Statewide Policy to Increase Provision of Take-Home Naloxone at Emergency Department Visits for Opioid Overdose, Rhode Island, 2018‒2019.

In 2017, Rhode Island responded to rising overdose deaths by establishing statewide emergency department (ED) treatment standards for opioid overdose and opioid use disorder. One requirement of the policy is that providers prescribe or provide take-home naloxone to anyone presenting to EDs with opioid overdose. Among adults presenting to EDs with opioid overdose from 2018 to 2019, approximately half received take-home naloxone. Receipt of naloxone was associated with administration of naloxone before ED presentation, ED policy certification level, and regional overdose frequency. (Am J Public Health. 2023;113(4):372-377. https://doi.org/10.2105/AJPH.2022.307213).

Opioid Analgesic Use After an Acute Pain Visit: Evidence from a Urolithiasis Patient Cohort.

INTRODUCTION: Urolithiasis causes severe acute pain and is commonly treated with opioid analgesics in the emergency department (ED). We examined opioid analgesic use after episodes of acute pain. METHODS: Using data from a longitudinal trial of ED patients with urolithiasis, we constructed multivariable models to estimate the adjusted probability of opioid analgesic use 3, 7, 30, and 90 days after ED discharge. We used multiple imputation to account for missing data and weighting to account for the propensity to be prescribed an opioid analgesic at ED discharge. We used weighted multivariable regression to compare longitudinal opioid analgesic use for those prescribed vs not prescribed an opioid analgesic at discharge, stratified by reported pain at ED discharge. RESULTS: Among 892 adult ED patients with urolithiasis, 79% were prescribed an opioid analgesic at ED discharge. Regardless of reporting pain at ED discharge, those who were prescribed an opioid analgesic were significantly more likely to report using it one, three, and seven days after the visit in weighted multivariable analysis. Among those who were not prescribed an opioid analgesic, an estimated 21% (not reporting pain at ED discharge) and 30% (reporting pain at discharge) reported opioid analgesic use at day three. Among those prescribed an opioid analgesic, 49% (no pain at discharge) and 52% (with pain at discharge) reported using an opioid analgesic at day three. CONCLUSION: Urolithiasis patients who received an opioid analgesic at ED discharge were more likely to continue using an opioid analgesic than those who did not receive a prescription at the initial visit, despite the time-limited nature of urolithiasis.

Protocol for mindfulness-oriented recovery enhancement (MORE) in the management of lumbosacral radiculopathy/radiculitis symptoms: A randomized controlled trial.

Introduction: Lumbosacral radiculopathy/radiculitis (LR) or "sciatica" is a commonly intractable sequelae of chronic low back pain (LBP), and challenges in the treatment of LR indicate that persistent pain may have both mechanical and neuropathic origins. Mindfulness-based interventions have been demonstrated to be effective tools in mitigating self-reported pain in LBP patients. This paper describes the protocol for a randomized controlled trial (RCT) evaluating the effects of the specific mindfulness-based intervention Mindfulness-Oriented Recovery Enhancement (MORE) on LR symptoms and sequelae, including mental health and physical function. Methods: Participants recruited from the Portland, OR area are screened before completing a baseline visit that includes a series of self-report questionnaires and surface electromyography (sEMG) of the lower extremity. Upon enrollment, participants are randomly assigned to the MORE (experimental) group or treatment as usual (control) group for 8 weeks. Self-reported assessments and sEMG studies are repeated after the intervention is complete for pre/post-intervention comparisons. The outcome measures evaluate self-reported pain, physical function, quality of life, depression symptoms, trait mindfulness, and reinterpretation of pain, with surface electromyography (sEMG) findings evaluating objective physical function in patients with LR. To our knowledge, this is the first trial to date using an objective measure, sEMG, to evaluate the effects of a mindfulness-based intervention on LR symptoms. Hypotheses: We hypothesize that MORE will be effective in improving self-reported pain, physical function, quality of life, depression symptoms, mindfulness, and reinterpretation of pain scores after 8 weeks of mindfulness training as compared to treatment as usual. Additionally, we hypothesize that individuals in the MORE group with abnormal sEMG findings at baseline will have improved sEMG findings at their 8-week follow-up visit.

