Reflections of patient and public involvement from a commissioned research project evaluating a nationally implemented NHS programme focused on diabetes prevention.

Patient and Public Involvement and Engagement (PPIE) in research is recognised by the National Institute for Health and Care Research as crucial for high quality research with practical benefit for patients and carers. Patient and public contributors can provide both personal knowledge and lived experiences which complement the perspectives of the academic research team. Nevertheless, effective PPIE must be tailored to the nature of the research, such as the size and scope of the research, whether it is researcher-led or independently commissioned, and whether the research aims to design an intervention or evaluate it. For example, commissioned research evaluations have potential limits on how PPIE can feed into the design of the research and the intervention. Such constraints may require re-orientation of PPIE input to other functions, such as supporting wider engagement and dissemination. In this commentary, we use the 'Guidance for Reporting Involvement of Patients and the Public' (GRIPP2) short form to share our own experiences of facilitating PPIE for a large, commissioned research project evaluating the National Health Service Diabetes Prevention Programme; a behavioural intervention for adults in England who are at high risk of developing type 2 diabetes. The programme was already widely implemented in routine practice when the research project and PPIE group were established. This commentary provides us with a unique opportunity to reflect on experiences of being part of a PPIE group in the context of a longer-term evaluation of a national programme, where the scope for involvement in the intervention design was more constrained, compared to PPIE within researcher-led intervention programmes. We reflect on PPIE in the design, analysis and dissemination of the research, including lessons learned for future PPIE work in large-scale commissioned evaluations of national programmes. Important considerations for this type of PPIE work include: ensuring the role of public contributors is clarified from the outset, the complexities of facilitating PPIE over longer project timeframes, and providing adequate support to public contributors and facilitators (including training, resources and flexible timelines) to ensure an inclusive and considerate approach. These findings can inform future PPIE plans for stakeholders involved in commissioned research.

Update on Neurodegenerative Diseases and Glutamate: A PMHNP Single Case Study Report of a Diagnostically Complex Adult Patient, Interventions, and Unexpected Outcomes.

OBJECTIVE: While dysfunction of serotonin and dopamine neurotransmitters has been studied in depth, in regard to the etiology of mental illness, the neurotransmitter glutamate and its dysfunction is now being explored as contributing to neurodegenerative psychiatric diseases, schizophrenia, autism, depression, and Alzheimer's disease. This article explains its synthesis, neurotransmission, and metabolism within the brain and subsequent dysfunction that is responsible for neurocognitive loss associated with several psychiatric disorders. METHOD: The case study will report on the screening for pseudobulbar affective (PBA) disorder in a 29-year-old male with bipolar disorder, autism spectrum disorder, and intellectual developmental disability who was experiencing extreme, uncontrolled emotional outbursts requiring continuous family isolation (pre-COVID-19) for safety. With the positive screen for PBA, the patient was subsequently treated with a glutamatergic drug, dextromethorphan/quinidine. RESULTS: The patient's unexpected response to this treatment including the acquisition of language, increased cognition, and improved executive functioning is presented. At 2 years post the initiation of treatment, his PBA screening score is reduced, uncontrolled outbursts and aggression have subsided, and the family can spend time outside of their home. CONCLUSIONS: Neurodegeneration and its impact is being researched and treated with medications affecting glutamate. The addition of a glutamatergic medication to this young man's medication regimen has improved both his and his family's quality of life. The psychiatric diagnoses, medications, and treatments associated with glutamate are explained in depth. The importance of nurses' understanding of glutamate, its synthesis, transmission, and dysfunction causing excitotoxicity and brain cell death and its impact on patients' behavior and safety is explained.

Significant Improvement of Somatic Symptom Disorder With Brief Psychoeducational Intervention by PMHNP in Primary Care.

OBJECTIVE: Patients with somatic symptom disorders (SSD) are prevalent in primary care, urgent care, and emergency rooms and present with reduced quality of life, increased disability, and suicidality . Criteria for SSD include (1) somatic symptoms that cause distress and disrupt life; (2) concurrent physical illness with thoughts and feelings that are disproportionate to the seriousness of the illness; and (3) distress which is persistent and causes suffering. The frequency of SSD in the general population is 5% to 7%; however, in primary care, it is 5% to 35% . Because patients present with anxiety, depression, and/or pain, providers are flummoxed when diagnostic findings do not match symptom intensity. The purpose of this project was to provide an intervention for patients with SSD and measure its effectiveness on their somatic symptoms. METHOD: This study provided a single-session, 30-minute psychoeducational intervention for patients to explain brain pathways for pain and the body's response to stress, including scientific benefits of exercise and healthy diet. Patients were asked questions using the motivational interviewing technique OARS (open-ended question, affirmation, reflection, summary) and were encouraged to talk about their concerns. The study used a pre- and post-intervention visual analogue scale and a self-reported Patient Health Questionnaire-15 both before and 3 weeks post-intervention. RESULTS: Measurements showed significant symptom improvement immediately after the intervention with sustained improvement 3 weeks post-intervention. CONCLUSIONS: This intervention demonstrates an effective treatment for this insidious illness, which plagues up to 35% of patients in primary care.

