Publications by authors named "Christopher Madden"

119 Publications

Hippocampal and rostral anterior cingulate blood flow is associated with affective symptoms in chronic traumatic brain injury.

Brain Res 2021 Aug 28:147631. Epub 2021 Aug 28.

Department of Neurology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX 75390, USA.

Objective: The purpose of this study was to assess cerebral blood flow (CBF) and its association with self-reported symptoms in chronic traumatic brain injury (TBI).

Participants: Sixteen participants with mild to severe TBI and persistent self-reported neurological symptoms, 6 to 72 months post-injury were included. For comparison, 16 age- and gender-matched healthy normal control participants were also included.

Main Measures: Regional CBF and brain volume were assessed using pseudo-continuous Arterial Spin Labeling (PCASL) and T-weighted data respectively. Cognitive function and self-reported symptoms were assessed in TBI participants using the national institutes of health (NIH) Toolbox Cognition Battery and Patient-Reported Outcome Measurement Information System respectively. Associations between CBF and cognitive function, symptoms were assessed.

Results: Global CBF and regional brain volumes were similar between groups, but region of interest (ROI) analysis revealed lower CBF bilaterally in the thalamus, hippocampus, left caudate, and left amygdala in the TBI group. Voxel-wise analysis revealed that CBF in the hippocampus, parahippocampus, rostral anterior cingulate, inferior frontal gyrus, and other temporal regions were negatively associated with self-reported anger, anxiety, and depression symptoms. Furthermore, region of interest (ROI) analysis revealed that hippocampal and rostral anterior cingulate CBF were negatively associated with symptoms of fatigue, anxiety, depression, and sleep issues.

Conclusion: Regional CBF deficit was observed in the group with chronic TBI compared to the normal control (NC) group despite similar volume of cerebral structures. The observed negative correlation between regional CBF and affective symptoms suggests that CBF-targeted intervention may potentially improve affective symptoms and quality of life after TBI, which needs to be assessed in future studies.
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http://dx.doi.org/10.1016/j.brainres.2021.147631DOI Listing
August 2021

Pathological Computed Tomography Features Associated With Adverse Outcomes After Mild Traumatic Brain Injury: A TRACK-TBI Study With External Validation in CENTER-TBI.

JAMA Neurol 2021 Sep;78(9):1137-1148

University of Washington, Seattle.

Importance: A head computed tomography (CT) with positive results for acute intracranial hemorrhage is the gold-standard diagnostic biomarker for acute traumatic brain injury (TBI). In moderate to severe TBI (Glasgow Coma Scale [GCS] scores 3-12), some CT features have been shown to be associated with outcomes. In mild TBI (mTBI; GCS scores 13-15), distribution and co-occurrence of pathological CT features and their prognostic importance are not well understood.

Objective: To identify pathological CT features associated with adverse outcomes after mTBI.

Design, Setting, And Participants: The longitudinal, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled patients with TBI, including those 17 years and older with GCS scores of 13 to 15 who presented to emergency departments at 18 US level 1 trauma centers between February 26, 2014, and August 8, 2018, and underwent head CT imaging within 24 hours of TBI. Evaluations of CT imaging used TBI Common Data Elements. Glasgow Outcome Scale-Extended (GOSE) scores were assessed at 2 weeks and 3, 6, and 12 months postinjury. External validation of results was performed via the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Data analyses were completed from February 2020 to February 2021.

Exposures: Acute nonpenetrating head trauma.

Main Outcomes And Measures: Frequency, co-occurrence, and clustering of CT features; incomplete recovery (GOSE scores <8 vs 8); and an unfavorable outcome (GOSE scores <5 vs ≥5) at 2 weeks and 3, 6, and 12 months.