Implementation and maintenance of an emergency department naloxone distribution and peer recovery specialist program.

STUDY OBJECTIVE: Emergency department (ED)-based naloxone distribution and peer-based behavioral counseling have been shown to be feasible, but little is known about utilization maintenance over time and clinician, patient, and visit level factors influencing implementation. METHODS: We conducted a retrospective cohort study of an ED overdose prevention program providing take-home naloxone, behavioral counseling, and treatment linkage for patients treated for an opioid overdose at two Rhode Island EDs from 2017 to 2020: one tertiary referral center and a community hospital. Utilizing a Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework, we evaluated program reach, adoption, implementation modifiers, and maintenance using logistic and Poisson regression. RESULTS: Seven hundred forty two patients were discharged after an opioid overdose, comprising 966 visits (median: 32 visits per month; interquartile range: 29, 41). At least one intervention was provided at most (86%, 826/966) visits. Take-home naloxone was provided at 69% of visits (637/919). Over half (51%, 495/966) received behavioral counseling and treatment referral (65%, 609/932). Almost all attending physicians provided take-home naloxone (97%, 105/108), behavioral counseling (95%, 103/108), or treatment referral (95%, 103/108) at least once. Most residents and advanced practice practitioners (APPs) provided take home naloxone (78% residents; 72% APPs), behavioral counseling (76% residents; 67% APPs), and treatment referral (80% residents; 81% APPs) at least once. Most clinicians provided these services for over half of the opioid overdose patients they cared for. Patients were twice as likely to receive behavioral counseling when treated by an attending in combination with a resident and/or APP (adjusted odds ratio: 2.29; 95% confidence interval, 1.68, 3.12) compared to an attending alone. There was no depreciation in use over time. CONCLUSIONS: ED naloxone distribution, behavioral counseling, and referral to treatment can be successfully integrated into usual emergency care and maintained over time with high reach and adoption. Further work is needed to identify low-cost implementation strategies to improve services use and dissemination across clinical settings.

Opioid Analgesics and Persistent Pain After an Acute Pain Emergency Department Visit: Evidence from a Cohort of Suspected Urolithiasis Patients.

BACKGROUND: Severe acute pain is still commonly treated with opioid analgesics in the United States, but this practice could prolong the duration of pain. OBJECTIVES: Estimate the risk of experiencing persistent pain after opioid analgesic use after emergency department (ED) discharge among patients with suspected urolithiasis. METHODS: We analyzed data collected for a longitudinal, multicenter clinical trial of ED patients with suspected urolithiasis. We constructed multilevel models to estimate the odds ratios (ORs) of reporting pain at 3, 7, 30, or 90 days after ED discharge, using multiple imputation to account for missing outcome data. We controlled for clinical, demographic, and institutional factors and used weighting to account for the propensity to be prescribed an opioid analgesic at ED discharge. RESULTS: Among 2413 adult ED patients with suspected urolithiasis, 62% reported persistent pain 3 days after discharge. Participants prescribed an opioid analgesic at discharge were OR 2.51 (95% confidence interval [CI] 1.82-3.46) more likely to report persistent pain than those without a prescription. Those who reported using opioid analgesics 3 days after discharge were OR 2.24 (95% CI 1.77-2.84) more likely to report pain at day 7 than those not using opioid analgesics at day 3, and those using opioid analgesics at day 30 had OR 3.25 (95% CI 1.96-5.40) greater odds of pain at day 90. CONCLUSIONS: Opioid analgesic prescription doubled the odds of persistent pain among ED patients with suspected urolithiasis. Limiting opioid analgesic prescribing at ED discharge for these patients might prevent persistent pain in addition to limiting access to these medications.