Evaluating the impact of patient and carer involvement in suicide and self-harm research: A mixed-methods, longitudinal study protocol.

BACKGROUND: Patient and public involvement (PPI) is becoming more commonplace in mental health research. There are strong moral and ethical arguments for good quality PPI. Few studies have documented and evaluated PPI in self-harm and suicide research. Inconsistent reporting of PPI makes it difficult to discern practices that deliver quality, effective and meaningful involvement. It is important to understand and address emotional support needs of PPI members contributing to sensitive topics such as suicide and self-harm. Therefore, this study will examine the effect of PPI on self-harm and suicide research and explore patients', carers' and researchers' experiences and views in relation to the quality of PPI practice and provision of appropriate support for PPI members. METHODS: This protocol outlines the longitudinal, mixed methodological approach that will be taken. Qualitative and quantitative data will be collected via baseline and repeated questionnaires, document review and semi-structured interviews. Both PPI members and researchers will be invited to participate in this study. The two-year data collection period will enable evaluation of PPI throughout the entire research cycle. An integrated approach will be taken to data analysis, using inductive thematic analysis and descriptive and repeated measures analyses, to address specified study aims. DISSEMINATION: Findings from this study will inform practical guidance to support self-harm and suicide researchers in effectively involving people with experiential knowledge in their research. Analyses will offer insight into the effect of PPI throughout the research process and assess changes in PPI members' and researchers' experiences of involvement across a two-year period.

Arginine metabolic control of airway inflammation.

Inducible nitric oxide synthase (iNOS) and arginase-2 (ARG2) share a common substrate, arginine. Higher expression of iNOS and exhaled NO are linked to airway inflammation in patients. iNOS deletion in animal models suggests that eosinophilic inflammation is regulated by arginine metabolism. Moreover, ARG2 is a regulator of Th2 response, as shown by the development of severe eosinophilic inflammation in ARG2-/- mice. However, potential synergistic roles of iNOS and ARG2 in asthma have not been explored. Here, we hypothesized that arginine metabolic fate via iNOS and ARG2 may govern airway inflammation. In an asthma cohort, ARG2 variant genotypes were associated with arginase activity. ARG2 variants with lower arginase activity, combined with levels of exhaled NO, identified a severe asthma phenotype. Airway inflammation was present in WT, ARG2-/-, iNOS-/-, and ARG2-/-/iNOS-/- mice but was greatest in ARG2-/-. Eosinophilic and neutrophilic infiltration in the ARG2-/- mice was abrogated in ARG2-/-/iNOS-/- animals. Similarly, angiogenic airway remodeling was greatest in ARG2-/- mice. Cytokines driving inflammation and remodeling were highest in lungs of asthmatic ARG2-/- mice and lowest in the iNOS-/-. ARG2 metabolism of arginine suppresses inflammation, while iNOS metabolism promotes airway inflammation, supporting a central role for arginine metabolic control of inflammation.

American Society of Hematology 2019 guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients.

BACKGROUND: Venous thromboembolism (VTE) is a common source of perioperative morbidity and mortality. OBJECTIVE: These evidence-based guidelines from the American Society of Hematology (ASH) intend to support decision making about preventing VTE in patients undergoing surgery. METHODS: ASH formed a multidisciplinary guideline panel balanced to minimize bias from conflicts of interest. The McMaster University GRADE Centre supported the guideline-development process, including performing systematic reviews. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations, which were subject to public comment. RESULTS: The panel agreed on 30 recommendations, including for major surgery in general (n = 8), orthopedic surgery (n = 7), major general surgery (n = 3), major neurosurgical procedures (n = 2), urological surgery (n = 4), cardiac surgery and major vascular surgery (n = 2), major trauma (n = 2), and major gynecological surgery (n = 2). CONCLUSIONS: For patients undergoing major surgery in general, the panel made conditional recommendations for mechanical prophylaxis over no prophylaxis, for pneumatic compression prophylaxis over graduated compression stockings, and against inferior vena cava filters. In patients undergoing total hip or total knee arthroplasty, conditional recommendations included using either aspirin or anticoagulants, as well as for a direct oral anticoagulant over low-molecular-weight heparin (LMWH). For major general surgery, the panel suggested pharmacological prophylaxis over no prophylaxis, using LMWH or unfractionated heparin. For major neurosurgery, transurethral resection of the prostate, or radical prostatectomy, the panel suggested against pharmacological prophylaxis. For major trauma surgery or major gynecological surgery, the panel suggested pharmacological prophylaxis over no prophylaxis.

