalence of CUD across reasons for cannabis use., Results: Of 1463 included primary care patients (weighted mean [SD] age, 47.4 [16.8] years; 748 [weighted proportion, 61.9%] female) who used cannabis, 42.4% (95% CI, 31.2%-54.3%) reported medical use only, 25.1% (95% CI, 17.8%-34.2%) nonmedical use only, and 32.5% (95% CI, 25.3%-40.8%) both reasons for use. The prevalence of CUD was 21.3% (95% CI, 15.4%-28.6%) and did not vary across groups. The prevalence of moderate to severe CUD was 6.5% (95% CI, 5.0%-8.6%) and differed across groups: 1.3% (95% CI, 0.0%-2.8%) for medical use, 7.2% (95% CI, 3.9%-10.4%) for nonmedical use, and 7.5% (95% CI, 5.7%-9.4%) for both reasons for use (P = .01)., Conclusions and Relevance: In this cross-sectional study of primary care patients in a state with legal recreational cannabis use, CUD was common among patients who used cannabis. Moderate to severe CUD was more prevalent among patients who reported any nonmedical use. These results underscore the importance of assessing patient cannabis use and CUD symptoms in medical settings.

Background: Opioid use disorder (OUD) contributes to rising morbidity and mortality. Life-saving OUD treatments can be provided in primary care but most patients with OUD don't receive treatment. Comorbid depression and other conditions complicate OUD management, especially in primary care. The MI-CARE trial is a pragmatic randomized encouragement (Zelen) trial testing whether offering collaborative care (CC) to patients with OUD and clinically-significant depressive symptoms increases OUD medication treatment with buprenorphine and improves depression outcomes compared to usual care., Methods: Adult primary care patients with OUD and depressive symptoms (n ≥ 800) from two statewide health systems: Kaiser Permanente Washington and Indiana University Health are identified with computer algorithms from electronic Health record (EHR) data and automatically enrolled. A random sub-sample (50%) of eligible patients is offered the MI-CARE intervention: a 12-month nurse-driven CC intervention that includes motivational interviewing and behavioral activation. The remaining 50% of the study cohort comprise the usual care comparison group and is never contacted. The primary outcome is days of buprenorphine treatment provided during the intervention period. The powered secondary outcome is change in Patient Health Questionnaire (PHQ)-9 depression scores. Both outcomes are obtained from secondary electronic healthcare sources and compared in "intent-to-treat" analyses., Conclusion: MI-CARE addresses the need for rigorous encouragement trials to evaluate benefits of offering CC to generalizable samples of patients with OUD and mental health conditions identified from EHRs, as they would be in practice, and comparing outcomes to usual primary care. We describe the design and implementation of the trial, currently underway., Trial Registration: ClinicalTrials.gov Identifier: NCT05122676. Clinical trial registration date: November 17, 2021., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Pragmatic primary care trials aim to test interventions in "real world" health care settings, but clinics willing and able to participate in trials may not be representative of typical clinics. This analysis compared patients in participating and non-participating clinics from the same health systems at baseline in the PRimary care Opioid Use Disorders treatment (PROUD) trial., Methods: This observational analysis relied on secondary electronic health record and administrative claims data in 5 of 6 health systems in the PROUD trial. The sample included patients 16-90 years at an eligible primary care visit in the 3 years before randomization. Each system contributed 2 randomized PROUD trial clinics and 4 similarly sized non-trial clinics. We summarized patient characteristics in trial and non-trial clinics in the 2 years before randomization ("baseline"). Using mixed-effect regression models, we compared trial and non-trial clinics on a baseline measure of the primary trial outcome (clinic-level patient-years of opioid use disorder (OUD) treatment, scaled per 10,000 primary care patients seen) and a baseline measure of the secondary trial outcome (patient-level days of acute care utilization among patients with OUD)., Results: Patients were generally similar between the 10 trial clinics (n = 248,436) and 20 non-trial clinics (n = 341,130), although trial clinics' patients were slightly younger, more likely to be Hispanic/Latinx, less likely to be white, more likely to have Medicaid/subsidized insurance, and lived in less wealthy neighborhoods. Baseline outcomes did not differ between trial and non-trial clinics: trial clinics had 1.0 more patient-year of OUD treatment per 10,000 patients (95% CI: - 2.9, 5.0) and a 4% higher rate of days of acute care utilization than non-trial clinics (rate ratio: 1.04; 95% CI: 0.76, 1.42)., Conclusions: trial clinics and non-trial clinics were similar regarding most measured patient characteristics, and no differences were observed in baseline measures of trial primary and secondary outcomes. These findings suggest trial clinics were representative of comparably sized clinics within the same health systems. Although results do not reflect generalizability more broadly, this study illustrates an approach to assess representativeness of clinics in future pragmatic primary care trials., (© 2022. The Author(s).)

