292 results on '"L. McRae"'
Search Results
2. Ex Vivo Modeling of the PC (Protein C) Pathway Using Endothelial Cells and Plasma: A Personalized Approach
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Nadine Schwarz, Jens Müller, Hamideh Yadegari, Hannah L. McRae, Sara Reda, Nasim Shahidi Hamedani, Johannes Oldenburg, Bernd Pötzsch, and Heiko Rühl
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Thrombin ,Humans ,Endothelial Cells ,Cardiology and Cardiovascular Medicine ,Blood Coagulation ,Protein C - Abstract
Background: The endothelial cell–dependent PC (protein C) pathway is critically involved in the regulation of coagulation, anti-inflammatory, and cytoprotective signaling. Its reactivity shows high interindividual variability, and it contributes to prothrombotic disorders, such as the FVL (factor V Leiden) mutation. Methods: Endothelial colony–forming cells (ECFCs) were isolated from heparinized peripheral blood from healthy individuals and FVL carriers. Confluent monolayers of ECFCs were overlaid with plasma, and thrombin formation was initiated by addition of tissue factor (1 pmol/L). Subsequently, thrombin and APC (activated PC) formation rates were measured over time using oligonucleotide-based enzyme capture assays. To induce downregulation of TM (thrombomodulin) expression, ECFCs were stimulated with IL-1β (interleukin 1β). In vivo APC response rates were monitored in study participants after infusion of low-dose rFVIIa (recombinant activated factor VII). Results: The median peak APC concentration was 1.12 nmol/L in experiments with IL-1β stimulated ECFCs and 3.66 nmol/L without IL-1β. Although thrombin formation rates were comparable, APC formation rates were significantly higher in FVL carriers (n=6) compared to noncarriers (n=5) as evidenced by a higher ratio between the area under the curve of APC generation to the area under the curve of thrombin generation (median 0.090 versus 0.031, P =0.017). These ex vivo results were correlated with an increased APC response to rFVIIa-induced thrombin formation in FVL carriers in vivo. Conclusions: Patient-specific ex vivo modeling of the PC pathway was achieved using blood-derived ECFCs. The correlation between in and ex vivo APC response rates confirms that the autologous PC model accurately depicts the in vivo situation.
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- 2023
3. DNA sensor-associated type I interferon signaling is increased in ulcerative colitis and induces JAK-dependent inflammatory cell death in colonic organoids
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Peter Flood, Aine Fanning, Jerzy A. Woznicki, Tadhg Crowley, Andrea Christopher, Alessandra Vaccaro, Aileen Houston, Sheila McSweeney, Sarah Ross, Aileen Hogan, Elizabeth Brint, Agnieszka Skowyra, Milan Bustamante, Monica Ambrose, Gerard Moloney, John MacSharry, Marie-Louise Hammarström, Margot Hurley, Christine Fitzgibbons, Eamonn M. M. Quigley, Fergus Shanahan, Syed A. Zulquernain, Jane McCarthy, G. Steven Dodson, Karim Dabbagh, Bradford L. McRae, Silvia Melgar, and Ken Nally
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Inflammasomes ,Physiology ,Epithelium ,Inflammasome ,Physiology (medical) ,NLR Family, Pyrin Domain-Containing 3 Protein ,Humans ,Janus Kinase Inhibitors ,Cell Death ,Hepatology ,Tumor Necrosis Factor-alpha ,Caspase 1 ,Interleukin-18 ,Gastroenterology ,DNA ,Pyrin ,Caspase Inhibitors ,Nucleotidyltransferases ,Antigens, Differentiation ,Organoids ,DNA-Binding Proteins ,Ulcerative colitis ,JAK inhibitor ,Interferon Type I ,Interferon ,Colitis, Ulcerative - Abstract
DNA sensor pathways can initiate inflammasome, cell death and type I interferon (IFN) signalling in immune-mediated inflammatory diseases (IMIDs); including type I interferonopathies. We investigated the involvement of these pathways in the pathogenesis of ulcerative colitis (UC); by analysing expression of DNA sensor, inflammasome, and type I IFN biomarker genes in colonic mucosal biopsy tissue from control (n=31), inactive UC (n=31), active UC (n=33) and a UC single cell RNA-Seq dataset. The effects of type I IFN (IFN-β), IFN-γ and TNF-α on gene expression, cytokine production and cell death were investigated in human colonic organoids. In organoids treated with cytokines alone, or in combination with NLRP3, caspase or JAK inhibitors, cell death was measured, and supernatants were assayed for IL-1β/IL-18/CXCL10. The expression of DNA sensor pathway genes - PYHIN family members (AIM2, IFI16, MNDA, PYHIN1), as well as ZBP1, cGAS and DDX41 were increased in active UC and expressed in a cell type restricted pattern. Inflammasome genes (CASP1, IL1B, IL18), type I IFN inducers (STING, TBK1, IRF3), IFNB1 and type I IFN biomarker genes (OAS2, IFIT2, MX2) were also increased in active UC. Co-treatment of organoids with IFN-β or IFN-γ and TNFα increased expression of IFI16, ZBP1, CASP1, cGAS and STING, induced cell death and IL-1β/IL-18 secretion. This inflammatory cell death was blocked by the JAK inhibitor tofacitinib but not by inflammasome or caspase inhibitors. Increased type I IFN activity may drive elevated expression of DNA sensor genes and JAK-dependent but inflammasome-independent inflammatory cell death of colonic epithelial cells in UC.
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- 2022
4. Assay for ADAMTS-13 Activity with Flow Cytometric Readout
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Jens Müller, Nasim Shahidi Hamedani, Hannah L. McRae, Heiko Rühl, Johannes Oldenburg, and Bernd Pötzsch
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General Chemical Engineering ,General Chemistry - Abstract
A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS-13) is a metalloprotease that regulates the size of circulating von Willebrand factor (vWF) multimers. Severe lack of ADAMTS-13 activity [10% of normal (0.1 IU/mL)] leads to thrombotic thrombocytopenic purpura (TTP), a specific type of thrombotic microangiopathy (TMA). Timely determination of plasma ADAMTS-13 activity is essential to discriminate TTP from other types of TMA with respect to adequate treatment. Identification of the minimal substrate motif for ADAMTS-13 within the A2 domain of vWF (vWF73) as well as the generation of monoclonal antibodies (mAbs) that specifically recognize the ADAMTS-13 cleavage site enabled the development of a variety of methods for determination of plasma ADAMTS-13 activity. In order to further extend the range of analytical platforms applicable for quantitative determination of plasma ADAMTS-13 activity, a specific, vWF/mAb-based assay with flow cytometric readout was developed and validated. Basic assay characteristics include a total assay time of 80 to 90 min, a near linear dynamic range from 0.005 (lower limit of quantification) to 0.2 IU/mL, and intra- and interassay coefficients of variation below 5 and 30% at input plasma ADAMTS-13 activities of 0.015 and ≤0.050 IU/mL, respectively. When compared to the results obtained with a commercially available quantitative ADAMTS-13 activity ELISA, analysis of 18 plasma samples obtained from patients with suspected TTP revealed full agreement of results with respect to the clinical 0.1 IU/mL TTP threshold. Based on these data, it is assumed that the described assay principle can be successfully transferred to virtually all laboratories that have a flow cytometer available.
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- 2022
5. Evaluating cannabis use risk reduction as an alternative clinical outcome for cannabis use disorder
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Jacob T. Borodovsky, Aimee L. McRae-Clark, Kevin M. Gray, Brian J. Sherman, Michael J. Sofis, and Alan J. Budney
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Adult ,Male ,Marijuana Abuse ,medicine.medical_specialty ,media_common.quotation_subject ,Medicine (miscellaneous) ,Hospital Anxiety and Depression Scale ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Child ,Depression (differential diagnoses) ,Cannabis ,media_common ,biology ,Repeated measures design ,Cannabis use ,Abstinence ,biology.organism_classification ,Clinical trial ,Psychiatry and Mental health ,Clinical Psychology ,Treatment Outcome ,Anxiety ,Female ,medicine.symptom ,Psychology ,Risk Reduction Behavior - Abstract
OBJECTIVE Abstinence is rarely achieved in clinical trials for cannabis use disorder (CUD). Cannabis reduction is associated with functional improvement, but reduction endpoints have not been established, indicating a need to identify and validate clinically meaningful reduction endpoints for assessing treatment efficacy. METHOD Data from a 12-week double-blind randomized placebo-controlled medication trial for cannabis cessation (NCT01675661) were analyzed. Participants (N = 225) were treatment-seeking adults, M = 30.6 (8.9) years old, 70.2% male, and 42.2% Non-White, with CUD who completed 12 weeks of treatment. Frequency (days of use per week) and quantity (grams per using day) were used to define high-, medium-, and low-risk levels. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale and cannabis-related problems were assessed using the Marijuana Problems Scale. General linear models for repeated measures tested associations between the magnitude of risk reduction and functional outcomes from baseline (BL) to end-of-treatment (EOT). RESULTS Cannabis risk levels were sensitive to reductions in use from BL to EOT for frequency- (χ² = 19.35, p = .004) and quantity-based (χ² = 52.06, p < .001) metrics. Magnitude reduction in frequency-based risk level was associated with magnitude decrease in depression (F = 2.76, p = .043, ηp² = .04), anxiety (F = 3.70, p = .013, ηp² = .05), and cannabis-related problems (F = 8.95, p < .001, ηp² = .12). Magnitude reduction in quantity-based risk level was associated with magnitude decrease in anxiety (F = 3.02, p = .031, ηp² = .04) and cannabis-related problems (F = 3.24, p = .023, ηp² = .05). CONCLUSIONS Cannabis use risk levels, as operationalized in this study, captured reductions in use during a clinical trial. Risk level reduction was associated with functional improvement suggesting that identifying risk levels and measuring the change in levels over time may be a viable and clinically meaningful endpoint for determining treatment efficacy. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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- 2022
6. Sex and drug differences in stress, craving and cortisol response to the trier social stress task
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Nathaniel L. Baker, Brian Neelon, Viswanathan Ramakrishnan, Kathleen T. Brady, Kevin M. Gray, Michael E. Saladin, Sudie E. Back, Julianne C. Flanagan, Constance Guille, and Aimee L McRae-Clark
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Pharmacology - Published
- 2022
7. OP073 [Post PICU » Post PICU Psychological Impact]: THE CARING INTENSIVELY STUDY: EXPLORING FAMILY MEMBERS’ PERCEPTIONS OF PSYCHOLOGICAL OUTCOMES 3-YEARS FOLLOWING PICU HOSPITALIZATION
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J. E. Rennick, A. M. Knox, K. Dryden Palmer, M. Campbell Yeo, C. Chambers, D. M. Stack, G. Dougherty, S. C. Treherne, L. Mcrae, M. Ho, and R. Stremler
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Pediatrics, Perinatology and Child Health ,Critical Care and Intensive Care Medicine - Published
- 2022
8. A review of sleep disturbance in adults prescribed medications for opioid use disorder: potential treatment targets for a highly prevalent, chronic problem
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Allison K. Wilkerson and Aimee L. McRae-Clark
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Adult ,Sleep Wake Disorders ,Pediatrics ,medicine.medical_specialty ,media_common.quotation_subject ,Population ,Comorbidity ,Polysomnography ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Insomnia ,Humans ,education ,media_common ,education.field_of_study ,Sleep disorder ,medicine.diagnostic_test ,business.industry ,Addiction ,Opioid use disorder ,General Medicine ,Opioid-Related Disorders ,medicine.disease ,Sleep in non-human animals ,030228 respiratory system ,Self Report ,medicine.symptom ,Sleep ,business ,030217 neurology & neurosurgery - Abstract
Background Sleep disturbance in individuals prescribed medications for opioid use disorder (MOUD) is common, though the nature and progression of such concerns are difficult to discern due to differing terminology and assessment type between studies. Accurately identifying and treating sleep problems in this growing population has the potential to improve comorbidity and other MOUD outcomes. Objective The aim of the present review is to provide an overview of sleep in individuals stabilized on MOUD. Specifically, the following aspects of sleep were reviewed: 1) prevalence of clinically significant sleep disturbance; 2) sleep disturbance compared to findings in those not prescribed MOUD; 3) correlates of sleep disturbance; 4) self-reported sleep compared to objective measures. Method Studies were identified using 6 large databases and included if they contained at least one measure of sleep during MOUD treatment as usual. Studies were excluded if they were case studies, not available in English, or participants were in withdrawal or detoxification. Results Forty-two studies were included and categorized by type of sleep assessment: validated self-report questionnaire; provider-assessed; polysomnography; multi-method. Correlates were included if they were statistically significant (generally p Conclusions This review indicates there is a high prevalence of chronic self-reported sleep disturbance (eg, insomnia symptoms) in this population and suggests quantitative sleep parameters (eg, total sleep time) and respiratory problems during sleep are worse than in the general population. These sleep problems are correlated with psychiatric comorbidity and other substance use. Other correlates (eg, sociodemographic factors) require further study to draw definitive conclusions.