Treatment Adherence in Youth with First-Episode Psychosis: Impact of Family Support and Telehealth Delivery.

Mental health-care delivery to young people with first-episode schizophrenia presents significant challenges especially in underserved areas. This chart review reveals the importance of family support as a predictor for medication and treatment adherence with this vulnerable group. An unexpected disengagement rate of 47% was discovered. It was further discovered that receiving care with telehealth delivery was a significant predictor of lost to follow-up or treatment nonadherence. Recommendations include psychoeducation for families during the initial crisis, initiation of long-acting injectable antipsychotics early in care, a hybrid telehealth intervention with in-home medication delivery, and collaboration with educational, vocational county agencies for employment support. A system of care must be developed to support young people with this severe illness for optimum outcome and protection of long-term cognitive functioning.

Analysis of Emergency Room Visits Reveals a Seriously Mentally Ill, Medically Fragile Population Requiring Strategic Management.

OBJECTIVE: This practice improvement project evaluated the cost of health care services utilized by patients with comorbid mental and physical chronic conditions who were psychiatrically hospitalized but transported for health care services of physical symptoms that developed during their psychiatric hospitalization. METHOD: A retrospective review of invoices to a regional psychiatric hospital for non-psychiatric health services utilized by inpatients revealed high costs of emergency room (ER) visits from July 2016 to June 2017. Medical records for these seriously mentally ill inpatients who visited the ER for evaluation of sudden emergent physical symptoms were reviewed. The collected data were analyzed. RESULTS: ER invoices revealed that 41 visits had been made by 28 patients with a total cost of $308,466.67, of which $258,668.15 was judged to be for the treatment of patients with symptoms of preventable side effect syndromes. This chart review and analysis suggest a need for improved strategic medication management in an integrated model of care. CONCLUSIONS: Polypharmacy was found to be responsible for increased debilitating physical symptoms requiring ER visits for this seriously mentally ill, medically fragile population. An integration of care services for comorbid conditions by advanced practice registered nurses with protocols specifically designed for this population was recommended.

Evaluation of tracer labelled methionine load test in vitamin B-12 deficient adolescent women.

BACKGROUND: Methionine loading test (MLT) has been used primarily to identify defects in transsulfuration of homocysteine in cystathionine beta synthase deficiency. It may not be as useful to evaluate remethylation pathway, in vitamin B-12 and folate deficiencies. OBJECTIVE: We used tracer isotope labelled MLT to interrogate transsulfuration and remethylation independently in vitamin B-12 deficiency. DESIGN: We studied vitamin B-12 deficient women with a tracer labelled MLT before and eleven months after treatment with vitamin B-12. The fractional contribution of [13C]homocysteine to breath CO2 was used as a measure of transsulfuration, and difference in the intracellular enrichment of [13C]methionine and that of [C2H3]methionine as a measure of remethylation of homocysteine. Combined pre- and post-treatment results were analyzed to investigate the association between plasma vitamin B-12 concentrations and measures of homocysteine metabolism. RESULTS: The subjects were 17 years old, with a BMI of 19.4 kg/m2. Treatment with vitamin B-12, 2µg/day increased plasma B-12 from 93 (78.7, 106.2) [median (25th, 75th centiles)] to 161.5 (125.5, 226.2) pmol/L; 44% were below <150pmol/L after treatment. Fasting homocysteine concentration was significantly lower and that of cysteine higher in subjects with B-12 levels >150pmol/L. The tracer estimated transsulfuration of homocysteine was lower and remethylation higher with B-12 levels >150pmol/L when compared with those <150pmol/L. CONCLUSIONS: The tracer labelled MLT in combination with fasting parameters is a robust way to estimate parameters of methionine metabolism and can be used in the field where prime-constant rate infusion studies cannot be done efficiently.

