Palliative Care Interventions for Persons With Neurodegenerative Disease: A Scoping Review of Clinical Trial Study Design Features.

Background: Within palliative care research, best practice guidelines to conduct scientifically rigorous clinical trials for neurodegenerative diseases are underexplored. This patient population experiences unique challenges, including fluctuations in cognitive capacity, care partner (CP) and proxy involvement, and high adverse events (AEs), that necessitate special consideration when designing clinical trials. Objective: The objective of this study was to describe and identify clinical trial design features that have been documented in studies involving a neuropalliative intervention for persons with neurodegenerative diseases, highlighting features that have been adapted for this unique patient population. Design: We conducted a scoping review of clinical trials with a neuropalliative intervention for persons with neurodegenerative disease. We searched Cochrane, Web of Science, EMBASE, Scopus, and PubMed (MEDLINE) databases for articles published in English between 1950 and 2023. Two reviewers screened, extracted, and synthesized data from the included articles. A third reviewer adjudicated instances of conflict. The data were analyzed using a thematic framework approach. Results: Of 1025 texts, 44 articles were included. Seven study design features were analyzed: (1) consent, (2) proxies and CPs, (3) recruitment strategies, (4) retention strategies, (5) choice of comparator, (6) AEs, and (7) internal validity. This scoping review found disparities in study design features around structured consent, proxies and CPs, comparators, and AEs. Conclusions: To date, neuropalliative care clinical trials have had varied study designs and the majority of research has focused on dementia. Research guideline development for high-quality neuropalliative care clinical trials is greatly needed across the range of neurodegenerative diseases. To increase the scientific rigor of clinical trials and neuropalliative care, we recommend a standardized capacity assessment for consent, defining conditions for the CP, proxy, and AEs, systematizing appropriate comparators, and outlining preemptive recruitment and retention strategies to address the broader unpredictable challenges of palliative care research.

Asian race is associated with peripheral arterial disease severity and postoperative outcomes.

OBJECTIVE: The nature of peripheral arterial disease and postoperative outcomes are understudied in Asian patients. We aimed to determine if there are disparities in disease severity at the time of presentation and postoperative outcomes with regard to Asian race. METHODS: We analyzed the Society for Vascular Surgery Vascular Quality Initiative Peripheral Vascular Intervention dataset from 2017 to 2021, which includes endovascular lower extremity interventions. Propensity scores were used to match White and Asian patients based on age, sex, comorbidities, ambulatory/functional status, and intervention level. Differences were examined with regard to Asian race across all patients in the United States, Canada, and Singapore, and separately in the United States and Canada only. The primary outcome was emergent intervention. We also examined differences in severity of disease and postoperative outcomes. RESULTS: A total of 80,312 White and 1689 Asian patients underwent peripheral vascular intervention. After propensity score matching, we identified 1669 matched pairs of patients across all centers including Singapore and 1072 matched pairs in the United States and Canada only. Among the matched cohort consisting of all centers, Asian patients had a higher rate of emergent intervention to prevent limb loss (5.6% vs 1.7%, P < .001). The majority of Asian patients presented with chronic limb threatening ischemia at a higher rate than White patients within the cohort including Singapore (71% vs 66%, P = .005). Within both propensity-matched cohorts, the rate of in-hospital death was higher in Asian patients (all centers: 3.1% vs 1.2%, P < .001; United States and Canada only: 2.1% vs 0.8%, P = .010). Logistic regression demonstrated greater odds of emergent intervention in Asian patients from all centers including Singapore (odds ratio [OR], 3.3; 95% confidence interval [CI], 2.2-5.1, P < .001) but not in the United States and Canada only (OR, 1.4; 95% CI, 0.8-2.8, P = .261). In addition, Asian patients had greater odds of in-hospital death in both matched cohorts (all centers: OR, 2.6; 95% CI, 1.5-4.4, P < .001; United States and Canada: OR, 2.5; 95% CI, 1.1-5.8, P = .026). Asian race was associated with a greater risk of loss of primary patency at 18 months (all centers: hazard ratio, 1.5; CI, 1.2-1.8, P = .001; United States and Canada only: hazard ratio, 1.5; CI, 1.2-1.9, P = .002). CONCLUSIONS: Asian patients are more likely to present with advanced peripheral arterial disease and undergo emergent intervention to prevent limb loss, in addition to having worse postoperative outcomes and long-term patency. These results highlight the need for improved screening and postoperative follow-up in this understudied population.