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- 2021
9. Developmental trajectories of alcohol and cannabis concurrent use in a nationally representative sample of United States youths
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Walter Roberts, Melissa R. Schick, Rachel L. Tomko, Aimee L. McRae-Clark, Brian Pittmann, Ralitza Gueorgieva, and Sherry A. McKee
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Pharmacology ,Psychiatry and Mental health ,Pharmacology (medical) ,Toxicology - Published
- 2023
10. Correction to: Consideration of sex and gender differences in addiction medication response
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Sherry A. McKee and Aimee L. McRae-Clark
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Gender Studies ,Endocrinology - Published
- 2022
11. Consideration of sex and gender differences in addiction medication response
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Sherry A. McKee and Aimee L. McRae-Clark
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Male ,Gender Studies ,Nicotine ,Sex Factors ,Endocrinology ,Substance-Related Disorders ,Surveys and Questionnaires ,Humans ,Female ,United States - Abstract
Substance use continues to contribute to significant morbidity and mortality in the United States, for both women and men, more so than any other preventable health condition. To reduce the public health burden attributable to substances, the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism have identified that medication development for substance use disorder is a high priority research area. Furthermore, both Institutes have stated that research on sex and gender differences in substance use medication development is a critical area. The purpose of the current narrative review is to highlight how sex and gender have been considered (or not) in medication trials for substance use disorders to clarify and summarize what is known regarding sex and gender differences in efficacy and to provide direction to the field to advance medication development that is consistent with current NIH ‘sex as a biological variable’ (SABV) policy. To that end, we reviewed major classes of abused substances (nicotine, alcohol, cocaine, cannabis, opioids) demonstrating that, sex and gender have not been well-considered in addiction medication development research. However, when adequate data on sex and gender differences have been evaluated (i.e., in tobacco cessation), clinically significant differences in response have been identified between women and men. Across the other drugs of abuse reviewed, data also suggest sex and gender may be predictive of outcome for some agents, although the relatively low representation of women in clinical research samples limits making definitive conclusions. We recommend the incorporation of sex and gender into clinical care guidelines and improved access to publicly available sex-stratified data from medication development investigations.
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- 2022
12. Whole blood haemostatic function throughout a 28‐day cold storage period: an in vitro study
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Hannah L McRae, Neil Blumberg, Christine Cahill, Chelsea Milito, Majed A. Refaai, and Ferhat Kara
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Blood Platelets ,Cold storage ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Refrigeration ,Free haemoglobin ,Humans ,In vitro study ,Medicine ,Blood Transfusion ,Platelet ,Whole blood ,Hemostasis ,medicine.diagnostic_test ,Platelet Count ,business.industry ,Complete blood count ,Hematology ,General Medicine ,Haemostatic function ,Thromboelastography ,Blood Cell Count ,Thrombelastography ,Blood Preservation ,Anesthesia ,business ,030215 immunology - Abstract
BACKGROUND In recent years, there has been renewed interest in whole blood (WB) transfusion, particularly in damage control resuscitation, in part due to the ability to provide the adequate ratio of blood components in a single transfusion. However, there is insufficient evidence to suggest that WB units maintain their haemostatic function during storage, which could compromise their quality and efficacy if transfused. Here, we evaluate the in vitro haemostatic function of stored WB units over a 28-day refrigeration period. METHODS Standard WB units were collected from healthy volunteers and stored at 4°C for 28 days. Samples were collected from each unit on several days throughout the storage period and tested for complete blood count (CBC), WB aggregation, clot kinetics as measured by thromboelastography (TEG), closure time and plasma-free haemoglobin. RESULTS Throughout the storage period, there were gradual, significant decreases in platelet count and function, including WB aggregation in response to collagen (P
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- 2020
13. Blockade of the G-CSF Receptor Is Protective in a Mouse Model of Renal Ischemia–Reperfusion Injury
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Monther Alhamdoosh, Milica Ng, Jennifer L. McRae, Evelyn J Salvaris, Martin J. Pearse, Peter J. Cowan, Ingela Vikstrom, Anjan K. Bongoni, Nella Fisicaro, and Adriana Baz Morelli
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Male ,Chemokine ,Neutrophils ,Immunology ,Gene Expression ,Inflammation ,Pharmacology ,Kidney ,Protective Agents ,urologic and male genital diseases ,Proinflammatory cytokine ,Mice ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Animals ,Urea ,Immunology and Allergy ,Medicine ,Complement Activation ,Creatinine ,biology ,Renal ischemia ,urogenital system ,business.industry ,Macrophages ,medicine.disease ,Mice, Inbred C57BL ,CXCL1 ,Disease Models, Animal ,medicine.anatomical_structure ,chemistry ,Reperfusion Injury ,Receptors, Granulocyte Colony-Stimulating Factor ,biology.protein ,Kidney Diseases ,Chemokines ,medicine.symptom ,business ,Reperfusion injury ,030215 immunology - Abstract
Ischemia–reperfusion injury (IRI) is a complex inflammatory process that detrimentally affects the function of transplanted organs. Neutrophils are important contributors to the pathogenesis of renal IRI. Signaling by G-CSF, a regulator of neutrophil development, trafficking, and function, plays a key role in several neutrophil-associated inflammatory disease models. In this study, we investigated whether targeting neutrophils with a neutralizing mAb to G-CSFR would reduce inflammation and protect against injury in a mouse model of warm renal IRI. Mice were treated with anti–G-CSFR 24 h prior to 22-min unilateral renal ischemia. Renal function and histology, complement activation, and expression of kidney injury markers, and inflammatory mediators were assessed 24 h after reperfusion. Treatment with anti–G-CSFR protected against renal IRI in a dose-dependent manner, significantly reducing serum creatinine and urea, tubular injury, neutrophil and macrophage infiltration, and complement activation (plasma C5a) and deposition (tissue C9). Renal expression of several proinflammatory genes (CXCL1/KC, CXCL2/MIP-2, MCP-1/CCL2, CXCR2, IL-6, ICAM-1, P-selectin, and C5aR) was suppressed by anti–G-CSFR, as was the level of circulating P-selectin and ICAM-1. Neutrophils in anti–G-CSFR–treated mice displayed lower levels of the chemokine receptor CXCR2, consistent with a reduced ability to traffic to inflammatory sites. Furthermore, whole transcriptome analysis using RNA sequencing showed that gene expression changes in IRI kidneys after anti–G-CSFR treatment were indistinguishable from sham-operated kidneys without IRI. Hence, anti–G-CSFR treatment prevented the development of IRI in the kidneys. Our results suggest G-CSFR blockade as a promising therapeutic approach to attenuate renal IRI.
- Published
- 2020
14. Evaluation of the procoagulant properties of a newly developed platelet modified lysate product
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Chad A. Hudson, Majed A. Refaai, Grace Conley, Sherry L. Spinelli, Hannah L McRae, Neil Blumberg, Craig N. Morrell, and Richard P. Phipps
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Blood Platelets ,Lysis ,Sonication ,Immunology ,Kinetics ,Drug Evaluation, Preclinical ,Platelet Transfusion ,030204 cardiovascular system & hematology ,Andrology ,03 medical and health sciences ,0302 clinical medicine ,Cell-Derived Microparticles ,In vivo ,medicine ,Humans ,Immunology and Allergy ,Platelet ,Blood Coagulation ,Coagulants ,Chemistry ,Hematology ,medicine.disease ,Thrombosis ,Platelet transfusion ,Hemolytic reactions ,030215 immunology - Abstract
Background Platelet transfusion is associated with logistical problems with the national storage guidelines of platelets. This results in decreased function in vivo as a result of the platelet storage lesion, and complications such as allergic or hemolytic reactions and thrombosis. We evaluated a new, freshly prepared platelet modified lysate (PML) product designed to be more procoagulant than fresh and stored platelets. Methods Fresh platelets were concentrated, sonicated, and centrifuged to produce PML. Samples of both washed and unwashed PML were evaluated for particle size, concentration, and activity, and then tested for clot kinetics and thrombin generation. PML samples were also stored at various temperatures for durations up to 6 months and evaluated for clot kinetics and thrombin generation throughout. Results PML showed significantly higher concentration of platelet microparticles, increased procoagulant properties, and increased thrombin generation as compared to fresh and stored platelets. In addition, PML maintained its clot kinetics over a 6-month storage period with variable storage conditions. Conclusions The newly proposed PML product is more procoagulant, stable, and has additional potential applications than currently available platelet products. Further studies will be performed to assess its functions in vivo and to assess thrombotic potential.