Arginine metabolic endotypes related to asthma severity.

AIMS: Arginine metabolism via inducible nitric oxide synthase (iNOS) and arginase 2 (ARG2) is higher in asthmatics than in healthy individuals. We hypothesized that a sub-phenotype of asthma might be defined by the magnitude of arginine metabolism categorized on the basis of high and low fraction of exhaled nitric oxide (FENO). METHODS: To test this hypothesis, asthmatics (n = 52) were compared to healthy controls (n = 51) for levels of FENO, serum arginase activity, and airway epithelial expression of iNOS and ARG2 proteins, in relation to clinical parameters of asthma inflammation and airway reactivity. In parallel, bronchial epithelial cells were evaluated for metabolic effects of iNOS and ARG2 expression in vitro. RESULTS: Asthmatics with high FENO (≥ 35 ppb; 44% of asthmatics) had higher expression of iNOS (P = 0.04) and ARG2 (P = 0.05) in the airway, indicating FENO is a marker of the high arginine metabolic endotype. High FENO asthmatics had the lowest FEV1% (P < 0.001), FEV1/FVC (P = 0.0002) and PC20 (P < 0.001) as compared to low FENO asthmatics or healthy controls. Low FENO asthmatics had near normal iNOS and ARG2 expression (both P > 0.05), and significantly higher PC20 (P < 0.001) as compared to high FENO asthmatics. In vitro studies to evaluate metabolic effects showed that iNOS overexpression and iNOS+ARG2 co-expression in a human bronchial epithelial cell line led to greater reliance on glycolysis with higher rate of pyruvate going to lactate. CONCLUSIONS: The high FENO phenotype represents a large portion of the asthma population, and is typified by greater arginine metabolism and more severe and reactive asthma.

Supporting public involvement in interview and other panels: a systematic review.

BACKGROUND: Members of the public are increasingly being invited to become members of a variety of different panels and boards. OBJECTIVE: This study aimed to systematically search the literature to identify studies relating to support or training provided to members of the public who are asked to be members of an interview panel. SEARCH STRATEGY: A systematic search for published and unpublished studies was carried out from June to September 2015. The search methods included electronic database searching, reference list screening, citation searching and scrutinizing online sources. INCLUSION CRITERIA: We included studies of any design including published and unpublished documents which outlined preparation or guidance relating to public participants who were members of interview panels or representatives on other types of panels or committees. DATA SYNTHESIS: Results were synthesised via narrative methods. MAIN RESULTS: Thirty-six documents were included in the review. Scrutiny of this literature highlighted ten areas which require consideration when including members of the public on interview panels: financial resources; clarity of role; role in the interview process; role in evaluation; training; orientation/induction; information needs; terminology; support; and other public representative needs such as timing, accessibility and support with information technology. DISCUSSION AND CONCLUSIONS: The results of the review emphasize a range of elements that need to be fully considered when planning the involvement of public participants on interview panels. It highlights potential issues relating to the degree of involvement of public representatives in evaluating/grading decisions and the need for preparation and on-going support.

Increased mitochondrial arginine metabolism supports bioenergetics in asthma.

High levels of arginine metabolizing enzymes, including inducible nitric oxide synthase (iNOS) and arginase (ARG), are typical in asthmatic airway epithelium; however, little is known about the metabolic effects of enhanced arginine flux in asthma. Here, we demonstrated that increased metabolism sustains arginine availability in asthmatic airway epithelium with consequences for bioenergetics and inflammation. Expression of iNOS, ARG2, arginine synthetic enzymes, and mitochondrial respiratory complexes III and IV was elevated in asthmatic lung samples compared with healthy controls. ARG2 overexpression in a human bronchial epithelial cell line accelerated oxidative bioenergetic pathways and suppressed hypoxia-inducible factors (HIFs) and phosphorylation of the signal transducer for atopic Th2 inflammation STAT6 (pSTAT6), both of which are implicated in asthma etiology. Arg2-deficient mice had lower mitochondrial membrane potential and greater HIF-2α than WT animals. In an allergen-induced asthma model, mice lacking Arg2 had greater Th2 inflammation than WT mice, as indicated by higher levels of pSTAT6, IL-13, IL-17, eotaxin, and eosinophils and more mucus metaplasia. Bone marrow transplants from Arg2-deficient mice did not affect airway inflammation in recipient mice, supporting resident lung cells as the drivers of elevated Th2 inflammation. These data demonstrate that arginine flux preserves cellular respiration and suppresses pathological signaling events that promote inflammation in asthma.