Background: States have enacted multiple types of laws, with a variety of constituent provisions, in response to the opioid epidemic, often simultaneously. This temporal proximity and variation in state-to-state operationalization has resulted in significant challenges for empirical research on their effects. Thus, expert consensus can be helpful to classify laws and their provisions by their degree of helpfulness and impact., Methods: We conducted a four-stage modified policy Delphi process to identify the top 10 most helpful and 5 most harmful provisions from eight opioid-related laws. This iterative consultation with six types of opioid experts included a preliminary focus group (n=12), two consecutive surveys (n=56 and n=40, respectively), and a final focus group feedback session (n=5)., Results: On a scale of very harmful (0) to very helpful (4), overdose Good Samaritan laws received the highest average helpfulness rating (3.62, 95% CI: 3.48-3.75), followed by naloxone access laws (3.37, 95% CI: 3.22-3.51), and pain management clinic laws (3.08, 95% CI: 2.89-3.26). Drug-induced homicide (DIH) laws were rated the most harmful (0.88, 95% CI: 0.66-1.11). Impact ratings aligned similarly, although Medicaid laws received the second highest overall impact rating (3.71, 95% CI: 3.45, 3.97). The two most helpful provisions were naloxone standing orders (3.94, 95% CI: 3.86-4.02) and Medicaid coverage of medications for opioid use disorder (MOUD) (3.89, 95% CI: 3.82). Mandatory minimum DIH laws were the most harmful provision (0.73, 95% CI 0.53-0.93); followed by requiring prior authorization for Medicaid coverage of MOUD (1.00 95% CI: 0.72-1.27)., Conclusion: Overall, experts rated laws and provisions that facilitated harm reduction efforts and access to MOUD as most helpful. Laws and provisions rated as most harmful criminalized substance use and placed restrictions on access to MOUD. These ratings provide a foundation for evaluating the overall overdose policy environment for each state., Competing Interests: Declarations of Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Samples has received consulting fees from the American Society of Addiction Medicine., (Copyright © 2022. Published by Elsevier B.V.)

Overdose Good Samaritan laws (GSLs) aim to reduce mortality by providing limited legal protections when a bystander to a possible drug overdose summons help. Most research into the impact of these laws is dated or potentially confounded by coenacted naloxone access laws. Lack of awareness and trust in GSL protections, as well as fear of police involvement and legal repercussions, remain key deterrents to help-seeking. These barriers may be unequally distributed by race/ethnicity due to racist policing and drug policies, potentially producing racial/ethnic disparities in the effectiveness of GSLs for reducing overdose mortality. We used 2015-2019 vital statistics data to estimate the effect of recent GSLs on overdose mortality, overall (8 states) and by Black/White race/ethnicity (4 states). Given GSLs' near ubiquity, few unexposed states were available for comparison. Therefore, we generated an "inverted" synthetic control method (SCM) to compare overdose mortality in new-GSL states with that in states that had GSLs throughout the analytical period. The estimated relationships between GSLs and overdose mortality, both overall and stratified by Black/White race/ethnicity, were consistent with chance. An absence of effect could result from insufficient protection provided by the laws, insufficient awareness of them, and/or reticence to summon help not addressable by legal protections. The inverted SCM may be useful for evaluating other widespread policies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The defining features of Alzheimer's disease (AD) include alterations in protein aggregation, immunity, lipid metabolism, synapses, and learning and memory. Of these, lipid abnormalities are the least understood. Here, we investigate the role of Stearoyl-CoA desaturase (SCD), a crucial regulator of fatty acid desaturation, in AD pathogenesis. We show that inhibiting brain SCD activity for 1-month in the 3xTg mouse model of AD alters core AD-related transcriptomic pathways in the hippocampus, and that it concomitantly restores essential components of hippocampal function, including dendritic spines and structure, immediate-early gene expression, and learning and memory itself. Moreover, SCD inhibition dampens activation of microglia, key mediators of spine loss during AD and the main immune cells of the brain. These data reveal that brain fatty acid metabolism links AD genes to downstream immune, synaptic, and functional impairments, identifying SCD as a potential target for AD treatment., (© 2022. The Author(s).)