Insurance status is associated with urgent carotid endarterectomy and worse postoperative outcomes.

OBJECTIVE: Underinsured patients can experience worse preoperative medical optimization. We aimed to determine whether insurance status was associated with carotid endarterectomy (CEA) urgency and postoperative outcomes. METHODS: We analyzed the Society for Vascular Surgery Vascular Quality Initiative Carotid Endarterectomy dataset from January 2012 to January 2021. Univariable and multivariable methods were used to analyze the differences across the insurance types for the primary outcome variable: CEA urgency. The analyses were limited to patients aged <65 years to minimize age confounding across insurers. We also examined differences in preoperative medical optimization and symptomatic disease and postoperative outcomes. A secondary analysis was performed to examine the effect of CEA urgency on the postoperative outcomes. RESULTS: A total of 27,331 patients had undergone first-time CEA. Of these patients, 4600 (17%) had Medicare, 3440 (13%) had Medicaid, 17,917 (65%) had commercial insurance, and 1374 (5%) were uninsured. The Medicaid and uninsured patients had higher rates of urgent operation compared with Medicare (20.0% and 34.7% vs 14.4%; P < .001), with no differences in the commercial group vs the Medicare group. Additionally, Medicaid and uninsured patients had lower rates of aspirin, statin, and/or antiplatelet use (93.6% and 93.5% vs 95.8%; P < .001) and higher rates of symptomatic disease (42.1% and 57.6% vs 36.2%; P < .001) compared with Medicare patients. The rate of perioperative stroke/death was higher for the Medicaid and uninsured patients than for the Medicare patients (1.63% and 1.89% vs 1.02%; P = .017 and P = .01, respectively), with no differences in the commercial group. Multivariable analysis demonstrated that compared with Medicare, Medicaid and uninsured status were associated with increased odds of an urgent operation (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.1-1.5; and OR, 2.3; 95% CI, 2.0-2.7, respectively), symptomatic disease (OR, 1.2; 95% CI, 1.1-1.4; and OR, 2.2; 95% CI, 1.9-2.5, respectively), and perioperative stroke/death (OR, 1.6; 95% CI, 1.1-2.4; and OR, 1.8; 95% CI, 1.1-3.0, respectively) and a decreased odds of aspirin, statin, and/or antiplatelet use (OR, 0.71; 95% CI, 0.6-0.9; and OR, 0.76; 95% CI, 0.6-0.99, respectively). Additionally, the rates of perioperative stroke/death were higher for patients who had required urgent surgery compared with elective surgery (2.8% vs 1.0%; P < .001). Multivariable analysis demonstrated increased odds of perioperative stroke/death for patients who had required urgent surgery (OR, 2.4; 95% CI, 1.9-3.1). CONCLUSIONS: Medicaid and uninsured patients were more likely to require urgent CEA, in part because of poor preoperative medical optimization. Additionally, urgent operation was independently associated with worse postoperative outcomes. These results highlight the need for improved preoperative follow-up for underinsured populations.

Incidental Pulmonary Nodules Found on Shoulder Arthroplasty Preoperative CT Scans.

With current emphasis on preoperative templating of anatomical and reverse shoulder arthroplasty (aTSA and rTSA, respectively), patients often receive thin slice (<1.0 mm) computerized tomography (CT) scans of the operative shoulder, which includes about two-thirds of the ipsilateral lung. The purpose of this study is to evaluate the prevalence and management of incidentally detected pulmonary nodules on preoperative CT scans for shoulder arthroplasty. In this single-center retrospective study, we queried records of aTSA and rTSA patients from 2015 to 2020 who received preoperative CT imaging of the shoulder. Compared to patients with negative CT findings, there were significantly more females (63.8% vs. 46.4%; P = .011), COPD (13.0% vs. 4.7%; P = .015), and asthma (18.8% vs. 6.9%; P = .003) among the patients with incidental nodules on CT. Binary logistic regression confirmed that female sex (odds ratio = 2.00; 95% CI = 1.04 to 3.88; P = .037), COPD history (OR = 3.02; 95% CI = 1.05 to 8.65; P = .040), and asthma history (OR = 3.17; 95% CI = 1.30 to 7.77; P = .011) were significantly associated with an incidental nodule finding. Incidental pulmonary nodules found on shoulder arthroplasty preoperative CT scans are often low risk in size with low risk of malignancy, and do not require further workup. This study may provide guidance to orthopedic surgeons on how to manage patients with incidental pulmonary nodules to increase chances of early cancer detection, avoid unnecessary referrals, reduce potentially harmful radiation exposure of serial CT scans, and improve cost efficiency.