Does younger age at marriage affect divorce? Evidence from Johnson's Executive Order 11241.

Before President Johnson's Executive Order 11241 in August 1965, married men received lower draft priority for military service. As the Vietnam War escalated in the summer of 1965, anecdotal evidence suggests draft-eligible men sought marriage to lower their likelihood of serving. This paper quantifies the effects of these Vietnam-era policies on marriage and finds that they significantly reduced the age at first marriage and altered the choice of spouse. However, younger marriages induced by the war were less likely to result in divorce 15 years later. Evidence also suggests that these younger marriages had little effect on long-term outcomes.

Rhode Island's Opioid Overdose Hospital Standards and Emergency Department Naloxone Distribution, Behavioral Counseling, and Referral to Treatment.

STUDY OBJECTIVE: We sought to determine the influence of the Levels of Care for Rhode Island Emergency Departments and Hospitals for Treating Overdose and Opioid Use Disorder (Levels of Care) on emergency department (ED) provision of take-home naloxone, behavioral counseling, and referral to treatment. METHODS: A retrospective analysis of Rhode Island ED visits for opioid overdose from 2017 to 2018 was performed using data from a statewide opioid overdose surveillance system. Changes in provision of take-home naloxone, behavioral counseling, and referral to treatment before and after Levels of Care implementation were assessed using interrupted time series analysis. We compared outcomes by hospital type using multivariable modified Poisson regression models with generalized estimating equation estimation to account for hospital-level variation. RESULTS: We analyzed 245 overdose visits prior to Levels of Care implementation (January to March 2017) and 1340 overdose visits after implementation (hospital certification to December 2018). After implementation, the proportion of patients offered naloxone increased on average by 13% (95% confidence interval [CI] 5.6% to 20.4%). Prior to implementation, the proportion of patients receiving behavioral counseling and treatment referral was declining. After implementation, this decline slowed and stabilized, and on average 18.6% more patients received behavioral counseling (95% CI 1.3% to 35.9%) and 23.1% more patients received referral to treatment (95% CI 2.7% to 43.5%). Multivariable analysis showed that after implementation, there was a significant increase in the likelihood of being offered naloxone at Level 1 (adjusted relative risk [aRR] 1.31 [95% CI 1.06 to 1.61]) and Level 3 (aRR 3.13 [95% CI 1.08 to 9.06]) hospitals and an increase in referrals for medication for opioid use disorder (from 2.5% to 17.8%) at Level 1 hospitals (RR 7.73 [95% CI 3.22 to 18.55]). Despite these increases, less than half of the patients treated for an opioid overdose received behavioral counseling or referral to treatment CONCLUSION: The establishment of ED policies for treatment and services after opioid overdose improved naloxone distribution, behavioral counseling, and referral to treatment at hospitals without previously established opioid overdose services. Future investigations are needed to better characterize implementation barriers and evaluate policy influence on patient outcomes.

Racialized algorithms for kidney function: Erasing social experience.

The rise of evidence-based medicine, medical informatics, and genomics --- together with growing enthusiasm for machine learning and other types of algorithms to standardize medical decision-making --- has lent increasing credibility to biomedical knowledge as a guide to the practice of medicine. At the same time, concern over the lack of attention to the underlying assumptions and unintended health consequences of such practices, particularly the widespread use of race-based algorithms, from the simple to the complex, has caught the attention of both physicians and social scientists. Epistemological debates over the meaning of "the social" and "the scientific" are consequential in discussions of race and racism in medicine. In this paper, we examine the socio-scientific processes by which one algorithm that "corrects" for kidney function in African Americans became central to knowledge production about chronic kidney disease (CKD). Correction factors are now used extensively and routinely in clinical laboratories and medical practices throughout the US. Drawing on close textual analysis of the biomedical literature, we use the theoretical frameworks of science and technology studies to critically analyze the initial development of the race-based algorithm, its uptake, and its normalization. We argue that race correction of kidney function is a racialized biomedical practice that contributes to the consolidation of a long-established hierarchy of difference in medicine. Consequentially, correcting for race in the assessment of kidney function masks the complexity of the lived experience of societal neglect that damages health.