The ventricular epithelium of the adult forebrain is a heterogeneous cell population that is a source of both quiescent and activated neural stem cells (qNSCs and aNSCs, respectively). We genetically targeted a subset of ventricle-contacting, glial fibrillary acidic protein (GFAP)-expressing cells, to study their involvement in qNSC/aNSC-mediated adult neurogenesis. Ventricle-contacting GFAP + cells were lineage-traced beginning in early adulthood using adult brain electroporation and produced small numbers of olfactory bulb neuroblasts until at least 21 mo of age. Notably, electroporated GFAP + neurogenic precursors were distinct from both qNSCs and aNSCs: they did not give rise to neurosphere-forming aNSCs in vivo or after extended passaging in vitro and they were not recruited during niche regeneration. GFAP + cells with these properties included a FoxJ1 + GFAP + subset, as they were also present in an inducible FoxJ1 transgenic lineage-tracing model. Transiently overexpressing Mash1 increased the neurogenic output of electroporated GFAP + cells in vivo, identifying them as a potentially recruitable population. We propose that the qNSC/aNSC lineage of the adult forebrain coexists with a distinct, minimally expanding subset of GFAP + neurogenic precursors., (© 2020 Joppé et al.)

Neural stem cell (NSC) activity and adult neurogenesis are physiologically relevant regulators of adult brain structure, function and repair. Given these roles, the NSC impairments observed in a wide range of neurodegenerative and psychiatric conditions likely factor into the overall cognitive dysfunction in these conditions. We investigated NSC regulation in the context of Alzheimer's disease (AD) using the well-characterised triple transgenic (3xTg) model of AD. In this review, we describe our recent findings that link 3xTg-AD neurogenesis impairments to AD-associated abnormalities in brain fatty acid metabolism. Notably, we identified an accumulation of triglycerides rich in oleic acid, a mono-unsaturated fatty acid, within the forebrain NSC niche in AD. Inhibiting the local conversion of saturated to mono-unsaturated fatty acids within the brain was sufficient to counteract the loss of NSC activity in 3xTg-AD mice (Hamilton et al., 2015). We place these findings within the context of recent evidence that dynamic changes in lipid metabolism occur during the transition from NSC quiescence to activation. The picture that emerges is that the critical NSC quiescence-to-activation decision is sensitive to the local levels of specific fatty acids and can be impaired by a disease-associated shift in brain fatty acid balance., (© 2017 Société Française des Microscopies and Société de Biologie Cellulaire de France. Published by John Wiley & Sons Ltd.)

Background: Much work has investigated the association between substance use, crime, and recidivism, yet little scholarship has examined these associations longitudinally among samples of recently released prisoners. We examine the lagged reciprocal effects of hard substance use and crime, among other covariates, in the context of the prisoner reentry process., Methods: We rely on data from the Serious and Violent Offender Reentry Initiative (SVORI) evaluation and employ cross-lagged panel models to examine short-term changes in substance use and crime over time among a large sample of high-risk, former prisoners (N = 1697)., Results: Substance use marginally predicted increased odds of rearrest at one wave, and rearrest significantly (p < .05) predicted increased odds of substance use at another. As such, the results provide limited evidence for a degree of lagged mutual causation; associations vary over the reentry process and are complicated by other realities of life after prison. A key finding is that both behaviors are more consistently influenced by other factors, such as service needs and instrumental and emotional supports., Conclusions: Although there are relationships between drug use and criminal behavior, these behaviors alone are insufficient explanations for one another in an adult reentry population. Alternatively, the compounding social and personal needs of the reentry population, and the extent to which they received support or services to address these needs, appear to have the strongest influence on both behaviors in the reentry context.