PharmOmics: A species- and tissue-specific drug signature database and gene-network-based drug repositioning tool.

Drug development has been hampered by a high failure rate in clinical trials due to our incomplete understanding of drug functions across organs and species. Therefore, elucidating species- and tissue-specific drug functions can provide insights into therapeutic efficacy, potential adverse effects, and interspecies differences necessary for effective translational medicine. Here, we present PharmOmics, a drug knowledgebase and analytical tool that is hosted on an interactive web server. Using tissue- and species-specific transcriptome data from human, mouse, and rat curated from different databases, we implemented a gene-network-based approach for drug repositioning. We demonstrate the potential of PharmOmics to retrieve known therapeutic drugs and identify drugs with tissue toxicity using in silico performance assessment. We further validated predicted drugs for nonalcoholic fatty liver disease in mice. By combining tissue- and species-specific in vivo drug signatures with gene networks, PharmOmics serves as a complementary tool to support drug characterization and network-based medicine.

Machine Learning Model Developed to Aid in Patient Selection for Outpatient Total Joint Arthroplasty.

BACKGROUND: Patient selection for outpatient total joint arthroplasty (TJA) is important for optimizing patient outcomes. This study develops machine learning models that may aid in patient selection for outpatient TJA based on medical comorbidities and demographic factors. METHODS: This study queried elective total knee arthroplasty (TKA) and total hip arthroplasty (THA) cases during 2010-2018 in the American College of Surgeons National Surgical Quality Improvement Program. Artificial neural network models predicted same-day discharge and length of stay (LOS) fewer than 2 days (short LOS). Multiple linear and logistic regression analyses were used to identify variables significantly associated with predicted outcomes. RESULTS: A total of 284,731 TKA cases and 153,053 THA cases met inclusion criteria. For TKA, prediction of short LOS had an area under the receiver operating characteristic curve (AUC) of 0.767 and accuracy of 84.1%; prediction of same-day discharge had an AUC of 0.802 and accuracy of 89.2%. For THA, prediction of short LOS had an AUC of 0.757 and accuracy of 70.6%; prediction of same-day discharge had an AUC of 0.814 and accuracy of 78.8%. CONCLUSION: This study developed machine learning models for aiding patient selection for outpatient TJA, through accurately predicting short LOS or outpatient vs inpatient cases. As outpatient TJA expands, it will be important to optimize preoperative patient selection and effectively screen surgical candidates from a broader patient population. Incorporating models such as these into electronic medical records could aid in decision-making and resource planning in real time.

Mergeomics 2.0: a web server for multi-omics data integration to elucidate disease networks and predict therapeutics.

The Mergeomics web server is a flexible online tool for multi-omics data integration to derive biological pathways, networks, and key drivers important to disease pathogenesis and is based on the open source Mergeomics R package. The web server takes summary statistics of multi-omics disease association studies (GWAS, EWAS, TWAS, PWAS, etc.) as input and features four functions: Marker Dependency Filtering (MDF) to correct for known dependency between omics markers, Marker Set Enrichment Analysis (MSEA) to detect disease relevant biological processes, Meta-MSEA to examine the consistency of biological processes informed by various omics datasets, and Key Driver Analysis (KDA) to identify essential regulators of disease-associated pathways and networks. The web server has been extensively updated and streamlined in version 2.0 including an overhauled user interface, improved tutorials and results interpretation for each analytical step, inclusion of numerous disease GWAS, functional genomics datasets, and molecular networks to allow for comprehensive omics integrations, increased functionality to decrease user workload, and increased flexibility to cater to user-specific needs. Finally, we have incorporated our newly developed drug repositioning pipeline PharmOmics for prediction of potential drugs targeting disease processes that were identified by Mergeomics. Mergeomics is freely accessible at http://mergeomics.research.idre.ucla.edu and does not require login.