- Published
- 2020
15. The effect of oxytocin, gender, and ovarian hormones on stress reactivity in individuals with cocaine use disorder
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Lisa M Nunn, Kathleen T. Brady, Jane E. Joseph, Nathaniel L. Baker, Aimee L. McRae-Clark, and Brian J. Sherman
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Adult ,Male ,Hypothalamo-Hypophyseal System ,endocrine system ,medicine.medical_specialty ,Hydrocortisone ,Pituitary-Adrenal System ,Neuropeptide ,Craving ,Oxytocin ,Placebo ,Article ,Cocaine-Related Disorders ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Gonadal Steroid Hormones ,Administration, Intranasal ,Progesterone ,Pharmacology ,Social stress ,Sex Characteristics ,Estradiol ,business.industry ,Ovary ,Stressor ,Middle Aged ,030227 psychiatry ,Treatment Outcome ,Endocrinology ,Cue reactivity ,Female ,medicine.symptom ,business ,Stress, Psychological ,hormones, hormone substitutes, and hormone antagonists ,030217 neurology & neurosurgery ,Hormone ,medicine.drug - Abstract
RATIONALE: Cocaine use disorder (CUD) is associated with dysregulation of the hypothalamic-pituitary-adrenal axis, which plays a critical role in the human stress response. Men and women with CUD differ in reactivity to social stressors. The hypothalamic neuropeptide oxytocin is involved in anxiolytic and natural reward processes, and has shown therapeutic potential for addictive disorders and stress reduction. OBJECTIVES: To examine the impact of oxytocin (oxytocin (OXY) vs. placebo (PBO)) and gender (female (F) vs. male (M)) on response to a social stress task in individuals with CUD. To explore whether ovarian hormones moderate this stress response. METHODS: One hundred twelve adults with CUD were randomized to receive 40 IU intranasal oxytocin (n = 56) or matching placebo (n = 56). Forty minutes after drug administration, participants were exposed to a social stressor. Generalized linear mixed models were used to examine neuroendocrine (cortisol) and subjective (craving, stress) response at pre-stressor, stressor + 0, + 10, + 30, + 60 min. RESULTS: Gender moderated the effect of oxytocin on neuroendocrine response (p = 0.048); women receiving oxytocin (F + OXY) showed blunted cortisol response compared to the other three groups (F + PBO; M + OXY; M + PBO). There was a main effect of gender on subjective stress response; women reported greater stress following the stressor compared to men (p = 0.016). Oxytocin had no significant effect on craving or stress, and gender did not moderate the effect of oxytocin on either measure. Higher endogenous progesterone was associated with lower craving response in women (p = 0.033). CONCLUSIONS: Oxytocin may have differential effects in men and women with CUD. Women may be at greater risk for relapse in response to social stressors, but ovarian hormones may attenuate this effect.
- Published
- 2020
16. Impact of exercise training status on the fiber type-specific abundance of proteins regulating intramuscular lipid metabolism
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Christopher S. Shaw, Tasman Erftemeyer, Maria G Morales-Scholz, Andrew Aldous, Natasha L. McRae, Courtney Swinton, Robyn M. Murphy, and Kirsten F. Howlett
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Male ,0301 basic medicine ,medicine.medical_specialty ,Physiology ,Biology ,03 medical and health sciences ,Oxygen Consumption ,0302 clinical medicine ,Physiology (medical) ,Lipid droplet ,Internal medicine ,medicine ,Humans ,Muscle, Skeletal ,Exercise ,Fiber type ,Athletes ,Skeletal muscle ,Lipid metabolism ,030229 sport sciences ,Lipid Metabolism ,biology.organism_classification ,Muscle Fibers, Slow-Twitch ,030104 developmental biology ,medicine.anatomical_structure ,Endocrinology ,Physical Endurance - Abstract
Endurance training enhances the capacity for fat oxidation during exercise due to increased utilization of intramuscular lipid (IMCL). This study quantitatively investigated the impact of exercise training status on muscle fiber type-specific abundance of regulatory proteins involved in IMCL utilization. Endurance-trained [ n = 7 subjects, peak oxygen consumption (V̇o2peak) 62.6 ± 4.1 (SD) mL·min−1·kg−1] and non-endurance-trained ( n = 8 subjects, V̇o2peak 44.9 ± 5.3 mL·min−1·kg−1) young men completed an incremental exercise test to determine maximal fat oxidation (MFO) and maximal oxygen uptake. Fiber type-specific IMCL content and protein abundance were assessed with immunofluorescence microscopy and immunoblot analysis of pooled single muscle fibers and whole muscle. Endurance-trained individuals displayed a higher MFO rate (0.45 ± 0.15 vs. 0.19 ± 0.07 g/min, P < 0.05), a greater proportion of type I muscle fibers, and higher IMCL content compared with untrained individuals ( P < 0.05). Adipose triglyceride lipase, hormone-sensitive lipase, perilipin 2, perilipin 5, and hydroxyacyl-coenzyme A dehydrogenase abundances were ~2–3-fold higher in type I muscle fibers compared with type IIa fibers ( P < 0.05). Correspondingly, these lipid proteins and oxidative enzymes were higher in endurance-trained individuals when assessed in whole muscle. MFO rate was strongly related to the proportion of type I fibers ( R = 0.81, P < 0.01). The abundance of proteins involved in the regulation of IMCL storage and oxidation is highly muscle fiber type specific. The increased capacity for fat oxidation in endurance-trained individuals corresponded with increased IMCL content and elevated abundance of lipolytic and oxidative enzymes in combination with a greater proportion of type I muscle fibers. NEW & NOTEWORTHY We have utilized contemporary techniques to compare the fiber type-specific characteristics of skeletal muscle from endurance-trained athletes and untrained individuals. We show that type I muscle fibers have a coordinated upregulation of proteins controlling intramuscular lipid storage, mobilization, and oxidation. Furthermore, the enhanced capacity for intramuscular lipid storage and utilization in endurance-trained individuals is related to the increased expression of lipid regulatory proteins combined with a greater proportion of type I muscle fibers.
- Published
- 2020
17. Depressive symptoms and cannabis use in a placebo-controlled trial of N-Acetylcysteine for adult cannabis use disorder
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Aimee L. McRae-Clark, Caitlyn O. Hood, Kevin M. Gray, Rachel L. Tomko, Nathaniel L. Baker, Susan C. Sonne, Erin A. McClure, Lindsay M. Squeglia, and Amanda K. Gilmore
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Adult ,Male ,Marijuana Abuse ,medicine.medical_specialty ,media_common.quotation_subject ,Placebo-controlled study ,Comorbidity ,Hospital Anxiety and Depression Scale ,Placebo ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Dronabinol ,Cannabis ,media_common ,Pharmacology ,Motivation ,biology ,Depression ,business.industry ,Free Radical Scavengers ,Abstinence ,biology.organism_classification ,medicine.disease ,Acetylcysteine ,030227 psychiatry ,Substance abuse ,Treatment Outcome ,Mood ,Female ,business ,030217 neurology & neurosurgery - Abstract
RATIONALE. Depression is common among individuals with cannabis use disorder (CUD), particularly individuals who present to CUD treatment. Treatments that consider this comorbidity are essential. OBJECTIVES. The goal of this secondary analysis was to examine whether N-Acetylcysteine (NAC) reduced depressive symptoms among adults (age 18–50) with CUD (N=302) and whether the effect of NAC on cannabis cessation varied as a result of baseline levels of depression. Bidirectional associations between cannabis use amount and depression were also examined. METHODS. Data for this secondary analysis were from a National Drug Abuse Treatment Clinical Trials Network (NIDA CTN) multi-site clinical trial for CUD. Adults with CUD (N=302) were randomized to receive 2400 mg of NAC daily or matched placebo for 12 weeks. All participants received abstinence-based contingency management. Cannabis quantity was measured by self-report, and weekly urinary cannabinoid levels (11-nor-9-carboxy-Δ9-tetrahydrocannabinol) confirmed abstinence. Depressive symptoms were measured by the Hospital Anxiety and Depression Scale. RESULTS. Depressive symptoms did not differ between the NAC and placebo groups during treatment. There was no significant interaction between treatment and baseline depression predicting cannabis abstinence during treatment. Higher baseline depression was associated with decreased abstinence throughout treatment and a significant gender interaction suggested that this may be particularly true for females. Cross-lagged panel models suggested that depressive symptoms preceded increased cannabis use amounts (in grams) during the subsequent month. The reverse pathway was not significant (i.e, greater cannabis use preceding depressive symptoms). CONCLUSIONS. Results from this study suggest that depression may be a risk factor for poor CUD treatment outcome and therefore should be addressed in the context of treatment. However, results do not support the use of NAC to concurrently treat co-occurring depressive symptoms and CUD in adults.
- Published
- 2019
18. Epithelial dysfunction is prevented by IL-22 treatment in a Citrobacter rodentium-induced colitis model that shares similarities with inflammatory bowel disease
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Qifan Zhu, Daniel Korenfeld, Abel Suarez-Fueyo, Sean Graham, Liang Jin, Shivesh Punit, Rachael Duffy, Munish Puri, Andrew Caruso, Chenqi Hu, Yu Tian, Bradford L. McRae, Raj Kamath, Lucy Phillips, Annette J. Schwartz-Sterman, Susan Westmoreland, Xiaohong Cao, Marc C. Levesque, Yingtao Bi, Jesus Paez-Cortez, and Radhika Goenka
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Intestines ,Mice, Inbred C57BL ,Mice ,Interleukins ,Immunology ,Enterobacteriaceae Infections ,Immunology and Allergy ,Animals ,Citrobacter rodentium ,Intestinal Mucosa ,Colitis ,Inflammatory Bowel Diseases - Abstract
Inflammatory bowel disease (IBD) is characterized by a dysregulated intestinal epithelial barrier leading to breach of barrier immunity. Here we identified similar protein expression changes between IBD and Citrobacter rodentium-infected FVB mice with respect to dysregulation of solute transporters as well as components critical for intestinal barrier integrity. We attribute the disease associated changes in the model to the emergence of undifferentiated intermediate intestinal epithelial cells. Prophylactic treatment with IL-22.Fc in C. rodentium-infected FVB mice reduced disease severity and rescued the mice from lethality. Multi-omics and solute analyses revealed that IL-22.Fc treatment prevented disease-associated changes including disruption of the solute transporter machinery and restored proper physiological functions of the intestine, respectively. Taken together, we established the disease relevance of the C. rodentium-induced colitis model to IBD, demonstrated the protective role of IL-22 in amelioration of epithelial dysfunction and elucidated the molecular mechanisms with IL-22's effect on intestinal epithelial cells.
- Published
- 2021
19. A preliminary investigation of the role of intraindividual sleep variability in substance use treatment outcomes
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Melissa R. Schick, Danica C. Slavish, Jessica R. Dietch, Sara M. Witcraft, Richard O. Simmons, Daniel J. Taylor, Joshua P. Smith, Sarah W. Book, Aimee L. McRae-Clark, and Allison K. Wilkerson
- Subjects
Adult ,Male ,Psychiatry and Mental health ,Clinical Psychology ,Recurrence ,Substance-Related Disorders ,Sleep Initiation and Maintenance Disorders ,Medicine (miscellaneous) ,Humans ,Female ,Toxicology ,Sleep ,Actigraphy - Abstract
Poor sleep health is common among individuals in early treatment for substance use disorders (SUDs) and may serve an important role in predicting SUD outcomes. However, sleep parameters have been inconsistently linked with risk of relapse, perhaps because previous research has focused on mean values of sleep parameters (e.g., total sleep time [TST], sleep efficiency [SE], and sleep midpoint [SM]) across multiple nights rather than night-to-night fluctuations (i.e., intraindividual variability [IIV]). The current study assessed sleep across the first week of SUD treatment, with the aim of prospectively examining the relationship between mean and IIV of TST, SE, and SM and treatment completion and relapse within one-month post-treatment.Treatment-seeking adults (N = 23, MGreater IIV in TST was associated with higher odds of relapse (OR = 3.55, p =.028). Greater IIV in SM was associated with lower odds of treatment completion, but only when removing mean SM from the model (OR = 0.75, p =.046).Night-to-night variability in actigraphy-measured TST is more strongly associated with SUD treatment outcomes than average sleep patterns across the week. Integrating circadian regulation into treatment efforts to improve SUD treatment outcomes may be warranted. Given the small sample size utilized in the present study, replication of these analyses with a larger sample is warranted.