Results: In 1935 patients with mTBI (mean [SD] age, 41.5 [17.6] years; 1286 men [66.5%]) in the TRACK-TBI cohort and 2594 patients with mTBI (mean [SD] age, 51.8 [20.3] years; 1658 men [63.9%]) in an external validation cohort, hierarchical cluster analysis identified 3 major clusters of CT features: contusion, subarachnoid hemorrhage, and/or subdural hematoma; intraventricular and/or petechial hemorrhage; and epidural hematoma. Contusion, subarachnoid hemorrhage, and/or subdural hematoma features were associated with incomplete recovery (odds ratios [ORs] for GOSE scores <8 at 1 year: TRACK-TBI, 1.80 [95% CI, 1.39-2.33]; CENTER-TBI, 2.73 [95% CI, 2.18-3.41]) and greater degrees of unfavorable outcomes (ORs for GOSE scores <5 at 1 year: TRACK-TBI, 3.23 [95% CI, 1.59-6.58]; CENTER-TBI, 1.68 [95% CI, 1.13-2.49]) out to 12 months after injury, but epidural hematoma was not. Intraventricular and/or petechial hemorrhage was associated with greater degrees of unfavorable outcomes up to 12 months after injury (eg, OR for GOSE scores <5 at 1 year in TRACK-TBI: 3.47 [95% CI, 1.66-7.26]). Some CT features were more strongly associated with outcomes than previously validated variables (eg, ORs for GOSE scores <5 at 1 year in TRACK-TBI: neuropsychiatric history, 1.43 [95% CI .98-2.10] vs contusion, subarachnoid hemorrhage, and/or subdural hematoma, 3.23 [95% CI 1.59-6.58]). Findings were externally validated in 2594 patients with mTBI enrolled in the CENTER-TBI study.

Conclusions And Relevance: In this study, pathological CT features carried different prognostic implications after mTBI to 1 year postinjury. Some patterns of injury were associated with worse outcomes than others. These results support that patients with mTBI and these CT features need TBI-specific education and systematic follow-up.
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http://dx.doi.org/10.1001/jamaneurol.2021.2120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290344PMC
September 2021

Evaluating extraction methods to study canine urine microbiota.

PLoS One 2021 9;16(7):e0253989. Epub 2021 Jul 9.

Department of Veterinary Preventive Medicine, Ohio State University College of Veterinary Medicine, Columbus, Ohio, United States of America.

The urinary microbiota is the collection of microbes present in urine that may play a role in host health. Studies of urine microbiota have traditionally relied upon culturing methods aimed at identifying pathogens. However, recent culture-free sequencing studies of the urine microbiota have determined that a diverse array of microbes is present in health and disease. To study these microbes and their potential role in diseases like bladder cancer or interstitial cystitis, consistent extraction and detection of bacterial DNA from urine is critical. However, urine is a low biomass substrate, requiring sensitive methods to capture DNA and making the risk of contamination high. To address this challenge, we collected urine samples from ten healthy dogs and extracted DNA from each sample using five different commercially available extraction methods. Extraction methods were compared based on total and bacterial DNA concentrations and bacterial community composition and diversity assessed through 16S rRNA gene sequencing. Significant differences in the urinary microbiota were observed by dog and sex but not extraction method. The Bacteremia Kit yielded the highest total DNA concentrations (Kruskal-Wallis, p = 0.165, not significant) and the highest bacterial DNA concentrations (Kruskal-Wallis, p = 0.044). Bacteremia also extracted bacterial DNA from the greatest number of samples. Taken together, these results suggest that the Bacteremia kit is an effective option for studying the urine microbiota. This work lays the foundation to study the urine microbiome in a wide range of urogenital diseases in dogs and other species.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253989PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270191PMC
July 2021

Functional Outcomes Over the First Year After Moderate to Severe Traumatic Brain Injury in the Prospective, Longitudinal TRACK-TBI Study.

JAMA Neurol 2021 Aug;78(8):982-992

University of Cincinnati, Cincinnati, Ohio.

Importance: Moderate to severe traumatic brain injury (msTBI) is a major cause of death and disability in the US and worldwide. Few studies have enabled prospective, longitudinal outcome data collection from the acute to chronic phases of recovery after msTBI.

Objective: To prospectively assess outcomes in major areas of life function at 2 weeks and 3, 6, and 12 months after msTBI.

Design, Setting, And Participants: This cohort study, as part of the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study, was conducted at 18 level 1 trauma centers in the US from February 2014 to August 2018 and prospectively assessed longitudinal outcomes, with follow-up to 12 months postinjury. Participants were patients with msTBI (Glasgow Coma Scale scores 3-12) extracted from a larger group of patients with mild, moderate, or severe TBI who were enrolled in TRACK-TBI. Data analysis took place from October 2019 to April 2021.

Exposures: Moderate or severe TBI.