Whole body creatine and protein kinetics in healthy men and women: effects of creatine and amino acid supplementation.

Creatine kinetics were measured in young healthy subjects, eight males and seven females, age 20-30 years, after an overnight fast on creatine-free diet. Whole body turnover of glycine and its appearance in creatine was quantified using [1-(13)C] glycine and the rate of protein turnover was quantified using L-ring [(2)H5] phenylalanine. The creatine pool size was estimated by the dilution of a bolus [C(2)H3] creatine. Studies were repeated following a five days supplement creatine 21 g.day(-1) and following supplement amino acids 14.3 g day(-1). Creatine caused a ten-fold increase in the plasma concentration of creatine and a 50 % decrease in the concentration of guanidinoacetic acid. Plasma amino acids profile showed a significant decrease in glycine, glutamine, and taurine and a significant increase in citrulline, valine, lysine, and cysteine. There was a significant decrease in the rate of appearance of glycine, suggesting a decrease in de-novo synthesis (p = 0.006). The fractional and absolute rate of synthesis of creatine was significantly decreased by supplemental creatine. Amino acid supplement had no impact on any of the parameters. This is the first detailed analysis of creatine kinetics and the effects of creatine supplement in healthy young men and women. These methods can be applied for the analysis of creatine kinetics in different physiological states.

Metabolomic Endotype of Asthma.

Metabolomics, the quantification of small biochemicals in plasma and tissues, can provide insight into complex biochemical processes and enable the identification of biomarkers that may serve as therapeutic targets. We hypothesized that the plasma metabolome of asthma would reveal metabolic consequences of the specific immune and inflammatory responses unique to endotypes of asthma. The plasma metabolomic profiles of 20 asthmatic subjects and 10 healthy controls were examined using an untargeted global and focused metabolomic analysis. Individuals were classified based on clinical definitions of asthma severity or by levels of fraction of exhaled NO (FENO), a biomarker of airway inflammation. Of the 293 biochemicals identified in the plasma, 25 were significantly different among asthma and healthy controls (p < 0.05). Plasma levels of taurine, lathosterol, bile acids (taurocholate and glycodeoxycholate), nicotinamide, and adenosine-5-phosphate were significantly higher in asthmatics compared with healthy controls. Severe asthmatics had biochemical changes related to steroid and amino acid/protein metabolism. Asthmatics with high FENO, compared with those with low FENO, had higher levels of plasma branched-chain amino acids and bile acids. Asthmatics have a unique plasma metabolome that distinguishes them from healthy controls and points to activation of inflammatory and immune pathways. The severe asthmatic and high FENO asthmatic have unique endotypes that suggest changes in NO-associated taurine transport and bile acid metabolism.

All-trans retinoic acid induces arginase-1 and inducible nitric oxide synthase-producing dendritic cells with T cell inhibitory function.

Hepatic stellate cells (HSC) are a major source of the immunoregulatory metabolite all-trans retinoic acid (ATRA), which may contribute to the generation of tolerogenic dendritic cells (DCs) in the liver. The present study seeks to clarify the mechanism(s) through which ATRA promotes the development of tolerogenic DCs. Although bone marrow-derived ATRA-treated DCs (RA-DCs) and conventional DCs had comparable surface phenotype, RA-DCs had diminished stimulatory capacity and could directly inhibit the expansion of DC/OVA-stimulated OT-II T cells. Arginase-1 (Arg-1) was found promote suppression because 1) ATRA was a potent inducer of Arg-1 protein and activity, 2) the Arg-1 inhibitor N(w)-hydroxy nor-l-arginine partially reversed suppression, and 3) the suppressive function of RA-DCs was partially compromised using OT-II T cells from GCN2(-/-) mice, which are insensitive to Arg-1. Inducible NO synthase (iNOS), however, was found to be a more significant contributor to RA-DC function because 1) ATRA potentiated the expression of IFN-γ-induced iNOS, 2) suppressive function in RA-DCs was blocked by the iNOS inhibitor N(G)-monomethyl-l-arginine, monoacetate salt, and 3) RA-DCs derived from iNOS(-/-) mice exhibited near complete loss of tolerogenic function, despite sustained Arg-1 activity. The expression of iNOS and the suppressive function of RA-DCs were dependent on both IFN-γ and ATRA. Furthermore, the in vivo behavior of RA-DCs proved to be consistent with their in vitro behavior. Thus, we conclude that ATRA enhances both Arg-1 and iNOS expression in IFN-γ-treated DCs, resulting in a tolerogenic phenotype. These findings elucidate mechanisms through which ATRA may contribute to liver immune tolerance.