- Published
- 2021
20. A potent truncated form of human soluble CR1 is protective in a mouse model of renal ischemia–reperfusion injury
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Jennifer L. McRae, Matthew P. Hardy, Martin J. Pearse, Anjan K. Bongoni, Sandra Wymann, Peter J. Cowan, Tony Rowe, Ingela Vikstrom, Nella Fisicaro, Evelyn J Salvaris, and Adriana Baz Morelli
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Male ,Physiology ,Science ,Complement receptor 1 ,Immunology ,Diseases ,Pathogenesis ,Pharmacology ,Kidney ,Article ,Mice ,Mediator ,Pharmacokinetics ,In vivo ,medicine ,Animals ,Humans ,Complement Activation ,Multidisciplinary ,biology ,Renal ischemia ,Chemistry ,medicine.disease ,Kidney Transplantation ,Peptide Fragments ,Complement system ,Mice, Inbred C57BL ,Transplantation ,Disease Models, Animal ,Solubility ,Nephrology ,Reperfusion Injury ,Receptors, Complement 3b ,Medicine ,biology.gene ,Kidney disease - Abstract
The complement system is a potent mediator of ischemia–reperfusion injury (IRI), which detrimentally affects the function and survival of transplanted kidneys. Human complement receptor 1 (HuCR1) is an integral membrane protein that inhibits complement activation by blocking the convertases that activate C3 and C5. We have previously reported that CSL040, a truncated form of recombinant soluble HuCR1 (sHuCR1), has enhanced complement inhibitory activity and improved pharmacokinetic properties compared to the parent molecule. Here, we compared the capacity of CSL040 and full-length sHuCR1 to suppress complement-mediated organ damage in a mouse model of warm renal IRI. Mice were treated with two doses of CSL040 or sHuCR1, given 1 h prior to 22 min unilateral renal ischemia and again 3 h later. 24 h after reperfusion, mice treated with CSL040 were protected against warm renal IRI in a dose-dependent manner, with the highest dose of 60 mg/kg significantly reducing renal dysfunction, tubular injury, complement activation, endothelial damage, and leukocyte infiltration. In contrast, treatment with sHuCR1 at a molar equivalent dose to 60 mg/kg CSL040 did not confer significant protection. Our results identify CSL040 as a promising therapeutic candidate to attenuate renal IRI and demonstrate its superior efficacy over full-length sHuCR1 in vivo.
- Published
- 2021
21. Evaluation of solvent/detergent-treated plasma safety and efficacy in orthotopic liver transplant and thrombotic thrombocytopenic purpura patients: A single center experience
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Hannah L. McRae, Chelsea Milito, Catherine A. Klapheke, and Majed A. Refaai
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Plasma Exchange ,Purpura, Thrombotic Thrombocytopenic ,Immunology ,Detergents ,Solvents ,Immunology and Allergy ,Humans ,Hematology ,Prospective Studies ,Liver Transplantation - Abstract
Solvent/detergent-treated, pooled plasma (SDP) is approved for use in orthotopic liver transplantation (OLT) and thrombotic thrombocytopenic purpura (TTP) patients; however, studies evaluating safety and effectiveness of SDP in these populations are limited.This prospective study included two cohorts: OLT patients (n = 40) who received either SDP (n = 20) or FFP (control group) (n = 20), and TTP patients (n = 20) who received either SDP (n = 10) or FFP (control group) (n = 10) throughout hospitalization. Medical, laboratory, and blood bank records were retroactively assessed for both cohorts for differences in clinical outcomes, laboratory values, and transfusion data from admission to discharge.In the OLT cohort, significant changes in AST and ALP were observed in the control group as compared to SDP (p .05 each), and creatinine levels improved significantly in the SDP group as compared to the control group (p .05) from admission to discharge. In the TTP cohort, platelet counts were significantly improved within the control and SDP groups from admission to discharge, but there were no significant differences between groups (p = .31). LDH levels improved between admission and discharge for both groups (70% decrease in the control group, p .001, and 80% decrease in the SDP group, p = .001). There were no significant differences detected in clinical outcomes in either cohort.As evidenced by the lack of adverse events in either cohort and similar clinical outcomes, we conclude that SDP is comparable in safety and effectiveness to FFP in OLT and TTP patients. Further studies are needed to evaluate the potential for improved safety with SDP.
- Published
- 2021
22. False‐positive heparin‐PF4 latex immunoturbidimetric assay due to lupus anti‐coagulant interference: a case report
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Jozal W. Moore, Jainulabdeen J. Ifthikharuddin, Hannah L McRae, and Majed A. Refaai
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Lupus anticoagulant ,Systemic lupus erythematosus ,business.industry ,Antiphospholipid syndrome ,Heparin-induced thrombocytopenia ,Immunology ,medicine ,Hematology ,Heparin ,medicine.disease ,business ,Interference (genetic) ,medicine.drug - Published
- 2021
23. Imaging the Alternatively Spliced D Domain of Tenascin C in Preclinical Models of Inflammatory Bowel Disease
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Christine M. Nelson, Heather Knight, Jamie Erickson, Bradford L. McRae, Victor Sun, Annette J. Schwartz Sterman, Stephanie M. Gaudette, Grace Lynch, Kristoff T. Homan, Calvin S. Pohl, Sahana Bose, Liang Zhang, and Soumya Mitra
- Subjects
biology ,business.industry ,Tenascin C ,medicine ,Cancer research ,biology.protein ,medicine.disease ,business ,Inflammatory bowel disease ,Domain (software engineering) - Abstract
Purpose To image colon-expressed alternatively spliced D domain of tenascin C in preclinical colitis models using near infrared (NIR) labeled targeted molecular imaging agents.Methods Human IgG and scFv fusion proteins specific to the alternatively spliced D domain of tenascin C were generated. Immunohistochemistry identified disease-specific expression of this extracellular matrix in mouse colitis models. Proteins were labeled with the NIR fluorophore IRDye 800CW via amine chemistry and intravenously dosed to evaluate targeting specificity in preclinical rodent and primate colitis models.Results The NIR labeled proteins successfully targeted colonic lesions in a murine model of colitis and appeared as distinct punctate spots. Co-administration of a blocking dose reduced the whole colon standardized uptake of the fluorescent dose >7-fold in mouse models. Estimates suggest local expression at >100 nM in diseased mouse colon. Macroscopic targeting specificity was not observed in diseased primate colon. Cellular level specificity was assessed via microscopy and immunohistochemistry.Conclusion Our imaging data suggest the alternatively spliced D domain of tenascin C is a promising target for delivery-based applications in inflammatory bowel diseases.
- Published
- 2021
24. Impact of electronic medical record‐based calculation of 4Ts on heparin‐induced thrombocytopenia (HIT) testing: A single center experience
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Mofiyin Obadina, Rialnat Lawal, Frank Akwaa, Majed A. Refaai, and Hannah L McRae
- Subjects
medicine.medical_specialty ,Heparin ,business.industry ,Biochemistry (medical) ,Clinical Biochemistry ,Electronic medical record ,Anticoagulants ,Hematology ,General Medicine ,medicine.disease ,Single Center ,Thrombocytopenia ,Pre- and post-test probability ,Heparin-induced thrombocytopenia ,Emergency medicine ,medicine ,Electronic Health Records ,Humans ,business ,medicine.drug - Published
- 2021
25. Distress tolerance and reactivity to negative affective cues in naturalistic environments of cannabis-using emerging adults
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Kathryn S, Gex, Kevin M, Gray, Aimee L, McRae-Clark, Michael E, Saladin, and Rachel L, Tomko
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Adult ,Cannabinoid Receptor Agonists ,Male ,Pharmacology ,Adolescent ,Environment ,Toxicology ,Article ,Young Adult ,Psychiatry and Mental health ,Hallucinogens ,Humans ,Female ,Pharmacology (medical) ,Cues ,Cannabis ,Craving - Abstract
BACKGROUND. Distress tolerance (DT) has been implicated as an important factor in the experience of negative affect (NA) and cannabis craving. However, previous research is limited by its use of laboratory paradigms that may not replicate in naturalistic settings. The current study examined how DT influenced reactivity to NA cues in daily life in a sample of frequent (≥3 times per week) cannabis-using emerging adults (age 18-21). METHODS. Using cue-reactivity ecological momentary assessment (CREMA), 63 (54% female; 85.7% white; M(age) = 19.62) participants reported on their cannabis craving and affect (sadness, relaxation) four semi-random times per day for two weeks (56 possible CREMA sessions/participant). We assessed affect and cannabis craving before and after exposure to neutral and NA cues. Multilevel modeling was used to examine within- and between-participant effects of cues, DT, and sex, as well as within- and between-participant average pre-cue affect and craving, on post-cue affect and craving. RESULTS. NA cues consistently predicted higher-than-normal post-cue sadness and lower relaxation, but not greater-than-normal post-cue craving. Cue type interacted with sex and DT to predict post-cue sadness, but not craving. Female participants and those reporting low DT reported higher sadness following NA cues compared to males and those with high DT, respectively. CONCLUSIONS. Frequent cannabis-using emerging adults differed in affect, but not cannabis craving, reactivity to NA cues as a function of sex and DT. Our results were partially consistent with prior human laboratory and CREMA research finding greater reactivity to NA cues among females and individuals with low DT.
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- 2022
26. Sex and drug differences in stress, craving and cortisol response to the trier social stress task
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Nathaniel L, Baker, Brian, Neelon, Viswanathan, Ramakrishnan, Kathleen T, Brady, Kevin M, Gray, Michael E, Saladin, Sudie E, Back, Julianne C, Flanagan, Constance, Guille, and Aimee L, McRae-Clark
- Subjects
Male ,Hypothalamo-Hypophyseal System ,Cocaine ,Hydrocortisone ,Humans ,Pituitary-Adrenal System ,Female ,Saliva ,Stress, Psychological ,Craving - Abstract
The hypothalamic-pituitary-adrenal (HPA) axis is a critical hormonal system involved in stress response. A number of studies have investigated the HPA axis response of drug-dependent individuals to stressors. Stress-induced vulnerabilities in the HPA axis may differ in response to chronic use of different substances, possibly leading to different target therapies. There has not been a direct comparison of HPA axis and subjective response between individuals with different types of substance use disorders following a laboratory stress intervention.The primary goal of the current study was to compare subjective and neuroendocrine response to the Trier Social Stress Task (TSST) across multiple primary types of substance use disorders and investigate differential response between males and females.Four hundred participants were drawn from seven studies completed at the Medical University of South Carolina between 2011 and 2021. The TSST was utilized across studies and subjective and neuroendocrine responses measured following completion. Generalized linear mixed effects models and area under the response curve analysis were used to compare both substance type and sex differences.The study groups involving individuals with cocaine use disorder had blunted stress, craving and cortisol response following the TSST as compared to other substance use groups. Females in the cocaine groups reported higher subjective stress but lower cortisol than males.The study results indicate that there may be differential effects of substances on the HPA axis, with cocaine using individuals exhibiting more blunting of the HPA axis response as compared to users of other substances.