Background: There is currently little research regarding sugar-sweetened beverage (SSB) consumption patterns of young people though adolescents are thought to be frequent consumers of these drinks. There is no research regarding the other foods and drinks consumed alongside SSBs by young people. The aim of this paper is to explore the patterns of SSB purchase and consumption amongst young people aged 13-15 years., Methods: A purchasing recall questionnaire (PRQ) was administered online in seven case study schools with 535 young people aged 13-15 years. Nutrient composition (kilocalories, fat, saturated fat, sodium and sugar) was also calculated for food/drink purchases. Chi-Square and Wilcoxon-Mann Whitney tests were conducted to examine patterns of SSB consumption and sugar/kilocalories consumption for SSB consumers and non-consumers., Results: SSB consumers were significantly more likely to consume a drink at mid-morning break. Fewer consumed food at mid-morning break, ate food before school or ate food at lunchtime, but this was not statistically significant. A higher percentage of SSB consumers consumed 'unhealthy' food and drinks in comparison to young people who did not consume a SSB. Both median lunchtime sugar consumption (40.7 g vs 10.2 g) and median sugar as a percentage of Kcals (39% vs 14%) were significantly higher for SSB purchasers in comparison to non-purchasers., Conclusion: The analysis highlights that SSB purchasers consume significantly more sugar at lunchtime than non-purchasers. However, both purchasers and non-purchasers exceeded WHO (2015) recommendations that sugar consumption be halved to form no more than 5% of daily energy intake. This study provides new insights for public health stakeholders and schools. Multifaceted and inventive strategies relevant to young people will be required to achieve the new WHO recommendations., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

A single asymmetric division by an adult neural stem cell (NSC) ultimately generates dozens of differentiated progeny, a feat made possible by the proliferative expansion of transit-amplifying progenitor cells (TAPs). Although NSC activation and TAP expansion is determined by pro- and anti-proliferative signals found within the niche, remarkably little is known about how these cells integrate simultaneous conflicting signals. We investigated this question focusing on the subventricular zone (SVZ) niche of the adult murine forebrain. Using primary cultures of SVZ cells, we demonstrate that Epidermal Growth Factor (EGF) and Bone Morphogenetic Protein (BMP)-2 are particularly powerful pro- and anti-proliferative factors for SVZ-derived neural precursors. Dose-response experiments showed that when simultaneously exposed to both signals, BMP dominantly suppressed EGF-induced proliferation; moreover, this dominance extended to all parameters of neural precursor behavior tested, including inhibition of proliferation, modulation of cell cycle, promotion of differentiation, and increase of cell death. BMP's anti-proliferative effect did not involve inhibition of mTORC1 or ERK signaling, key mediators of EGF-induced proliferation, and had distinct stage-specific consequences, promoting TAP differentiation but NSC quiescence. In line with these in vitro data, in vivo experiments showed that exogenous BMP limits EGF-induced proliferation of TAPs while inhibition of BMP-SMAD signaling promotes activation of quiescent NSCs. These findings clarify the stage-specific effects of BMPs on SVZ neural precursors, and support a hierarchical model in which the anti-proliferative effects of BMP dominate over EGF proliferation signaling to constitutively drive TAP differentiation and NSC quiescence.