Main Outcomes And Measures: The Glasgow Outcome Scale-Extended (GOSE) and Disability Rating Scale (DRS) were used to assess global functional status 2 weeks and 3, 6, and 12 months postinjury. Scores on the GOSE were dichotomized to determine favorable (scores 4-8) vs unfavorable (scores 1-3) outcomes. Neurocognitive testing and patient reported outcomes at 12 months postinjury were analyzed.

Results: A total of 484 eligible patients were included from the 2679 individuals in the TRACK-TBI study. Participants with severe TBI (n = 362; 283 men [78.2%]; median [interquartile range] age, 35.5 [25-53] years) and moderate TBI (n = 122; 98 men [80.3%]; median [interquartile range] age, 38 [25-53] years) were comparable on demographic and premorbid variables. At 2 weeks postinjury, 36 of 290 participants with severe TBI (12.4%) and 38 of 93 participants with moderate TBI (41%) had favorable outcomes (GOSE scores 4-8); 301 of 322 in the severe TBI group (93.5%) and 81 of 103 in the moderate TBI group (78.6%) had moderate disability or worse on the DRS (total score ≥4). By 12 months postinjury, 142 of 271 with severe TBI (52.4%) and 54 of 72 with moderate TBI (75%) achieved favorable outcomes. Nearly 1 in 5 participants with severe TBI (52 of 270 [19.3%]) and 1 in 3 with moderate TBI (23 of 71 [32%]) reported no disability (DRS score 0) at 12 months. Among participants in a vegetative state at 2 weeks, 62 of 79 (78%) regained consciousness and 14 of 56 with available data (25%) regained orientation by 12 months.

Conclusions And Relevance: In this study, patients with msTBI frequently demonstrated major functional gains, including recovery of independence, between 2 weeks and 12 months postinjury. Severe impairment in the short term did not portend poor outcomes in a substantial minority of patients with msTBI. When discussing prognosis during the first 2 weeks after injury, clinicians should be particularly cautious about making early, definitive prognostic statements suggesting poor outcomes and withdrawal of life-sustaining treatment in patients with msTBI.
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http://dx.doi.org/10.1001/jamaneurol.2021.2043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261688PMC
August 2021

Alterations in gut microbiota linked to provenance, sex, and chronic wasting disease in white-tailed deer (Odocoileus virginianus).

Sci Rep 2021 Jun 24;11(1):13218. Epub 2021 Jun 24.

Veterinary Preventive Medicine Department, The Ohio State University College of Veterinary Medicine, 1900 Coffey Rd., Columbus, OH, 43210, USA.

Chronic wasting disease (CWD) is a fatal, contagious, neurodegenerative prion disease affecting both free-ranging and captive cervid species. CWD is spread via direct or indirect contact or oral ingestion of prions. In the gastrointestinal tract, prions enter the body through microfold cells (M-cells), and the abundance of these cells can be influenced by the gut microbiota. To explore potential links between the gut microbiota and CWD, we collected fecal samples from farmed and free-ranging white-tailed deer (Odocoileus virginianus) around the Midwest, USA. Farmed deer originated from farms that were depopulated due to CWD. Free-ranging deer were sampled during annual deer harvests. All farmed deer were tested for CWD via ELISA and IHC, and we used 16S rRNA gene sequencing to characterize the gut microbiota. We report significant differences in gut microbiota by provenance (Farm 1, Farm 2, Free-ranging), sex, and CWD status. CWD-positive deer from Farm 1 and 2 had increased abundances of Akkermansia, Lachnospireacea UCG-010, and RF39 taxa. Overall, differences by provenance and sex appear to be driven by diet, while differences by CWD status may be linked to CWD pathogenesis.
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http://dx.doi.org/10.1038/s41598-021-89896-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225879PMC
June 2021

Co-Created Messaging for Influenza Vaccination in a High-Risk Hispanic Community Provides Groundwork for COVID-19 Vaccine.