Systems toxicogenomics of prenatal low-dose BPA exposure on liver metabolic pathways, gut microbiota, and metabolic health in mice.

Bisphenol A (BPA) is an industrial plasticizer widely found in consumer products, and exposure to BPA during early development has been associated with the prevalence of various cardiometabolic diseases including obesity, metabolic syndrome, type 2 diabetes, and cardiovascular diseases. To elucidate the molecular perturbations underlying the connection of low-dose prenatal BPA exposure to cardiometabolic diseases, we conducted a multi-dimensional systems biology study assessing the liver transcriptome, gut microbial community, and diverse metabolic phenotypes in both male and female mouse offspring exposed to 5 µg/kg/day BPA during gestation. Prenatal exposure to low-dose BPA not only significantly affected liver genes involved in oxidative phosphorylation, PPAR signaling and fatty acid metabolism, but also affected the gut microbial composition in an age- and sex-dependent manner. Bacteria such as those belonging to the S24-7 and Lachnospiraceae families were correlated with offspring phenotypes, differentially expressed liver metabolic genes such as Acadl and Dgat1, and key drivers identified in our gene network modeling such as Malat1 and Apoa2. This multiomics study provides insight into the relationship between gut bacteria and host liver genes that could contribute to cardiometabolic disease risks upon low-dose BPA exposure.

Association between shoulder coracoacromial arch morphology and anterior instability of the shoulder.

BACKGROUND: Glenohumeral instability is a common condition of the shoulder. Glenoid bone loss and humeral head bone loss are well recognized as risk factors for recurrent instability. There are few studies in the literature that examine the role of coracoacromial arch anatomy in the pathogenesis of glenohumeral instability. Previous reports found an association between posterior acromial coverage (PAC) and posterior instability. We hypothesize that coracoacromial arch anatomy is related to anterior shoulder instability. METHODS: In this retrospective cohort study, 50 patients with unidirectional anterior shoulder instability were matched to a control group of 50 glenohumeral arthritis patients without any history of shoulder instability. Radiographic measurements of the coracoacromial arch anatomy were made: shoulder arch angle, scapular Y angle, anterior coracoid tilt (ACT), posterior acromial tilt, anterior acromial coverage angle, PAC angle, coracoid height, posterior acromial height, and critical shoulder angle were determined using standard lateral scapular and anteroposterior radiographs. RESULTS: Logistic regression analyses found a significant association between the presence of anterior instability and flatter coracoacromial arch angles (mean, 124.1°) vs. the arthritis control group (mean, 120.6°) (odds ratios [OR] = 1.113; 95% confidence interval [CI] = 1.039-1.191; P = .002). There was a significant association between anterior instability and ACT (OR = 1.144; 95% CI = 1.053-1.243; P = .001), whereas a negative association was found between anterior instability and PAC (OR = 0.909; 95% CI = 0.853-0.969; P = .004) and posterior acromial tilt (OR = 0.878; 95% CI = 0.773-0.998; P = .046). Lower critical shoulder angle values were associated with the arthritis group (28.2° vs. 33.9°) (OR = 1.555; 95% CI = 1.202-2.012; P = .001). CONCLUSIONS: Shoulder coracoacromial arch morphology may play a role in the stability of the shoulder joint and development of recurrent anterior instability. Shoulders with a decreased shoulder arch angle, a less contained and flatter coracoacromial arch and larger ACT, were associated with anterior instability. This study identifies the shoulder coracoacromial arch angle and anterior coracoid tile angles as risk factors for anterior shoulder instability. Our findings suggest that measuring these angles may help orthopedic surgeons understand the risk of anterior instability and analyze risk factors to improve clinical decision making.

Host Genetic Background and Gut Microbiota Contribute to Differential Metabolic Responses to Fructose Consumption in Mice.