Variation in opioid analgesia administration and discharge prescribing for emergency department patients with suspected urolithiasis.

OBJECTIVE: Previous research has suggested caution about opioid analgesic usage in the emergency department (ED) setting and raised concerns about variations in prescription opioid analgesic usage, both across institutions and for whom they are prescribed. We examined opioid analgesic usage in ED patients with suspected urolithiasis across fifteen participating hospitals. METHODS: This is a secondary analysis of a clinical trial including adult ED patients with suspected urolithiasis. In multilevel models accounting for clustering by hospital, we assessed demographic, clinical, state-level, and hospital-level factors associated with opioid analgesic administration during the ED visit and prescription at discharge. RESULTS: Of 2352 participants, 67% received an opioid analgesic during the ED visit and 61% were prescribed one at discharge. Opioid analgesic usage varied greatly across hospitals, ranging from 46% to 88% (during visit) and 34% to 85% (at discharge). Hispanic patients were less likely than non-Hispanic white patients to receive opioid analgesics during the ED visit (OR 0.72, 95% CI 0.55-0.94). Patients with higher education (OR 1.29, 95% CI 1.05-1.59), health insurance coverage (OR 1.27, 95% CI 1.02-1.60), or receiving care in states with a prescription drug monitoring program (OR 1.64, 95% CI 1.06-2.53) were more likely to receive an opioid analgesic prescription at ED discharge. CONCLUSION: We found marked hospital-level differences in opioid analgesic administration and prescribing, as well as associations with education, healthcare insurance, and race/ethnicity groups. These data might compel clinicians and hospitals to examine their opioid use practices to ensure it is congruent with accepted medical practice.

Mindfulness and cardiovascular health: Qualitative findings on mechanisms from the mindfulness-based blood pressure reduction (MB-BP) study.

BACKGROUND: Mindfulness-based programs hold promise for improving cardiovascular health (e.g. physical activity, diet, blood pressure). However, despite theoretical frameworks proposed, no studies have reported qualitative findings on how study participants themselves believe mindfulness-based programs improved their cardiovascular health. With an emphasis on in-depth, open-ended investigation, qualitative methods are well suited to explore the mechanisms underlying health outcomes. The objective of this qualitative study was to explore the mechanisms through which the mindfulness-based program, Mindfulness-Based Blood Pressure Reduction (MB-BP), may influence cardiovascular health. METHODS: This qualitative study was conducted as part of a Stage 1 single arm trial with one-year follow-up. The MB-BP curriculum was adapted from Mindfulness-Based Stress Reduction to direct participants' mindfulness skills towards modifiable determinants of blood pressure. Four focus group discussions were conducted (N = 19 participants), and seven additional participants were selected for in-depth interviews. Data analysis was conducted using the standard approach of thematic analysis. Following double-coding of audio-recorded transcripts, four members of the study team engaged in an iterative process of data analysis and interpretation. RESULTS: Participants identified self-awareness, attention control, and emotion regulation as key mechanisms that led to improvements in cardiovascular health. Within these broader themes, many participants detailed a process beginning with increased self-awareness to sustain attention and regulate emotions. Many also explained that the specific relationship between self-awareness and emotion regulation enabled them to respond more skillfully to stressors. In a secondary sub-theme, participants suggested that higher self-awareness helped them engage in positive health behaviors (e.g. healthier dietary choices). CONCLUSION: Qualitative analyses suggest that MB-BP mindfulness practices allowed participants to engage more effectively in self-regulation skills and behaviors lowering cardiovascular disease risk, which supports recent theory. Results are consistent with quantitative mechanistic findings showing emotion regulation, perceived stress, interoceptive awareness, and attention control are influenced by MB-BP.