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- 2021
27. Sleep and substance use disorder treatment: A preliminary study of subjective and objective assessment of sleep during an intensive outpatient program
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Allison K. Wilkerson, Richard O. Simmons, Daniel J. Taylor, Sarah W. Book, Aimee L. McRae-Clark, Joshua P. Smith, and Gregory L Sahlem
- Subjects
Male ,medicine.medical_specialty ,Substance-Related Disorders ,Population ,Medicine (miscellaneous) ,Alcohol use disorder ,Comorbidity ,Article ,03 medical and health sciences ,0302 clinical medicine ,Sleep Initiation and Maintenance Disorders ,Outpatients ,medicine ,Insomnia ,Humans ,030212 general & internal medicine ,Psychiatry ,education ,education.field_of_study ,Sleep disorder ,business.industry ,Actigraphy ,medicine.disease ,Mental health ,Substance abuse ,Psychiatry and Mental health ,Clinical Psychology ,medicine.symptom ,business ,Sleep ,030217 neurology & neurosurgery - Abstract
BACKGROUND AND OBJECTIVES Characteristics of sleep concerns and their relationship to mental health in heterogeneous substance use disorder (SUD) treatment settings are not well understood. The purpose of this preliminary study was to assess sleep using subjective and objective measures at two time points during SUD treatment and compare sleep changes to changes in mental health measures. METHODS Treatment-seeking participants completed an assessment battery at the beginning of treatment (Time 1, N = 30) and again upon treatment completion (Time 2, approximately 4 weeks later, N = 22). The majority of participants were White (80%), male (63%), and presenting for alcohol use disorder (60.0%), though almost half reported polysubstance abuse (43%). Comorbidity was common (53%). Sleep and mental health questionnaires with 1 week of actigraphy and sleep diaries were completed at both time points. RESULTS Most participants met the criteria for a sleep disorder and mean scores on questionnaires showed poor sleep quality, insomnia symptoms, and frequent nightmares, with sleep quality and insomnia improving over time but remaining clinically significant. Nightmares did not improve. Actigraphy indicated poor sleep at both time points. Improvement in insomnia was related to improvement in measures of mental health while changes in actigraphy variables were not related to these measures. DISCUSSION AND CONCLUSIONS Multiple types of sleep disturbance are prevalent in this population, with nightmares persisting throughout treatment and insomnia symptoms showing a relationship with mental health symptoms. SCIENTIFIC SIGNIFICANCE This was the first study to longitudinally assess mental health with subjective and objective measures of sleep across multiple types of SUDs in a community SUD treatment setting.
- Published
- 2021
28. The impact of lofexidine on stress-related opioid craving and relapse: Design and methodology of a randomized clinical trial
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Nathaniel L. Baker, Courtney E. King, Kathleen T. Brady, Lisa M Nunn, Viswanathan Ramakrishnan, Aimee L. McRae-Clark, Bernadette M. Cortese, Constance Guille, and Taylor Rogers
- Subjects
medicine.medical_specialty ,Hypothalamo-Hypophyseal System ,Pituitary-Adrenal System ,Craving ,Drug overdose ,Clonidine ,Article ,law.invention ,Randomized controlled trial ,law ,Recurrence ,medicine ,Humans ,Pharmacology (medical) ,Adrenergic agonist ,Psychiatry ,Pandemics ,business.industry ,SARS-CoV-2 ,COVID-19 ,Opioid use disorder ,General Medicine ,medicine.disease ,Analgesics, Opioid ,Lofexidine ,medicine.symptom ,business ,Methadone ,medicine.drug ,Buprenorphine - Abstract
Opioid Use Disorders (OUDs) and drug overdose deaths are increasing at alarmingly high rates in the United States. Stress and dysregulation in biologic stress response systems such as the hypothalamic-pituitary-adrenal axis and noradrenergic system appear to play an important role in the pathophysiology of substance use disorders and relapse to drug use, particularly for women. Alpha-2 adrenergic agonist medications effectively decrease noradrenergic activity and have demonstrated benefit in preventing relapse to substance use and decreasing stress-reactivity and craving in cocaine- and nicotine-dependent women, compared to men. Alpha-2 adrenergic agonists may help decrease stress reactivity in individuals with OUDs and prevent relapse to drug use, but gender differences have yet to be systematically explored. We describe the rationale, study design and methodology of a randomized, double-blind, placebo-controlled clinical trial examining gender differences in stress, craving and drug use among adult men and women with OUD taking methadone or buprenorphine and randomly assigned to an alpha-2 adrenergic agonist, lofexidine, compared to placebo. In addition, we describe methods for measuring daily stress, craving and drug use in participant's natural environment as well as participant's physiological (i.e., heart rate, cortisol) and psychological (i.e., stress, craving) response to laboratory social and drug cue stressors. Lastly, we detail methods adopted to sustain research activity while following guidelines for the COVID-19 pandemic. ClinicalTrials.gov Registration Number: NCT03718065.
- Published
- 2021
29. Adherence Across FDA-Approved Medications for Alcohol Use Disorder in a Veterans Administration Population
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Jeffrey E. Korte, James R. Walker, Karen J. Hartwell, and Aimee L. McRae-Clark
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Male ,medicine.medical_specialty ,Health (social science) ,Acamprosate ,Population ,MEDLINE ,Medication adherence ,Alcohol use disorder ,Toxicology ,Medication Adherence ,Food and drug administration ,Disulfiram ,Humans ,Medicine ,education ,Retrospective Studies ,Veterans ,education.field_of_study ,United States Food and Drug Administration ,business.industry ,Extramural ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Naltrexone ,United States ,Treatment ,Alcoholism ,United States Department of Veterans Affairs ,Psychiatry and Mental health ,Emergency medicine ,Female ,business ,Administration (government) ,Alcohol Deterrents - Abstract
OBJECTIVE: U.S. Food and Drug Administration (FDA)–approved medications exist for the treatment of alcohol use disorders. However, their effectiveness depends on proper adherence to the prescribed regimen. Differences in adherence across medications may have implications for clinical outcomes and may provide helpful information in considering treatment options. This study aims to identify significant differences in adherence if present. METHOD: A retrospective chart review was conducted in the Veterans Integrated Service Networks (VISN)-7 region of Veterans Affairs hospital and community-based outpatient clinics within South Carolina and Georgia. Prescriptions of FDA-approved alcohol use disorder medications from 2010 through 2015 were reviewed. Adherence was determined by the proportion of days the veteran had oral or injectable medication available over a 6-month period as noted by medication fills (reported as 0%–100% medication availability). We compared adherence for specific medications using chi-square, t test, logistic regression for dichotomous outcomes, and linear regression for continuous outcomes. RESULTS: A total of 715 subjects and 807 medication trials were included. Mean adherence (percentage of days that medication was available) was 41.3% for disulfiram, 44.7% for acamprosate, 49.8% for oral naltrexone, and 54.6% for extended-release injectable naltrexone. The mean adherence was significantly different between disulfiram and oral naltrexone (p = .002) as well as disulfiram and extended-release injectable naltrexone (p = .004). Adherence of 80% was achieved in 11.9%, 19.4%, 22.7%, and 24.4% of treatment courses with disulfiram, acamprosate, naltrexone, and extended-release injectable naltrexone, respectively. These differences were significant for disulfiram versus oral naltrexone (p = .004) and disulfiram versus extended-release injectable naltrexone (p = .05). CONCLUSIONS: These results demonstrate that overall adherence to medication-assisted treatment for alcohol use disorder is low across all medications. When directly compared, disulfiram had significantly lower adherence than both oral and extended-release injectable naltrexone.
- Published
- 2019
30. Use of an Early Onset-Sepsis Calculator to Decrease Unnecessary NICU Admissions and Increase Exclusive Breastfeeding
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Elizabeth Pesek, Margie Bridges, Michele L. McRae, and Shilpi Chabra
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Male ,medicine.medical_specialty ,Psychological intervention ,Breastfeeding ,Critical Care Nursing ,Chorioamnionitis ,Pediatrics ,Sepsis ,03 medical and health sciences ,0302 clinical medicine ,Practice change ,Early onset sepsis ,Pregnancy ,Intensive Care Units, Neonatal ,030225 pediatrics ,Maternity and Midwifery ,Humans ,Medicine ,Retrospective Studies ,030219 obstetrics & reproductive medicine ,business.industry ,Infant, Newborn ,Antibiotic exposure ,Antibiotic Prophylaxis ,medicine.disease ,Community hospital ,Breast Feeding ,Emergency medicine ,Female ,Neonatal Sepsis ,business - Abstract
Objective To evaluate the effects of use of the Kaiser Neonatal Early-Onset Sepsis Calculator (NEOSC) on NICU admissions, laboratory testing, antibiotic exposure, and exclusive breastfeeding (EBF) rates in full-term neonates exposed to chorioamnionitis. Design Quality improvement project with review of retrospective data. Setting/Local Problem In this single-site, community hospital with approximately 4,000 births per year, all neonates exposed to chorioamnionitis required NICU admission, laboratory evaluation, and empiric antibiotics. Participants Term neonates born to mothers diagnosed with chorioamnionitis identified through the International Classification of Diseases, Tenth Revision codes based on the discharge diagnosis. Intervention/Measurements The baseline retrospective analysis included calculation of sepsis risk with the Kaiser NEOSC through a chart review of neonates exposed to chorioamnionitis from January 1, 2015, to December 31, 2016. We compared the risk for sepsis with actual laboratory testing and antibiotic use and examined EBF before implementation of the use of the NEOSC. Implementation began January 2017; postintervention data were examined at 6 months and 1 year. All cases of neonates exposed to chorioamnionitis after the intervention were reviewed for use of the NEOSC, NICU admission/readmission for sepsis, laboratory testing, use of antibiotics, and EBF. Results In the 12 months after NEOSC use was implemented, NICU admissions, laboratory testing, and antibiotic use decreased. Among all neonates exposed to chorioamnionitis after implementation (N = 74), 68 (93%) were not admitted to the NICU, and only 8 (11%) required laboratory evaluation. Rates of EBF in neonates exposed to chorioamnionitis increased from less than 10% to greater than 50% after implementation. The length of the NICU stay for neonates exposed to chorioamnionitis decreased from an average of 138 to 12 days with no negative consequences. Conclusion Most neonates exposed to chorioamnionitis appeared well and did not require NICU admission, laboratory testing, or antibiotic therapy. Rates of EBF improved after use of NEOSC was implemented. The practice change helped prevent adverse consequences, such as painful interventions and separation of the mother and neonate. No neonates were readmitted for sepsis.
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- 2019
31. In Vitro and In Vivo Comparison of Hemoglobin and Electrolytes Following the Collection of Cell Saver Blood Washed with Either Normal Saline or Plasma-Lyte A
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Jill M, Cholette, Hannah L, McRae, Ron, Angona, Christine, Cahill, Michael F, Swartz, George M, Alfieris, and Majed A, Refaai
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Technique Articles ,Electrolytes ,Hemoglobins ,Erythrocytes ,Humans ,Infant ,Saline Solution - Abstract
Cell saver blood is typically washed with normal saline (NS); however, recent studies have reported decreased red blood cell hemolysis and increased platelet function when a more physiologic washing solution, such as Plasma-Lyte A (PL-A) is used. We evaluated the in vitro and in vivo effects of NS compared to PL-A as washing solutions for cell saver blood in pediatric cardiac surgery. Cell saver blood was re-infused for up to 24 hours post-collection. Laboratory and clinical data were collected from infants receiving cell saver washed with either NS (n = 20) or PL-A (n = 21). Compositions of the cell saver blood were compared between groups at 5 in vitro time points and in vivo patient blood at 24 hours post-bypass. Although there were differences in in vitro laboratory values between groups; 24 hours post-bypass, in vivo results were similar. Our data supports 24-hour reinfusion of cell saver washed with either NS versus PL-A in pediatric cardiac surgery patients, and provides data on the differences in cell saver composition to guide future studies.