Health Equity 2021 24;5(1):345-352. Epub 2021 May 24.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

Influenza/pneumonia is the eighth leading cause of death in the United States. The 2020-2021 influenza season is predicted to be further impacted by COVID-19 infections. Historical data reflect disproportionate morbidity and mortality rates in the Hispanic population for influenza and COVID-19. Influenza vaccination rates remain low in the Hispanic community. We aim to improve vaccination through a community-led event, partnering with the Cristo Rey School Dallas, located in a zip code with a higher age-adjusted influenza/pneumonia mortality rate. A survey was administered to adults attending the Influenza vaccine event to understand attitudes and perceptions about influenza, vaccination, and effective messaging strategies for the campaign. Messaging was cocreated with student health ambassadors to promote immunization and delivered through trusted sources. The health department administered vaccines to individuals >age 3 at no cost. Adults were asked to complete a 19-question survey postvaccination offered in both English and Spanish. Two hundred and forty-one of 394 (61.2%) participants completed the survey. Ninety-eight percent identified as Hispanic/Latino, and the majority of surveys were administered in Spanish. Among Spanish language participants, the church bulletins (57.3%) and Spanish language radio (30.5%) were reported to be most effective modes of messaging versus word of mouth (32.9%) and social media (26.3%) for English-speaking participants. Sixteen percent of participants surveyed had never received an influenza vaccine before this event. Cocreated messaging delivered by trusted sources in the Hispanic community led to a successful Influenza vaccine drive with the Dallas County health department.
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http://dx.doi.org/10.1089/heq.2020.0132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170719PMC
May 2021

Association of Sex and Age With Mild Traumatic Brain Injury-Related Symptoms: A TRACK-TBI Study.

JAMA Netw Open 2021 04 1;4(4):e213046. Epub 2021 Apr 1.

Virginia Commonwealth University, Richmond, Virginia.

Importance: Knowledge of differences in mild traumatic brain injury (mTBI) recovery by sex and age may inform individualized treatment of these patients.

Objective: To identify sex-related differences in symptom recovery from mTBI; secondarily, to explore age differences within women, who demonstrate poorer outcomes after TBI.

Design, Setting, And Participants: The prospective cohort study Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) recruited 2000 patients with mTBI from February 26, 2014, to July 3, 2018, and 299 patients with orthopedic trauma (who served as controls) from January 26, 2016, to July 27, 2018. Patients were recruited from 18 level I trauma centers and followed up for 12 months. Data were analyzed from August 19, 2020, to March 3, 2021.

Exposures: Patients with mTBI (defined by a Glasgow Coma Scale score of 13-15) triaged to head computed tomography in 24 hours or less; patients with orthopedic trauma served as controls.

Main Outcomes And Measures: Measured outcomes included (1) the Rivermead Post Concussion Symptoms Questionnaire (RPQ), a 16-item self-report scale that assesses postconcussion symptom severity over the past 7 days relative to preinjury; (2) the Posttraumatic Stress Disorder Checklist for the Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (PCL-5), a 20-item test that measures the severity of posttraumatic stress disorder symptoms; (3) the Patient Health Questionnaire-9 (PHQ-9), a 9-item scale that measures depression based on symptom frequency over the past 2 weeks; and (4) the Brief Symptom Inventory-18 (BSI-18), an 18-item scale of psychological distress (split into Depression and Anxiety subscales).

Results: A total of 2000 patients with mTBI (1331 men [67%; mean (SD) age, 41.0 (17.3) years; 1026 White (78%)] and 669 women [33%; mean (SD) age, 43.0 (18.5) years; 505 (76%) White]). After adjustment of multiple comparisons, significant TBI × sex interactions were observed for cognitive symptoms (B = 0.76; 5% false discovery rate-corrected P = .02) and somatic RPQ symptoms (B = 0.80; 5% false discovery rate-corrected P = .02), with worse symptoms in women with mTBI than men, but no sex difference in symptoms in control patients with orthopedic trauma. Within the female patients evaluated, there was a significant TBI × age interaction for somatic RPQ symptoms, which were worse in female patients with mTBI aged 35 to 49 years compared with those aged 17 to 34 years (B = 1.65; P = .02) or older than 50 years (B = 1.66; P = .02).

Conclusions And Relevance: This study found that women were more vulnerable than men to persistent mTBI-related cognitive and somatic symptoms, whereas no sex difference in symptom burden was seen after orthopedic injury. Postconcussion symptoms were also worse in women aged 35 to 49 years than in younger and older women, but further investigation is needed to corroborate these findings and to identify the mechanisms involved. Results suggest that individualized clinical management of mTBI should consider sex and age, as some women are especially predisposed to chronic postconcussion symptoms even 12 months after injury.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.3046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025125PMC
April 2021

Latent Profile Analysis of Neuropsychiatric Symptoms and Cognitive Function of Adults 2 Weeks After Traumatic Brain Injury: Findings From the TRACK-TBI Study.