Mindfulness-Based Blood Pressure Reduction (MB-BP): Stage 1 single-arm clinical trial.

BACKGROUND AND OBJECTIVES: Impacts of mindfulness-based programs on blood pressure remain equivocal, possibly because the programs are not adapted to engage with determinants of hypertension, or due to floor effects. Primary objectives were to create a customized Mindfulness-Based Blood Pressure Reduction (MB-BP) program, and to evaluate acceptability, feasibility, and effects on hypothesized proximal self-regulation mechanisms. Secondary outcomes included modifiable determinants of blood pressure (BP), and clinic-assessed systolic blood pressure (SBP). METHODS: This was a Stage 1 single-arm trial with one year follow-up. Focus groups and in-depth interviews were performed to evaluate acceptability and feasibility. Self-regulation outcomes, and determinants of BP, were assessed using validated questionnaires or objective assessments. The MB-BP curriculum was adapted from Mindfulness-Based Stress Reduction to direct participants' mindfulness skills towards modifiable determinants of blood pressure. RESULTS: Acceptability and feasibility findings showed that of 53 eligible participants, 48 enrolled (91%). Of these, 43 (90%) attended at least 7 of the 10 MB-BP classes; 43 were followed to one year (90%). Focus groups (n = 19) and semi-structured interviews (n = 10) showed all participants viewed the delivery modality favorably, and identified logistic considerations concerning program access as barriers. A priori selected primary self-regulation outcomes showed improvements at one-year follow-up vs. baseline, including attention control (Sustained Attention to Response Task correct no-go score, p<0.001), emotion regulation (Difficulties in Emotion Regulation Score, p = 0.02), and self-awareness (Multidimensional Assessment of Interoceptive Awareness, p<0.001). Several determinants of hypertension were improved in participants not adhering to American Heart Association guidelines at baseline, including physical activity (p = 0.02), Dietary Approaches to Stop Hypertension-consistent diet (p<0.001), and alcohol consumption (p<0.001). Findings demonstrated mean 6.1 mmHg reduction in SBP (p = 0.008) at one year follow-up; effects were most pronounced in Stage 2 uncontrolled hypertensives (SBP≥140 mmHg), showing 15.1 mmHg reduction (p<0.001). CONCLUSION: MB-BP has good acceptability and feasibility, and may engage with self-regulation and behavioral determinants of hypertension.

Blood Donation, Sexual Practices, and Self-Perceived Risk for HIV in the United States Among Young Adult Men Who Have Sex With Men.

OBJECTIVES: In the United States, all men who have sex with men (MSM) were banned from donating blood from 1985 through 2015. In 2016, the guideline was amended such that men who had sexual contact with other men within the previous 12 months could not donate blood. We aimed to identify blood donation practices and their relationship with HIV risk and testing among young adult MSM (YMSM) at risk for having HIV. METHODS: In 2014, we recruited HIV-negative non-Hispanic black, Hispanic, and non-Hispanic white YMSM aged 18-24 from across the United States through social media platforms to complete an online survey. Among these YMSM who previously donated blood, we conducted a secondary analysis examining the relationship between having donated blood within the past 12 months and sexual risk behavior from recent condomless anal intercourse (CAI), HIV testing, and self-perceived risk of having an undiagnosed HIV infection. RESULTS: Of the 2261 YMSM surveyed, 1104 (48.8%) had ever previously donated blood and 305 (13.5%) had donated blood within the past 12 months. Of the 305 blood donors, 50 (16.4%) had ever had CAI before their most recent blood donation. Among YMSM who donated blood, past-12-month blood donation was more likely among YMSM who never had CAI (adjusted odds ratio [aOR] = 1.84; 95% confidence interval [CI], 1.24-2.73) than among YMSM who had CAI and more likely among YMSM who believed it was not possible at all that they had an undiagnosed HIV infection (aOR = 1.57; 95% CI, 1.14-2.16) than among YMSM who believed there was any possibility of having an undiagnosed HIV infection; it was not related to past-12-month HIV testing. CONCLUSIONS: YMSM donated blood frequently, suggesting that the deferral process in place did not prevent YMSM from donating blood. The current donor screening process should be reconsidered if it is to prevent YMSM from donating blood. Future research could identify screening questions that permit YMSM with a low risk of HIV infection to donate blood while maintaining the safety of the blood supply.