- Published
- 2021
32. Efficacy of viscoelastic hemostatic assay testing in patients with sepsis-induced disseminated intravascular coagulation
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Yue Lin Hu, Hannah L McRae, and Majed A. Refaai
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Disseminated intravascular coagulation ,medicine.diagnostic_test ,business.industry ,Hematology ,General Medicine ,Disseminated Intravascular Coagulation ,medicine.disease ,Blood Viscosity ,Thromboelastography ,Sepsis ,Thromboelastometry ,Anesthesia ,Medicine ,Humans ,In patient ,business - Published
- 2021
33. Neurobiology of Marijuana
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Gregory L Sahlem, Aimee L. McRae-Clark, and Brian J. Sherman
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Neuroscience - Published
- 2021
34. Chronic Cannabis Smoking-Enriched Oral Pathobiont Drives Behavioral Changes and Increases β-Amyloid Protein Production in the Brain
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Aimee L. McRae-Clark, Nicolas Funderburg, Eric D. Hamlett, Xiaoyu Fu, Yongxia Wu, Amanda Wagner, Syliva Fitting, Zhenwu Luo, Catrina Robinson, Wangbin Ning, Andreana Benitez, wei jiang, Min Li, and Davide Amato
- Subjects
medicine.medical_specialty ,Cannabis smoking ,Endocrinology ,business.industry ,medicine.medical_treatment ,Internal medicine ,β amyloid protein ,medicine ,business - Abstract
Background Little is known about chronic cannabis smoking-associated oral microbiome and its effects on central nervous system (CNS) functions. Results In the current study, we have analyzed the saliva microbiome in individuals who chronically smoked cannabis with cannabis use disorder and in non-smoking controls. We found that cannabis smoking in humans was associated with oral microbial dysbiosis. The most increased oral bacteria were Streptococcus and Actinomyces genus and the most decreased bacteria were Neisseria genus in chronic cannabis smokers compared to those in non-smokers. To investigate the function of cannabis use-associated microbiome, mice were orally exposured to Actinomyces. meyeri, Actinomyces. odontolyticus, or Neisseria. elongate through oral gavage twice per week for six months which mimics human conditions. Strikingly, oral exposure of Actinomyces meyeri, an oral pathobiont, but not the other two control bactreria, decreased global activity and increased β-amyloid 42 protein production in the mouse brains. Conclusions This is the first study to reveal that cannabis-associated enrichment of Actinomyces meyeri may contribute to a hallmark of neuropathology.
- Published
- 2020
35. Impact of RBC Transfusion on Peripheral Capillary Oxygen Saturation and Partial Pressure of Arterial Oxygen
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Alexa Turgeman, Hannah L McRae, Majed A. Refaai, Neil Blumberg, and Christine Cahill
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Adult ,Male ,Anemia ,Partial Pressure ,chemistry.chemical_element ,030204 cardiovascular system & hematology ,Oxygen ,03 medical and health sciences ,Hemoglobins ,0302 clinical medicine ,In vivo ,Medicine ,Humans ,Aged ,Retrospective Studies ,business.industry ,030208 emergency & critical care medicine ,General Medicine ,Oxygenation ,Middle Aged ,medicine.disease ,Peripheral ,Oxygen Saturation Measurement ,chemistry ,Anesthesia ,Female ,Hemoglobin ,business ,Erythrocyte Transfusion ,Perfusion - Abstract
Objectives RBCs are known to undergo deleterious changes during storage, known as storage lesions, which have been shown to result in decreased oxygen-carrying capacity. However, there is inadequate literature describing the effects of stored RBC allogeneic transfusion on oxygen parameters in vivo. The oxygen standard parameters were retrospectively assessed before and after RBC transfusion. Methods Patients who received 1 RBC transfusion were assessed for hemoglobin (Hb) levels, peripheral capillary oxygen saturation (Spo2), and partial pressure of arterial oxygen (Pao2) from 12 hours before and 24 hours after transfusion. Results In total, 78 patients who were monitored by Spo2 and 28 patients monitored by Pao2 were included in this analysis. Following RBC transfusion, Hb levels increased significantly (P Conclusions This single-center, retrospective study revealed evidence of significantly decreased oxygenation and tissue perfusion after single-unit RBC transfusion, despite corrected Hb levels.
- Published
- 2020
36. Living Planet Report 2020. Bending the curve of biodiversity loss: A deep dive into the Living Planet Index
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V. Marconi, L. McRae, S. Deinet, Ledger, Sophie, and R. Freeman
- Published
- 2020
- Full Text
- View/download PDF
37. The state of clinical outcome assessments for cannabis use disorder clinical trials: A review and research agenda
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Tatiana Ramey, Mallory J E Loflin, Joshua A. Lile, Frances R. Levin, Roger D. Weiss, Ryan Vandrey, Robert H. Dworkin, Barbara J. Mason, Brian D. Kiluk, Kathleen M. Carroll, Deborah S. Hasin, Bernard Le Foll, Erica N. Peters, Ivan D. Montoya, Alan J. Budney, Marilyn A. Huestis, Aimee L. McRae-Clark, Kevin M. Gray, Dennis C. Turk, Dustin C. Lee, Deepak Cyril D'Souza, Eric C. Strain, and Will M. Aklin
- Subjects
Adult ,Male ,medicine.medical_specialty ,Marijuana Abuse ,Biomedical Research ,media_common.quotation_subject ,Toxicology ,Outcome (game theory) ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Clinical endpoint ,Humans ,Pharmacology (medical) ,030212 general & internal medicine ,Intensive care medicine ,media_common ,Cannabis use disorder ,Pharmacology ,Psychomotor learning ,Clinical Trials as Topic ,Motivation ,biology ,business.industry ,Flexibility (personality) ,Abstinence ,biology.organism_classification ,medicine.disease ,Clinical trial ,Patient Outcome Assessment ,Psychiatry and Mental health ,Female ,Cannabis ,Self Report ,business ,030217 neurology & neurosurgery - Abstract
There is considerable variability in the use of outcome measures in clinical trials for cannabis use disorder (CUD), and a lack of consensus regarding optimal outcomes may have hindered development and approval of new pharmacotherapies. The goal of this paper is to summarize an evaluation of assessment measures and clinical endpoints for CUD clinical trials, and propose a research agenda and priorities to improve CUD clinical outcome assessments. The primary recommendation is that sustained abstinence from cannabis should not be considered the primary outcome for all CUD clinical trials as it has multiple limitations. However, there are multiple challenges to the development of a reliable and valid indicator of cannabis reduction, including the lack of a standard unit of measure for the various forms of cannabis and products and the limitations of currently available biological and self-report assessments. Development of a core toolkit of assessments is needed to both allow flexibility for study design, while facilitating interpretation of outcomes across trials. Four primary agenda items for future research are identified to expedite development of improved clinical outcome assessments for this toolkit: (1) determine whether minimally invasive biologic assays could identify an acute level of cannabis use associated with psychomotor impairment or other cannabis-related harms; (2) create an indicator of quantity of cannabis use that is consistent across product types; (3) examine the presence of cannabis-specific functional outcomes; and (4) identify an optimal duration to assess changes in CUD diagnostic criteria.
- Published
- 2019
38. Drug Use is Associated with Anti-CD4 IgG-mediated CD4+ T Cell Death and Poor CD4+ T Cell Recovery in Viral-suppressive HIV-infected Individuals Under Antiretroviral Therapy
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Zhenwu Luo, Sonya L. Heath, Azizul Haque, Zhuang Wan, Lisa Martin, Amanda Wagner, Pingfu Fu, Aimee L. McRae-Clark, Binhua Ling, and Wei Jiang
- Subjects
CD4-Positive T-Lymphocytes ,Male ,0301 basic medicine ,Drug ,Anti-HIV Agents ,media_common.quotation_subject ,T cell ,HIV Infections ,HIV Antibodies ,Article ,Immunoglobulin G ,Pathogenesis ,03 medical and health sciences ,Immune system ,Antiretroviral Therapy, Highly Active ,Virology ,Humans ,Medicine ,media_common ,Antibody-dependent cell-mediated cytotoxicity ,biology ,business.industry ,Antibody-Dependent Cell Cytotoxicity ,virus diseases ,biology.organism_classification ,CD4 Lymphocyte Count ,030104 developmental biology ,Infectious Diseases ,medicine.anatomical_structure ,CD4 Antigens ,Immunology ,biology.protein ,Female ,Cannabis ,business ,CD8 - Abstract
Background: The role and mechanism of drug use or abuse in Antiretroviral Therapy (ART)-treated HIV disease are not completely known. Methods: To investigate the impact of drug use on HIV pathogenesis without confounding by HIV replication and ART adherence, we first analyzed the data from our clinical database in 103 HIV+ subjects with viral-suppressed ART treatment by a multiple regression test. Results: We found that HIV+ drug users had lower CD4+ T cell counts but higher CD8+ T cell counts compared to HIV+ non-drug users, and both drug use and nadir CD4+ T cell counts was independently associated with CD4+ T cell recovery after controlling for sex and age. Next, we enrolled individuals from four study groups, HIV-negative and HIV+ subjects without any substance use, HIV-negative and HIV+ subjects with current illicit drug use (either non-injection cocaine or cannabis). All HIV+ subjects were viral-suppressed with ART treatment (≥ 2 years). Notably, HIV+ drug users had increased plasma anti-CD4 IgG levels compared to the other three study groups which were inversely correlated with decreased CD4+ T cell counts only in HIV+ drug users. There was a significant increase in CD4+ T cell recovery following ART in HIV+ non-drug users but not in HIV+ drug users. Anti-CD4 IgGs purified from plasma of HIV+ drug users induced CD4+ T cell death in vitro through Antibody-Dependent Cytotoxicity (ADCC). Conclusion: These results suggest that drug use prevents immune reconstitution in HIV-infected individuals despite long-term ART treatment and viral suppression.