BACKGROUND: It is unclear how high fructose consumption induces disparate metabolic responses in genetically diverse mouse strains. OBJECTIVE: We aimed to investigate whether the gut microbiota contributes to differential metabolic responses to fructose. METHODS: Eight-week-old male C57BL/6J (B6), DBA/2J (DBA), and FVB/NJ (FVB) mice were given 8% fructose solution or regular water (control) for 12 wk. The gut microbiota composition in cecum and feces was analyzed using 16S ribosomal DNA sequencing, and permutational multivariate ANOVA (PERMANOVA) was used to compare community across mouse strains, treatments, and time points. Microbiota abundance was correlated with metabolic phenotypes and host gene expression in hypothalamus, liver, and adipose tissues using Biweight midcorrelation. To test the causal role of the gut microbiota in determining fructose response, we conducted fecal transplants from B6 to DBA mice and vice versa for 4 wk, as well as gavaged antibiotic-treated DBA mice with Akkermansia for 9 wk, accompanied with or without fructose treatment. RESULTS: Compared with B6 and FVB, DBA mice had significantly higher Firmicutes to Bacteroidetes ratio and lower baseline abundance of Akkermansia and S24-7 (P < 0.05), accompanied by metabolic dysregulation after fructose consumption. Fructose altered specific microbial taxa in individual mouse strains, such as a 7.27-fold increase in Akkermansia in B6 and 0.374-fold change in Rikenellaceae in DBA (false discovery rate <5%), which demonstrated strain-specific correlations with host metabolic and transcriptomic phenotypes. Fecal transplant experiments indicated that B6 microbes conferred resistance to fructose-induced weight gain in DBA mice (F = 43.1, P < 0.001), and Akkermansia colonization abrogated the fructose-induced weight gain (F = 17.8, P < 0.001) and glycemic dysfunctions (F = 11.8, P = 0.004) in DBA mice. CONCLUSIONS: Our findings support that differential microbiota composition between mouse strains is partially responsible for host metabolic sensitivity to fructose, and that Akkermansia is a key bacterium that confers resistance to fructose-induced metabolic dysregulation.

Omega-3 fatty acids increase OXPHOS energy for immune therapy of Alzheimer disease patients.

Sporadic late-onset Alzheimer disease (LOAD) preceded by mild cognitive impairment (MCI) is the most common type of dementia. Long-term studies of immunity to pathogenic amyloid-ß (Aß) in LOAD are lacking. Innate immunity of LOAD patients is malfunctioning in phagocytosis and degradation of Aß and LOAD patients' macrophage transcriptome and metabolome are deregulated. We previously showed omega-3 fatty acid (ω-3)-mediated repair of unfolded protein response and here we show much broader transcriptomic effects. ω-3 treatment in vitro and ω-3 supplementation by the drink Smartfish (SMF) in vivo increased the transcripts of the genes and pathways of immunity, glycolysis, tricarboxylic acid cycle, OX-PHOS, nicotinamide dinucleotide (NAD+ ) synthesis, and reversed the defects in Aß phagocytosis. In both peripheral blood mononuclear cells (PBMC) and macrophages, ω-3 increased ATP-linked oxygen consumption rate (OCR) and ω-3 with carnitine was superior to ω-3. ω-3 treatment in vitro and supplementation by the ω-3 drink SMF in vivo rescued macrophage phagocytosis when glycolysis or glycosylation were blocked. ω-3 provide flexible energy for immune clearance of the brain throughout the diurnal cycle, even in hypo- or hyper-glycemia. In certain LOAD patients, ω-3 may delay progression to dementia.

Shigella flexneri Adherence Factor Expression in In Vivo-Like Conditions.

The Shigella species are Gram-negative, facultative intracellular pathogens that invade the colonic epithelium and cause significant diarrheal disease. Despite extensive research on the pathogen, a comprehensive understanding of how Shigella initiates contact with epithelial cells remains unknown. Shigella maintains many of the same Escherichia coli adherence gene operons; however, at least one critical gene component in each operon is currently annotated as a pseudogene in reference genomes. These annotations, coupled with a lack of structures upon microscopic analysis following growth in laboratory media, have led the field to hypothesize that Shigella is unable to produce fimbriae or other traditional adherence factors. Nevertheless, our previous analyses have demonstrated that a combination of bile salts and glucose induces both biofilm formation and adherence to colonic epithelial cells. The goal of this study was to perform transcriptomic and genetic analyses to demonstrate that adherence gene operons in Shigella flexneri strain 2457T are functional, despite the gene annotations. Our results demonstrate that at least three structural genes facilitate S. flexneri 2457T adherence for epithelial cell contact and biofilm formation. Furthermore, our results demonstrate that host factors, namely, glucose and bile salts at their physiological concentrations in the small intestine, offer key environmental stimuli required for adherence factor expression in S. flexneri This research may have a significant impact on Shigella vaccine development and further highlights the importance of utilizing in vivo-like conditions to study bacterial pathogenesis.IMPORTANCE Bacterial pathogens have evolved to regulate virulence gene expression at critical points in the colonization and infection processes to successfully cause disease. The Shigella species infect the epithelial cells lining the colon to result in millions of cases of diarrhea and a significant global health burden. As antibiotic resistance rates increase, understanding the mechanisms of infection is vital to ensure successful vaccine development. Despite significant gains in our understanding of Shigella infection, it remains unknown how the bacteria initiate contact with the colonic epithelium. Most pathogens harbor multiple adherence factors to facilitate this process, but Shigella was thought to have lost the ability to produce these factors. Interestingly, we have identified conditions that mimic some features of gastrointestinal transit and that enable Shigella to express adherence structural genes. This work highlights aspects of genetic regulation for Shigella adherence factors and may have a significant impact on future vaccine development.