Preparing NPs for primary care: unraveling complexity with unfolding cases.

Patients with comorbid mental and physical illnesses often present in the primary care setting. To explore the complexities of caring for these patients, a Behavioral Health Therapeutics course was developed and taught in the first semester of a Doctor of Nursing Practice program. This article describes the research, theories, and curricular innovations used in the online learning environment, which provide the foundation for the course and reflect the essential changes called for in the 2010 Carnegie report. Highlighted in this article is the unfolding case study method using Backward Design by Wiggins and McTighe in the planning phase, Zull's model for engaging the brain in the Implementation phase, and grading criteria created from Tanner's "Case for Cases: A Pedagogy for Developing Habits of Thought" in the evaluation phase.

Methionine and protein metabolism in non-alcoholic steatohepatitis: evidence for lower rate of transmethylation of methionine.

Hepatic metabolism of methionine is the source of cysteine, the precursor of glutathione, the major intracellular antioxidant in the body. Methionine also is the immediate precursor of SAM (S-adenosylmethionine) the key methyl donor for phosphatidylcholine synthesis required for the export of VLDL (very-low-density lipoprotein) triacylglycerols (triglycerides) from the liver. We have examined the kinetics of methionine, its transmethylation and trans-sulfuration with estimates of whole body rate of protein turnover and urea synthesis in clinically stable biopsy-confirmed subjects with NASH (non-alcoholic steatohepatitis). Subjects with NASH were more insulin-resistant and had significantly higher plasma concentrations of usCRP (ultrasensitive C-reactive protein), TNFα (tumour necrosis factor α) and other inflammatory cytokines. There was no significant effect of insulin resistance and NASH on whole body rate of protein turnover [phenylalanine Ra (rate of appearance)] and on the rate of urea synthesis. The rates of methylation of homocysteine and transmethylation of methionine were significantly lower in NASH compared with controls. There was no difference in the rate of trans-sulfuration of methionine between the two groups. Enteric mixed nutrient load resulted in a significant increase in all the measured parameters of methionine kinetics. Heterozygosity for MTHFR (5,10-methylene-tetrahydrofolate reductase) (677C→T) did not have an impact on methionine metabolism. We speculate that, as a result of oxidant stress possibly due to high fatty acid oxidation, the activity of methionine adenosyltransferase is attenuated resulting in a lower rate of transmethylation of methionine and of SAM synthesis. These results are the first evidence for perturbed metabolism of methionine in NASH in humans and provide a rationale for the development of targeted intervention strategies.

Elevated hepatic fatty acid oxidation, high plasma fibroblast growth factor 21, and fasting bile acids in nonalcoholic steatohepatitis.

BACKGROUND: Data from studies in patients with nonalcoholic steatohepatitis (NASH) suggest an increased hepatic fatty acid oxidation. We have previously shown higher fasting plasma bile acid concentrations in patients with NASH. In-vivo and in-vitro studies suggest that bile acids by binding to peroxisome proliferator-activated receptor α activate fibroblast growth factor 21 (FGF21) and increase hepatic fatty acid oxidation. METHODS: Plasma bile acid levels were quantified in healthy controls (n=38) and patients with biopsy-proven NASH (n=36). Plasma concentration of fatty acids, ß-hydroxybutyrate, insulin, glucose, leptin, alanine aminotransferase, FGF21, and 8-hydroxydeoxyguanosine, a measure of oxidative stress, were measured in 16 healthy controls and 10 patients with NASH in the fasted state and in response to 3 h of infusion of intralipid. In a subgroup of these patients (n=6 each), plasma ceramide subspecies were quantified. RESULTS: Fasting plasma bile acids, FGF21, and leptin concentrations were significantly higher in patients with NASH. In response to intralipid infusion there was an increase in plasma ß-hydroxybutyrate and free fatty acid levels in both controls and NASH; however, the ratio of ß-hydroxybutyrate/free fatty acid was higher in NASH (P=0.02). Plasma FGF21 concentration increased in response to intralipid in patients with NASH only (P<0.01). Plasma leptin, insulin, glucose, and alanine transferase concentrations did not change in either group after infusion of intralipid. Increase in total ceramides in response to intralipid was greater in NASH. CONCLUSION: Elevated bile acids and FGF21 may be responsible for the higher hepatic fatty acid oxidation in NASH.