- Published
- 2018
39. Deficiency of selenoprotein S, an endoplasmic reticulum resident oxidoreductase, impairs the contractile function of fast-twitch hindlimb muscles
- Author
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Zoe M. Smith, Craig R. Wright, Leonard G. Forgan, Sofianos Andrikopoulos, Chia-Heng Weng, Alex B. Addinsall, Nicole Stupka, Xavier A. Conlan, Paul S. Francis, Christopher S. Shaw, and Natasha L. McRae
- Subjects
Adult ,Male ,0301 basic medicine ,Physiology ,Inflammation ,Hindlimb ,Motor Activity ,Endoplasmic Reticulum ,Young Adult ,03 medical and health sciences ,Thioredoxins ,0302 clinical medicine ,Oxidoreductase ,Physiology (medical) ,medicine ,Animals ,Humans ,Muscle Strength ,Selenoproteins ,Mice, Knockout ,chemistry.chemical_classification ,Mice, Inbred BALB C ,Membrane Glycoproteins ,biology ,Endoplasmic reticulum ,Selenoprotein S ,Membrane Proteins ,Endoplasmic Reticulum Stress ,Electric Stimulation ,Cell biology ,Mice, Inbred C57BL ,Muscle Fibers, Slow-Twitch ,030104 developmental biology ,chemistry ,Muscle Fibers, Fast-Twitch ,Body Composition ,Unfolded protein response ,biology.gene ,medicine.symptom ,Thioredoxin ,Carrier Proteins ,Transcription Factor CHOP ,030217 neurology & neurosurgery ,Function (biology) ,Muscle Contraction - Abstract
Selenoprotein S (Seps1) is an endoplasmic reticulum (ER) resident antioxidant implicated in ER stress and inflammation. In human vastus lateralis and mouse hindlimb muscles, Seps1 localization and expression were fiber-type specific. In male Seps1+/− heterozygous mice, spontaneous physical activity was reduced compared with wild-type littermates ( d = 1.10, P = 0.029). A similar trend was also observed in Seps1−/− knockout mice ( d = 1.12, P = 0.051). Whole body metabolism, body composition, extensor digitorum longus (EDL), and soleus mass and myofiber diameter were unaffected by genotype. However, in isolated fast EDL muscles from Seps1−/− knockout mice, the force frequency curve (FFC; 1–120 Hz) was shifted downward versus EDL muscles from wild-type littermates ( d = 0.55, P = 0.002), suggestive of reduced strength. During 4 min of intermittent, submaximal (60 Hz) stimulation, the genetic deletion or reduction of Seps1 decreased EDL force production ( d = 0.52, P < 0.001). Furthermore, at the start of the intermittent stimulation protocol, when compared with the 60-Hz stimulation of the FFC, EDL muscles from Seps1−/− knockout or Seps1+/− heterozygous mice produced 10% less force than those from wild-type littermates ( d = 0.31, P < 0.001 and d = 0.39, P = 0.015). This functional impairment was associated with reduced mRNA transcript abundance of thioredoxin-1 ( Trx1), thioredoxin interacting protein ( Txnip), and the ER stress markers Chop and Grp94, whereas, in slow soleus muscles, Seps1 deletion did not compromise contractile function and Trx1 ( d = 1.38, P = 0.012) and Txnip ( d = 1.27, P = 0.025) gene expression was increased. Seps1 is a novel regulator of contractile function and cellular stress responses in fast-twitch muscles.
- Published
- 2018
40. Parenting outcomes of parenting interventions in integrated substance-use treatment programs: A systematic review
- Author
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Aimee L. McRae-Clark and Angela D. Moreland
- Subjects
Child abuse ,Substance-Related Disorders ,Mothers ,030508 substance abuse ,Medicine (miscellaneous) ,Parenting interventions ,Article ,03 medical and health sciences ,Intervention (counseling) ,Adaptation, Psychological ,Humans ,0501 psychology and cognitive sciences ,Parent-Child Relations ,High prevalence ,Parenting ,Depression ,05 social sciences ,Mental health ,Psychiatry and Mental health ,Clinical Psychology ,Female ,Pshychiatric Mental Health ,Substance use ,0305 other medical science ,Psychology ,Psychosocial ,Substance use treatment ,050104 developmental & child psychology ,Clinical psychology - Abstract
The high prevalence of women in substance use treatment programs with children, and the co-occurring negative physical and mental health outcomes associated with substance use, led to the development of integrated substance use treatment programs that target a range of women-specific issues. Integrated programs typically offer some type of parenting component, although the level of parenting services varies widely. Existing reviews have found positive child and parent outcomes following integrated treatment programs in general, although studies were not selected on the basis of whether they included parenting interventions. Due to the large percentage of substance using parents and research that parenting interventions contribute to decreased maternal substance use, this critical review examines parental outcomes of published studies on integrated programs that specifically include a parenting intervention component, as well as moderators of parenting and parental substance use/relapse. Across the 15 studies identified, this systematic review primarily focused on 8 parenting outcomes, including program retention, substance use, parenting stress, psychosocial adjustment, depression, child abuse potential, parenting behaviors, and parent-child interaction; as well as 5 additional secondary outcomes. The review discusses results on each of these outcomes, as well as retention rates across the parenting interventions.
- Published
- 2018
41. Biological correlates of self-reported new and continued abstinence in cannabis cessation treatment clinical trials
- Author
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Aimee L. McRae-Clark, Kevin M. Gray, Brian J. Sherman, Nathaniel L. Baker, Amanda Wagner, Gregory L. Sahlem, and Kristen Morella
- Subjects
Adult ,Male ,Marijuana Abuse ,medicine.medical_specialty ,Biological correlates ,media_common.quotation_subject ,Single measurement ,Contingency management ,Medical Marijuana ,Urine ,Toxicology ,Article ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,Behavior Therapy ,Internal medicine ,Humans ,Medicine ,Pharmacology (medical) ,Dronabinol ,030212 general & internal medicine ,media_common ,Pharmacology ,biology ,Cannabinoids ,business.industry ,Abstinence ,biology.organism_classification ,Substance Abuse Detection ,Clinical trial ,Psychiatry and Mental health ,Treatment Outcome ,Mixed effects ,Female ,Self Report ,Cannabis ,business ,Biomarkers ,030217 neurology & neurosurgery - Abstract
Background The agreement between self-reported cannabis abstinence with urine cannabinoid concentrations in a clinical trials setting is not well characterized. We assessed the agreement between various cannabinoid cutoffs and self-reported abstinence across three clinical trials, one including contingency management for abstinence. Methods Three cannabis cessation clinical trials where participants reported use and provided weekly urine samples for cannabis and creatinine concentration measurements were included. Bootstrapped data were assessed for agreement between self-reported 7+ day abstinence and urine cannabinoid tests using generalized linear mixed effects models for clustered binary outcomes. One study implemented contingency management for cannabis abstinence. Four hundred and seventy-three participants with 3787 valid urine specimens were included. Urine was analyzed for 11-nor-9-carboxy-Δ9-tetrahydrocannabinol and creatinine using immunoassay methods Biological cutoffs of 50, 100, and 200 ng/ml, as well as changes in CN normalized THCCOOH (25%/50% decrease), were assessed for agreement with self-reported abstinence during the three clinical trials. Results Agreement between measured THCCOOH and self-reported abstinence increases with increasing cutoff concentrations, while the agreement with self-reported non-abstinence decreases with increasing cutoff concentrations. Combining THCCOOH cutoffs with recent changes in CN-THCCOOH provides a better agreement in those self-reporting abstinence. Participants in the studies that received CM for abstinence had a lower agreement between self-reported abstinence and returned to use than those in studies that did not have a contingency management component. Conclusion Using combinations of biological measurements and self-reported abstinence, confirmation of study related abstinence may be verifiable earlier and with greater accuracy than relying on a single measurement.
- Published
- 2018
42. Impact of cannabis legalization on treatment and research priorities for cannabis use disorder
- Author
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Gregory L. Sahlem, Aimee L. McRae-Clark, Kevin M. Gray, Brian J. Sherman, and Rachel L. Tomko
- Subjects
medicine.medical_specialty ,Recreational use ,Article ,03 medical and health sciences ,0302 clinical medicine ,Political science ,medicine ,Humans ,030212 general & internal medicine ,Psychiatry ,health care economics and organizations ,Cannabis ,Legalization ,Cannabis use disorder ,biology ,Public health ,Legislature ,Legislation, Drug ,biology.organism_classification ,medicine.disease ,humanities ,Psychiatry and Mental health ,Marijuana Use ,Public Health ,030217 neurology & neurosurgery - Abstract
An increasing proportion of the world has legalized cannabis for medicinal or recreational use. The legalization trend appears to be continuing. These changes in the legislative landscape may have important health, treatment, and research implications. This review discusses public health outcomes that may be impacted by increases in cannabis availability and use. It additionally considers potential research and treatment priorities in the face of widespread cannabis legalization.
- Published
- 2018
43. Large and Small Assembly: Combining Functional Macromolecules with Small Peptides to Control the Morphology of Skeletal Muscle Progenitor Cells
- Author
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Rui Li, David R. Nisbet, Colin J. Barrow, Richard J. Williams, Natasha L. McRae, Daniel R. McCulloch, Nicole Stupka, and Mitchell Boyd-Moss
- Subjects
0301 basic medicine ,Myoblast proliferation ,Polymers and Plastics ,Cell Survival ,Myoblasts, Skeletal ,Bioengineering ,02 engineering and technology ,Matrix (biology) ,Biomaterials ,03 medical and health sciences ,chemistry.chemical_compound ,Versicans ,Polysaccharides ,Materials Chemistry ,Humans ,Myocyte ,Cell Proliferation ,Syncytium ,Tissue Scaffolds ,biology ,Chemistry ,Fucoidan ,021001 nanoscience & nanotechnology ,Nanostructures ,HEK293 Cells ,030104 developmental biology ,Self-healing hydrogels ,biology.protein ,Biophysics ,Versican ,Peptides ,0210 nano-technology ,C2C12 - Abstract
The material properties of natural tissues, such as skeletal muscle, are highly sophisticated and are synthetically challenging to mimic. Using natural biomacromolecules to functionalize self-assembled peptide (SAP) hydrogels has the potential to increase the utility of these materials by more closely reproducing the natural cellular environment. Here, to demonstrate that a conserved co-assembly pathway can retain distinct function, the biocompatible peptide derivative Fmoc-FRGDF was co-assembled with either a sulfated polysaccharide, fucoidan, or the provisional matrix proteoglycan, versican. Our results demonstrate that thermodynamically driven co-assembly with biologically active macromolecules is facile, stable, and does not affect the final assembled nanostructure. Biologically, the incorporation of these functionally distinct molecules had no effect on C2C12 myoblast proliferation and viability but strongly altered their morphology. The surface area of myoblasts cultured on the fucoidan scaffold was reduced at 24 and 72 h post seeding, with a reduction in the formation of multinucleated syncytia. Myoblasts cultured on versican scaffolds were smaller compared to cells grown on the empty vector scaffolds at 24 h but not 72 h post seeding, with multinucleated syncytia formation being unaffected. This work allows programmed and distinct morphological effects of cell behavior, paving the way for further mechanistic studies.
- Published
- 2018
44. Incremental validity of estimated cannabis grams as a predictor of problems and cannabinoid biomarkers: Evidence from a clinical trial
- Author
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Nathaniel L. Baker, Aimee L. McRae-Clark, Kevin M. Gray, Brian J. Sherman, Erin A. McClure, Susan C. Sonne, and Rachel L. Tomko
- Subjects
Adult ,Male ,Marijuana Abuse ,medicine.medical_specialty ,Adolescent ,Laboratory Procedure ,medicine.medical_treatment ,030508 substance abuse ,Marijuana Smoking ,Toxicology ,Article ,Developmental psychology ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Predictive Value of Tests ,Secondary analysis ,medicine ,Humans ,Pharmacology (medical) ,Dronabinol ,030212 general & internal medicine ,Cannabis ,Pharmacology ,Timeline followback ,biology ,Cannabinoids ,Reproducibility of Results ,Middle Aged ,biology.organism_classification ,medicine.disease ,Clinical trial ,Substance abuse ,Psychiatry and Mental health ,Emergency medicine ,Female ,Self Report ,Cannabinoid ,0305 other medical science ,Psychology ,Incremental validity ,Biomarkers - Abstract
Background Quantifying cannabis use is complex due to a lack of a standardized packaging system that contains specified amounts of constituents. A laboratory procedure has been developed for estimating physical quantity of cannabis use by utilizing a surrogate substance to represent cannabis, and weighing the amount of the surrogate to determine typical use in grams. Method This secondary analysis utilized data from a multi-site, randomized, controlled pharmacological trial for adult cannabis use disorder (N = 300), sponsored by the National Drug Abuse Treatment Clinical Trials Network, to test the incremental validity of this procedure. In conjunction with the Timeline Followback, this physical scale-based procedure was used to determine whether average grams per cannabis administration predicted urine cannabinoid levels (11-nor-9-carboxy-Δ9-tetrahydrocannabinol) and problems due to use, after accounting for self-reported number of days used (in the past 30 days) and number of administrations per day in a 12-week clinical trial for cannabis use disorder. Results Likelihood ratio tests suggest that model fit was significantly improved when grams per administration and relevant interactions were included in the model predicting urine cannabinoid level (X2 = 98.3; p Conclusions This study provides support for the use of a scale-based method for quantifying cannabis use in grams. This methodology may be useful when precise quantification is necessary (e.g., measuring reduction in use in a clinical trial).