Small and large size for gestational age and neighborhood deprivation measured within increasing proximity to homes.

Neighborhood deprivation is consistently associated with greater risk of low birthweight. However, large birth size is increasingly relevant but overlooked in neighborhood health research, and proximity within which neighborhood deprivation may affect birth outcomes is unknown. We estimated race/ethnic-specific effects of neighborhood deprivation index (NDI) within 1, 3, 5, and 8km buffers around Oregon Pregnancy Risk Assessment Monitoring System (n=3716; 2004-2007) respondents׳ homes on small and large for gestational age (SGA, LGA). NDI was positively associated with LGA and SGA in most race/ethnic groups. The results varied little across the four buffer sizes.

Successful adaptation to ketosis by mice with tissue-specific deficiency of ketone body oxidation.

During states of low carbohydrate intake, mammalian ketone body metabolism transfers energy substrates originally derived from fatty acyl chains within the liver to extrahepatic organs. We previously demonstrated that the mitochondrial enzyme coenzyme A (CoA) transferase [succinyl-CoA:3-oxoacid CoA transferase (SCOT), encoded by nuclear Oxct1] is required for oxidation of ketone bodies and that germline SCOT-knockout (KO) mice die within 48 h of birth because of hyperketonemic hypoglycemia. Here, we use novel transgenic and tissue-specific SCOT-KO mice to demonstrate that ketone bodies do not serve an obligate energetic role within highly ketolytic tissues during the ketogenic neonatal period or during starvation in the adult. Although transgene-mediated restoration of myocardial CoA transferase in germline SCOT-KO mice is insufficient to prevent lethal hyperketonemic hypoglycemia in the neonatal period, mice lacking CoA transferase selectively within neurons, cardiomyocytes, or skeletal myocytes are all viable as neonates. Like germline SCOT-KO neonatal mice, neonatal mice with neuronal CoA transferase deficiency exhibit increased cerebral glycolysis and glucose oxidation, and, while these neonatal mice exhibit modest hyperketonemia, they do not develop hypoglycemia. As adults, tissue-specific SCOT-KO mice tolerate starvation, exhibiting only modestly increased hyperketonemia. Finally, metabolic analysis of adult germline Oxct1(+/-) mice demonstrates that global diminution of ketone body oxidation yields hyperketonemia, but hypoglycemia emerges only during a protracted state of low carbohydrate intake. Together, these data suggest that, at the tissue level, ketone bodies are not a required energy substrate in the newborn period or during starvation, but rather that integrated ketone body metabolism mediates adaptation to ketogenic nutrient states.

Hepatic steatosis, inflammation, and ER stress in mice maintained long term on a very low-carbohydrate ketogenic diet.

Low-carbohydrate diets are used to manage obesity, seizure disorders, and malignancies of the central nervous system. These diets create a distinctive, but incompletely defined, cellular, molecular, and integrated metabolic state. Here, we determine the systemic and hepatic effects of long-term administration of a very low-carbohydrate, low-protein, and high-fat ketogenic diet, serially comparing these effects to a high-simple-carbohydrate, high-fat Western diet and a low-fat, polysaccharide-rich control chow diet in C57BL/6J mice. Longitudinal measurement of body composition, serum metabolites, and intrahepatic fat content, using in vivo magnetic resonance spectroscopy, reveals that mice fed the ketogenic diet over 12 wk remain lean, euglycemic, and hypoinsulinemic but accumulate hepatic lipid in a temporal pattern very distinct from animals fed the Western diet. Ketogenic diet-fed mice ultimately develop systemic glucose intolerance, hepatic endoplasmic reticulum stress, steatosis, cellular injury, and macrophage accumulation, but surprisingly insulin-induced hepatic Akt phosphorylation and whole-body insulin responsiveness are not impaired. Moreover, whereas hepatic Pparg mRNA abundance is augmented by both high-fat diets, each diet confers splice variant specificity. The distinctive nutrient milieu created by long-term administration of this low-carbohydrate, low-protein ketogenic diet in mice evokes unique signatures of nonalcoholic fatty liver disease and whole-body glucose homeostasis.