JAMA Netw Open 2021 03 1;4(3):e213467. Epub 2021 Mar 1.

TIRR Memorial Hermann, Houston, Texas.

Importance: Heterogeneity across patients with traumatic brain injury (TBI) presents challenges for clinical care and intervention design. Identifying distinct clinical phenotypes of TBI soon after injury may inform patient selection for precision medicine clinical trials.

Objective: To investigate whether distinct neurobehavioral phenotypes can be identified 2 weeks after TBI and to characterize the degree to which early neurobehavioral phenotypes are associated with 6-month outcomes.

Design, Setting, And Participants: This prospective cohort study included patients presenting to 18 US level 1 trauma centers within 24 hours of TBI from 2014 to 2019 as part of the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study. Data were analyzed from January 28, 2020, to January 11, 2021.

Exposures: TBI.

Main Outcomes And Measures: Latent profiles (LPs) were derived from common dimensions of neurobehavioral functioning at 2 weeks after injury, assessed through National Institutes of Health TBI Common Data Elements (ie, Brief Symptom Inventory-18, Patient Health Questionnaire-9 Depression checklist, Posttraumatic Stress Disorder Checklist for DSM-5, PROMIS Pain Intensity scale, Insomnia Severity Index, Rey Auditory Verbal Learning Test, Wechsler Adult Intelligence Scale-Fourth Edition Coding and Symbol Search subtests, Trail Making Test, and NIH Toolbox Cognitive Battery Pattern Comparison Processing Speed, Dimensional Change Card Sort, Flanker Inhibitory Control and Attention, and Picture Sequence Memory subtests). Six-month outcomes were the Satisfaction With Life Scale (SWLS), Quality of Life after Brain Injury-Overall Scale (QOLIBRI-OS), Glasgow Outcome Scale-Extended (GOSE), and Rivermead Post-Concussion Symptoms Questionnaire (RPQ).

Results: Among 1757 patients with TBI included, 1184 (67.4%) were men, and the mean (SD) age was 39.9 (17.0) years. LP analysis revealed 4 distinct neurobehavioral phenotypes at 2 weeks after injury: emotionally resilient (419 individuals [23.8%]), cognitively impaired (368 individuals [20.9%]), cognitively resilient (620 individuals [35.3%]), and neuropsychiatrically distressed (with cognitive weaknesses; 350 individuals [19.9%]). Adding LP group to models including demographic characteristics, medical history, Glasgow Coma Scale score, and other injury characteristics was associated with significantly improved estimation of association with 6-month outcome (GOSE R2 increase = 0.09-0.19; SWLS R2 increase = 0.12-0.22; QOLIBRI-OS R2 increase = 0.14-0.32; RPQ R2 = 0.13-0.34).

Conclusions And Relevance: In this cohort study of patients with TBI presenting to US level-1 trauma centers, qualitatively distinct profiles of symptoms and cognitive functioning were identified at 2 weeks after TBI. These distinct phenotypes may help optimize clinical decision-making regarding prognosis, as well as selection and stratification for randomized clinical trials.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.3467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010589PMC
March 2021

Activation of Transient Receptor Potential Vanilloid 1 Channels in the Nucleus of the Solitary Tract and Activation of Dynorphin Input to the Median Preoptic Nucleus Contribute to Impaired BAT Thermogenesis in Diet-Induced Obesity.

eNeuro 2021 Mar-Apr;8(2). Epub 2021 Apr 9.

Department of Neurological Surgery, Oregon Health & Science University, Portland, OR 97239

The impairment of cold-evoked activation of brown adipose tissue (BAT) in rats fed a high-fat diet (HFD) requires the activity of a vagal afferent to the medial nucleus of the solitary tract (mNTS). We determined the role of transient receptor potential vanilloid 1 (TRPV1) activation in the mNTS, and of a dynorphin input to the median preoptic nucleus (MnPO) in the impaired BAT thermogenic response to cold in HFD-fed rats. The levels of some linoleic acid (LA) metabolites, which can act as endogenous TRPV1 agonists, were elevated in the NTS of HFD rats compared with chow-fed rats. In HFD rats, nanoinjections of the TRPV1 antagonist, capsazepine (CPZ) in the NTS rescued the impaired BAT sympathetic nerve activity (BAT SNA) and thermogenic responses to cold. In contrast, in chow-fed rats, cold-evoked BAT SNA and BAT thermogenesis were not changed by nanoinjections of CPZ into the NTS. Axon terminals of NTS neurons that project to the dorsal lateral parabrachial nucleus (LPBd) were closely apposed to LPBd neurons that project to the MnPO. Many of the neurons in the LPBd that expressed c-fos during cold challenge were dynorphinergic. In HFD rats, nanoinjections of the κ opioid receptor (KOR) antagonist, nor-binaltorphimine (nor-BNI), in the MnPO rescued the impaired BAT SNA and thermogenic responses to cold. These data suggest that HFD increases the content of endogenous ligands of TRPV1 in the NTS, which increases the drive to LPBd neurons that in turn release dynorphin in the MnPO to impair activation of BAT.
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http://dx.doi.org/10.1523/ENEURO.0048-21.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174036PMC
July 2021