Lipid metabolism is fundamental for brain development and function, but its roles in normal and pathological neural stem cell (NSC) regulation remain largely unexplored. Here, we uncover a fatty acid-mediated mechanism suppressing endogenous NSC activity in Alzheimer's disease (AD). We found that postmortem AD brains and triple-transgenic Alzheimer's disease (3xTg-AD) mice accumulate neutral lipids within ependymal cells, the main support cell of the forebrain NSC niche. Mass spectrometry and microarray analyses identified these lipids as oleic acid-enriched triglycerides that originate from niche-derived rather than peripheral lipid metabolism defects. In wild-type mice, locally increasing oleic acid was sufficient to recapitulate the AD-associated ependymal triglyceride phenotype and inhibit NSC proliferation. Moreover, inhibiting the rate-limiting enzyme of oleic acid synthesis rescued proliferative defects in both adult neurogenic niches of 3xTg-AD mice. These studies support a pathogenic mechanism whereby AD-induced perturbation of niche fatty acid metabolism suppresses the homeostatic and regenerative functions of NSCs., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The adult mammalian spinal cord has limited regenerative capacity in settings such as spinal cord injury (SCI) and multiple sclerosis (MS). Recent studies have revealed that ependymal cells lining the central canal possess latent neural stem cell potential, undergoing proliferation and multi-lineage differentiation following experimental SCI. To determine whether reactive ependymal cells are a realistic endogenous cell population to target in order to promote spinal cord repair, we assessed the spatiotemporal dynamics of ependymal cell proliferation for up to 35 days in three models of spinal pathologies: contusion SCI using the Infinite Horizon impactor, focal demyelination by intraspinal injection of lysophosphatidylcholine (LPC), and autoimmune-mediated multi-focal demyelination using the active experimental autoimmune encephalomyelitis (EAE) model of MS. Contusion SCI at the T9-10 thoracic level stimulated a robust, long-lasting and long-distance wave of ependymal proliferation that peaked at 3 days in the lesion segment, 14 days in the rostral segment, and was still detectable at the cervical level, where it peaked at 21 days. This proliferative wave was suppressed distal to the contusion. Unlike SCI, neither chemical- nor autoimmune-mediated demyelination triggered ependymal cell proliferation at any time point, despite the occurrence of demyelination (LPC and EAE), remyelination (LPC) and significant locomotor defects (EAE). Thus, traumatic SCI induces widespread and enduring activation of reactive ependymal cells, identifying them as a robust cell population to target for therapeutic manipulation after contusion; conversely, neither demyelination, remyelination nor autoimmunity appears sufficient to trigger proliferation of quiescent ependymal cells in models of MS-like demyelinating diseases.

In the brains of adult vertebrates, including humans, neurogenesis occurs in restricted niches where it maintains cellular turnover and cognitive plasticity. In virtually all species, however, aging is associated with a significant decline in adult neurogenesis. Moreover, an acceleration of neurogenic defects is observed in models of Alzheimer's disease and other neurodegenerative diseases, suggesting an involvement in aging- and disease-associated cognitive deficits. To gain insights into when, how and why adult neurogenesis decreases in the aging brain, we critically reviewed the scientific literature on aging of the rodent subventricular zone, the neurogenic niche of the adult forebrain. Our analysis revealed that deficits in the neurogenic pathway are largely established by middle age, but that there remains striking ambiguity in the underlying mechanisms, especially at the level of stem and progenitor cells. We identify and discuss several challenging issues that have contributed to these key gaps in our current knowledge. In the future, addressing these issues should help untangle the interactions between neurogenesis, aging and aging-associated diseases., (© 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Adult forebrain neurogenesis is dynamically regulated. Multiple families of niche-derived cues have been implicated in this regulation, but the precise roles of key intracellular signaling pathways remain vaguely defined. Here, we show that mammalian target of rapamycin (mTOR) signaling is pivotal in determining proliferation versus quiescence in the adult forebrain neural stem cell (NSC) niche. Within this niche, mTOR complex-1 (mTORC1) activation displays stage specificity, occurring in transiently amplifying (TA) progenitor cells but not in GFAP+ stem cells. Inhibiting mTORC1 depletes the TA progenitor pool in vivo and suppresses epidermal growth factor (EGF)-induced proliferation within neurosphere cultures. Interestingly, mTORC1 inhibition induces a quiescence-like phenotype that is reversible. Likewise, mTORC1 activity and progenitor proliferation decline within the quiescent NSC niche of the aging brain, while EGF administration reactivates the quiescent niche in an mTORC1-dependent manner. These findings establish fundamental links between mTOR signaling, proliferation, and aging-associated quiescence in the adult forebrain NSC niche.