- Published
- 2018
45. Sclerosing lipogranulomatosis-induced chronic hypercalcemia and acute pancreatitis
- Author
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Stephan F. Duran, Fiora L. McRae, Edward Prodanovic, and Andrew Villanueva
- Subjects
sclerosing lipogranulomatosis ,medicine.medical_specialty ,business.industry ,pancreatitis ,hypercalcemia ,Case Report ,Dermatology ,medicine.disease ,Gastroenterology ,FMAR, foreign modeling agent reactions ,Internal medicine ,medicine ,Pancreatitis ,Acute pancreatitis ,paraffinoma ,business - Published
- 2019
46. Varenicline as a treatment for cannabis use disorder: A placebo-controlled pilot trial
- Author
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Gregory L Sahlem, Amanda Wagner, Aimee L. McRae-Clark, Kevin M. Gray, Brian J. Sherman, Nathaniel L. Baker, Lindsay M. Squeglia, and Rachel L. Tomko
- Subjects
Marijuana Abuse ,medicine.medical_specialty ,media_common.quotation_subject ,Pilot Projects ,Toxicology ,Placebo ,Article ,chemistry.chemical_compound ,Pharmacotherapy ,Double-Blind Method ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Adverse effect ,Varenicline ,media_common ,Pharmacology ,biology ,business.industry ,Motivational enhancement therapy ,Abstinence ,biology.organism_classification ,Clinical trial ,Psychiatry and Mental health ,chemistry ,Smoking Cessation ,Cannabis ,business - Abstract
Background An efficacious pharmacotherapy for cannabis use disorder (CUD) has yet to be established. This study preliminarily evaluated the safety and efficacy of varenicline for CUD in a proof-of-concept clinical trial. Methods Participants in this 6-week randomized, placebo-controlled pilot trial received either varenicline (n = 35) or placebo (n = 37), added to a brief motivational enhancement therapy intervention. Outcomes included cannabis withdrawal, cannabis abstinence, urine cannabinoid levels, percent cannabis use days, and cannabis sessions per day. Results Both treatment groups noted significant decreases in self-reported cannabis withdrawal, percentage of days used, and use sessions per day during treatment compared to baseline. While this pilot trial was not powered to detect statistically significant between-group differences, participants randomized to varenicline evidenced numerically greater rates of self-reported abstinence at the final study visit [Week 6 intent-to-treat (ITT): Varenicline: 17.1% vs. Placebo: 5.4%; RR = 3.2 (95% CI: 0.7,14.7)]. End-of-treatment urine creatinine corrected cannabinoid levels were numerically lower in the varenicline group and higher in the placebo group compared to baseline [Change from baseline: Varenicline -1.7 ng/mg (95% CI: -4.1,0.8) vs. Placebo: 1.9 ng/mg (95% CI: -0.4,4.3); Δ = 3.5 (95% CI: 0.1,6.9)]. Adverse events related to study treatment did not reveal new safety signals. Conclusions Findings support the feasibility of conducting clinical trials of varenicline as a candidate pharmacotherapy for CUD, and indicate that a full-scale efficacy trial, powered based on effect sizes and variability yielded in this study, is warranted.
- Published
- 2021
47. Consideration of sex as a biological variable in the translation of pharmacotherapy for stress-associated drug seeking
- Author
-
Elizabeth M. Doncheck, Erin L. Martin, Aimee L. McRae-Clark, and Carmela M. Reichel
- Subjects
Neurophysiology and neuropsychology ,Drug ,Translation ,Neuroactive steroid ,Physiology ,media_common.quotation_subject ,Addiction ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Stress ,Bioinformatics ,Biochemistry ,Cellular and Molecular Neuroscience ,Review article ,Endocrinology ,Pharmacotherapy ,Medicine ,RC346-429 ,Molecular Biology ,Endogenous opioid ,media_common ,biology ,Endocrine and Autonomic Systems ,business.industry ,QP351-495 ,biology.organism_classification ,Treatment ,Clinical trial ,Drug development ,Sex ,Neurology. Diseases of the nervous system ,Cannabis ,business ,RC321-571 - Abstract
Stress is a frequent precipitant of relapse to drug use. Pharmacotherapies targeting a diverse array of neural systems have been assayed for efficacy in attenuating stress-induced drug-seeking in both rodents and in humans, but none have shown enough evidence of utility to warrant routine use in the clinic. We posit that a critical barrier in effective translation is inattention to sex as a biological variable at all phases of the research process. In this review, we detail the neurobiological systems implicated in stress-induced relapse to cocaine, opioids, methamphetamine, and cannabis, as well as the pharmacotherapies that have been used to target these systems in rodent models, the human laboratory, and in clinical trials. In each of these areas we additionally describe the potential influences of biological sex on outcomes, and how inattention to fundamental sex differences can lead to biases during drug development that contribute to the limited success of large clinical trials. Based on these observations, we determine that of the pharmacotherapies discussed only α2-adrenergic receptor agonists and oxytocin have a body of research with sufficient consideration of biological sex to warrant further clinical evaluation. Pharmacotherapies that target β-adrenergic receptors, other neuroactive peptides, the hypothalamic-pituitary-adrenal axis, neuroactive steroids, and the endogenous opioid and cannabinoid systems require further assessment in females at the preclinical and human laboratory levels before progression to clinical trials can be recommended.
- Published
- 2021
48. Therapeutic Benefit of Smoked Cannabis in Randomized Placebo-Controlled Studies
- Author
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Aimee L. McRae-Clark and Lynneice L. Bowen
- Subjects
medicine.medical_specialty ,Pain ,Marijuana Smoking ,Medical Marijuana ,Anorexia ,Placebo ,Article ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Quality of life ,law ,Internal medicine ,Clinical endpoint ,Humans ,Medicine ,Pharmacology (medical) ,Dronabinol ,030212 general & internal medicine ,Tetrahydrocannabinol ,Intraocular Pressure ,Randomized Controlled Trials as Topic ,biology ,business.industry ,biology.organism_classification ,Treatment Outcome ,Quality of Life ,Cannabis ,medicine.symptom ,business ,030217 neurology & neurosurgery ,medicine.drug - Abstract
The medicinal use of marijuana has been legalized in 28 states, with a wide range of specificity for approved medical conditions. Even with the emergence of non–combustion-based delivery systems, in 2014, 90% of marijuana users used smoked marijuana. The purpose of this review is to summarize the data available on use of smoked marijuana for medical purposes. A literature search was performed to retrieve randomized controlled trials exploring the efficacy of smoked cannabis for treatment of a medical condition. Studies with the primary endpoint listed as the effect of smoked cannabis on a disease-specific characteristic were included. Open-label studies and studies using other administration methods were excluded. Seven studies met these criteria and were included in this review. Cannabis did not outperform placebo on experimentally evoked pain or times walk test. There is clear evidence that smoked cannabis reduces intraocular pressure, but the effect is too brief (< 4 hours) to be of therapeutic benefit for this chronic disorder. There was also consistent evidence that smoked marijuana, even at lower concentrations of tetrahydrocannabinol, increased total daily calorie intake and number of eating occasions. Neither of the studies with quality of life as secondary outcome measures revealed statistically significantly improved outcomes with cannabis use.
- Published
- 2017
49. P0490 / #1769: THE CARING INTENSIVELY STUDY: FAMILY MEMBERS’ PERCEPTIONS OF PSYCHOLOGICAL OUTCOMES ONE YEAR FOLLOWING PEDIATRIC INTENSIVE CARE UNIT HOSPITALIZATION
- Author
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Karen Dryden-Palmer, Alyssa M. Knox, C. Chambers, Janet E. Rennick, Robyn Stremler, D. Stack, Geoffrey Dougherty, L. Mcrae, S. Treherne, M. Campbell-Yeo, M. Ho, and H. Fudge
- Subjects
Pediatric intensive care unit ,medicine.medical_specialty ,business.industry ,Family medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Critical Care and Intensive Care Medicine ,business - Published
- 2021
50. Repetitive transcranial magnetic stimulation (rTMS) administration to heavy cannabis users
- Author
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Gregory L. Sahlem, Aimee L. McRae-Clark, Robert Malcolm, Mark S. George, and Nathaniel L. Baker
- Subjects
Adult ,Male ,Marijuana Abuse ,medicine.medical_specialty ,medicine.medical_treatment ,Prefrontal Cortex ,Medicine (miscellaneous) ,Craving ,Article ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Double-Blind Method ,medicine ,Humans ,Psychiatry ,Cannabis use disorder ,Cross-Over Studies ,biology ,medicine.disease ,biology.organism_classification ,Transcranial Magnetic Stimulation ,030227 psychiatry ,Transcranial magnetic stimulation ,Psychiatry and Mental health ,Clinical Psychology ,Treatment Outcome ,Female ,Cannabis ,Substance use ,medicine.symptom ,Psychology ,030217 neurology & neurosurgery - Abstract
Cannabis use disorder (CUD) is a common condition with few treatments. Several studies in other substance use disorders have found that applying repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex (DLPFC) decreases cue-elicited craving and possibly decreases use. To date, there have been no studies attempting to use rTMS in CUD.This study was conducted to determine if rTMS could be feasibly delivered to a group of non-treatment seeking CUD participants. Secondarily, the study aimed to estimate the effect of rTMS on craving.In a double-blind, sham-controlled, crossover design, a single session of active or sham rTMS (Left DLPFC, 10 Hz, 110% rMT, 4000 pulses) was delivered during a validated cannabis cue paradigm. Participants crossed over to complete the other condition one week later. The feasibility and tolerability were measured by the rate of retention, and the percentage of participants able to tolerate full dose rTMS, respectively. Craving was measured using the Marijuana Craving Questionnaire (MCQ).Eighteen non-treatment seeking CUD participants were recruited from the community; 16 (three women) completed the trial (89% retained for the three study visits). All of the treatment completers tolerated rTMS at full dose without adverse effects. There was not a significant reduction in the total MCQ when participants received active rTMS as compared to sham rTMS.rTMS can be safely and feasibly delivered to CUD participants, and treatment is well tolerated. A single session of rTMS applied to the DLPFC may not reduce cue-elicited craving in heavy cannabis users.
- Published
- 2017
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