Network modeling of single-cell omics data: challenges, opportunities, and progresses.

Single-cell multi-omics technologies are rapidly evolving, prompting both methodological advances and biological discoveries at an unprecedented speed. Gene regulatory network modeling has been used as a powerful approach to elucidate the complex molecular interactions underlying biological processes and systems, yet its application in single-cell omics data modeling has been met with unique challenges and opportunities. In this review, we discuss these challenges and opportunities, and offer an overview of the recent development of network modeling approaches designed to capture dynamic networks, within-cell networks, and cell-cell interaction or communication networks. Finally, we outline the remaining gaps in single-cell gene network modeling and the outlooks of the field moving forward.

Integrative analysis of gene expression and methylation data for breast cancer cell lines.

BACKGROUND: The deadly costs of cancer and necessity for an accurate method of early cancer detection have demanded the identification of genetic and epigenetic factors associated with cancer. DNA methylation, an epigenetic event, plays an important role in cancer susceptibility. In this paper, we use DNA methylation and gene expression data integration and pathway analysis to further explore and understand the complex relationship between methylation and gene expression. RESULTS: Through linear modeling and analysis of variance, we obtain genes that show a significant correlation between methylation and gene expression. We then examine the functions and relationships of these genes using bioinformatic tools and databases. In particular, using ConsensusPathDB, we analyze the networks of statistically significant genes to identify hub genes, genes with a large number of links to other genes. We identify eight major hub genes, all in strong association with cancer susceptibility. Through further analysis of the function, gene expression level, and methylation level of these hub genes, we conclude that they are novel potential biomarkers for breast cancer. CONCLUSIONS: Our findings have various implications for cancer screening, early detection methods, and potential novel treatments for cancer. Researchers can also use our results to develop more effective methods for cancer study.

11ß-HSD Types 1 and 2 in the Songbird Brain.

Glucocorticoid (GC) hormones act on the brain to regulate diverse functions, from behavior and homeostasis to the activity of the hypothalamic-pituitary-adrenal axis. Local regeneration and metabolism of GCs can occur in target tissues through the actions of the 11ß-hydroxysteroid dehydrogenases [11 beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) and 11 beta-hydroxysteroid dehydrogenase type 2 (11ß-HSD2), respectively] to regulate access to GC receptors. Songbirds have become especially important model organisms for studies of stress hormone action; however, there has been little focus on neural GC metabolism. Therefore, we tested the hypothesis that 11ß-HSD1 and 11ß-HSD2 are expressed in GC-sensitive regions of the songbird brain. Localization of 11ß-HSD expression in these regions could provide precise temporal and spatial control over GC actions. We quantified GC sensitivity in zebra finch (Taeniopygia guttata) brain by measuring glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) expression across six regions, followed by quantification of 11ß-HSD1 and 11ß-HSD2 expression. We detected GR, MR, and 11ß-HSD2 mRNA expression throughout the adult brain. Whereas 11ß-HSD1 expression was undetectable in the adult brain, we detected low levels of expression in the brain of developing finches. Across several adult brain regions, expression of 11ß-HSD2 covaried with GR and MR, with the exception of the cerebellum and hippocampus. It is possible that receptors in these latter two regions require direct access to systemic GC levels. Overall, these results suggest that 11ß-HSD2 expression protects the adult songbird brain by rapid metabolism of GCs in a context and region-specific manner.