Alzheimer's disease (AD) affects cognitive modalities that are known to be regulated by adult neurogenesis, such as hippocampal- and olfactory-dependent learning and memory. However, the relationship between AD-associated pathologies and alterations in adult neurogenesis has remained contentious. In the present study, we performed a detailed investigation of adult neurogenesis in the triple transgenic (3xTg) mouse model of AD, a unique model that generates both amyloid plaques and neurofibrillary tangles, the hallmark pathologies of AD. In both neurogenic niches of the brain, the hippocampal dentate gyrus and forebrain subventricular zone, we found that 3xTg mice had decreased numbers of (i) proliferating cells, (ii) early lineage neural progenitors, and (iii) neuroblasts at middle age (11months old) and old age (18months old). These decreases correlated with major reductions in the addition of new neurons to the respective target areas, the dentate granule cell layer and olfactory bulb. Within the subventricular zone niche, cytological alterations were observed that included a selective loss of subependymal cells and the development of large lipid droplets within the ependyma of 3xTg mice, indicative of metabolic changes. Temporally, there was a marked acceleration of age-related decreases in 3xTg mice, which affected multiple stages of neurogenesis and was clearly apparent prior to the development of amyloid plaques or neurofibrillary tangles. Our findings indicate that AD-associated mutations suppress neurogenesis early during disease development. This suggests that deficits in adult neurogenesis may mediate premature cognitive decline in AD., (© 2010 The Authors. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.)

A stem cell's microenvironment, or "niche," is a critical regulator of its behaviour. In the adult mammalian spinal cord, central canal ependymal cells possess latent neural stem cell properties, but the ependymal cell niche has not yet been described. Here, we identify important similarities and differences between the central canal ependymal zone and the forebrain subventricular zone (SVZ), a well-characterized niche of neural stem cells. First, direct immunohistochemical comparison of the spinal cord ependymal zone and the forebrain SVZ revealed distinct patterns of neural precursor marker expression. In particular, ependymal cells in the spinal cord were found to be bordered by a previously uncharacterized sub-ependymal layer, which is relatively less elaborate than that of the SVZ and comprised of small numbers of astrocytes, oligodendrocyte progenitors and neurons. Cell proliferation surrounding the central canal occurs in close association with blood vessels, but unlike in the SVZ, involves mainly ependymal rather than sub-ependymal cells. These proliferating ependymal cells typically self-renew rather than produce transit-amplifying progenitors, as they generate doublets of progeny that remain within the ependymal layer and show no evidence of a lineage relationship to sub-ependymal cells. Interestingly, the dorsal pole of the central canal was found to possess a sub-population of tanycyte-like cells that express markers of both ependymal cells and neural precursors, and their presence correlates with higher numbers of dorsally proliferating ependymal cells. Together, these data identify key features of the spinal cord ependymal cell niche, and suggest that dorsal ependymal cells possess the potential for stem cell activity. This work provides a foundation for future studies aimed at understanding ependymal cell regulation under normal and pathological conditions.

In the authors' 2-dimensional model of prejudice, explicit and implicit attitudes are used to create 4 profiles: truly low prejudiced (TLP: double lows), aversive racists (AR: low explicit modern racism/high implicit prejudice), principled conservatives (PC: high explicit modern racism/low implicit prejudice), and modern racists (MR: double highs). Students completed an Asian Modern Racism Scale and an Asian/White Implicit Association Test. The authors compared the 4 groups' prejudice-related ideologies (i.e., egalitarianism/humanism and social conservatism) and economic/political conservatism (Study 1, N=132). The authors also tested whether MR but not PC (Study 2, N=65) and AR but not TLP (Study 3, N=143) are more likely to negatively evaluate an Asian target when attributional ambiguity is high (vs. low). In support of the model, TLP did not hold prejudice-related ideologies and did not discriminate; AR were low in conservatism and demonstrated the attributional-ambiguity effect; PC did not strongly endorse prejudice-related ideologies and did not discriminate; MR strongly endorsed prejudice-related ideologies, were conservative, and demonstrated the attributional-ambiguity effect. The authors discuss implications for operationalizing and understanding the nature of prejudice., ((PsycINFO Database Record (c) 2008 APA, all rights reserved).)