Obligate role for ketone body oxidation in neonatal metabolic homeostasis.

To compensate for the energetic deficit elicited by reduced carbohydrate intake, mammals convert energy stored in ketone bodies to high energy phosphates. Ketone bodies provide fuel particularly to brain, heart, and skeletal muscle in states that include starvation, adherence to low carbohydrate diets, and the neonatal period. Here, we use novel Oxct1(-/-) mice, which lack the ketolytic enzyme succinyl-CoA:3-oxo-acid CoA-transferase (SCOT), to demonstrate that ketone body oxidation is required for postnatal survival in mice. Although Oxct1(-/-) mice exhibit normal prenatal development, all develop ketoacidosis, hypoglycemia, and reduced plasma lactate concentrations within the first 48 h of birth. In vivo oxidation of (13)C-labeled ß-hydroxybutyrate in neonatal Oxct1(-/-) mice, measured using NMR, reveals intact oxidation to acetoacetate but no contribution of ketone bodies to the tricarboxylic acid cycle. Accumulation of acetoacetate yields a markedly reduced ß-hydroxybutyrate:acetoacetate ratio of 1:3, compared with 3:1 in Oxct1(+) littermates. Frequent exogenous glucose administration to actively suckling Oxct1(-/-) mice delayed, but could not prevent, lethality. Brains of newborn SCOT-deficient mice demonstrate evidence of adaptive energy acquisition, with increased phosphorylation of AMP-activated protein kinase α, increased autophagy, and 2.4-fold increased in vivo oxidative metabolism of [(13)C]glucose. Furthermore, [(13)C]lactate oxidation is increased 1.7-fold in skeletal muscle of Oxct1(-/-) mice but not in brain. These results indicate the critical metabolic roles of ketone bodies in neonatal metabolism and suggest that distinct tissues exhibit specific metabolic responses to loss of ketone body oxidation.

Adaptation of myocardial substrate metabolism to a ketogenic nutrient environment.

Heart muscle is metabolically versatile, converting energy stored in fatty acids, glucose, lactate, amino acids, and ketone bodies. Here, we use mouse models in ketotic nutritional states (24 h of fasting and a very low carbohydrate ketogenic diet) to demonstrate that heart muscle engages a metabolic response that limits ketone body utilization. Pathway reconstruction from microarray data sets, gene expression analysis, protein immunoblotting, and immunohistochemical analysis of myocardial tissue from nutritionally modified mouse models reveal that ketotic states promote transcriptional suppression of the key ketolytic enzyme, succinyl-CoA:3-oxoacid CoA transferase (SCOT; encoded by Oxct1), as well as peroxisome proliferator-activated receptor alpha-dependent induction of the key ketogenic enzyme HMGCS2. Consistent with reduction of SCOT, NMR profiling demonstrates that maintenance on a ketogenic diet causes a 25% reduction of myocardial (13)C enrichment of glutamate when (13)C-labeled ketone bodies are delivered in vivo or ex vivo, indicating reduced procession of ketones through oxidative metabolism. Accordingly, unmetabolized substrate concentrations are higher within the hearts of ketogenic diet-fed mice challenged with ketones compared with those of chow-fed controls. Furthermore, reduced ketone body oxidation correlates with failure of ketone bodies to inhibit fatty acid oxidation. These results indicate that ketotic nutrient environments engage mechanisms that curtail ketolytic capacity, controlling the utilization of ketone bodies in ketotic states.