Results and lessons from a hospital-wide initiative incentivised by delivery system reform to improve infection prevention and sepsis care.

BMJ Open Qual 2021 02;10(1)

Health System Administration, Parkland Health and Hospital System, Dallas, Texas, USA.

Background: An academic safety-net hospital leveraged the federally funded state Delivery System Reform Incentive Payment programme to implement a hospital-wide initiative to reduce healthcare-associated infections (HAIs) and improve sepsis care.

Methods: The study period was from 2013 to 2017. The setting is a 770-bed urban hospital with six intensive care units and a large emergency department. Key interventions implemented were (1) awareness campaign and clinician engagement, (2) implementation of HAI and sepsis bundles, (3) education of clinical personnel using standardised curriculum on bundles, (4) training of key managers, leaders and personnel in quality improvement methods, and (5) electronic medical record-based clinical decision support. Throughout the 5-year period, staff received frequent, clear, visible and consistent messages from leadership regarding the importance of their participation in this initiative, performing hand hygiene and preventing potential regulatory failures. Several process measures including bundle compliance, hand hygiene and culture of safety were monitored. The primary outcomes were rates of central line-associated bloodstream infection (CLABSI), catheter-associated urinary tract infection (CAUTI), surgical site infection (SSI) and sepsis mortality.

Results: From 2013 to 2017, the hospital-wide rates of HAI reduced: CLABSI from 1.6 to 0.8 per 1000 catheter-days (Poisson regression estimate: -0.19; 95% CI -0.29 to -0.09; p=0.0002), CAUTI from 4.7 to 1.3 per 1000 catheter-days (-0.34; -0.43 to -0.26; p<0.0001) and SSI after 18 types of procedures from 3.4% to 1.3% (-0.29; -0.34 to -0.24; p<0.0001). Mortality of patients presenting to emergency department with sepsis reduced from 9.4% to 2.9% (-0.42; -0.49 to -0.36; p<0.0001). Adherence to bundles of care and hand hygiene and the hospital culture of patient safety improved. Results were sustained through 2019.

Conclusion: A hospital-wide initiative incentivised by the Delivery System Reform Incentive Payment programme succeeded in reducing HAI and sepsis mortality over 5 years in a sustainable manner.
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http://dx.doi.org/10.1136/bmjoq-2020-001189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7871234PMC
February 2021

A proof-of-concept trial of a community-based aerobic exercise program for individuals with traumatic brain injury.

Brain Inj 2021 01 1;35(2):233-240. Epub 2021 Jan 1.

Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

: To assess the feasibility of conducting an aerobic exercise training study in a community setting for individuals with traumatic brain injury (TBI): This is a prospective, randomized, and controlled study. Nine participants (three moderate-to-severe and six mild TBI) were randomized to a community-based 3-month individualized aerobic exercise training program (AET). Seven participants (four moderate-to-severe, three mild TBI) were randomized to a stretching and toning program (SAT). Cardiorespiratory fitness (CRF) level was assessed with peak oxygen uptake (VO) testing.: After 3 months of training, the AET trended toward improved VO when compared with the SAT group (8% vs - 4%, = .059) with a large effect size of 1.27. Only 50% of participants in the AET group completed more than 70% of the assigned exercise sessions. No adverse events were reported. Both the AET and SAT groups reported small improvements in self-reported mood symptoms, including depression, anxiety, and anger.: It is feasible to conduct an exercise training study and improve CRF for persons with TBI in community settings with structured exercise protocols. However, exploring methods to enhance adherence is crucial for future exercise clinical trials to improve brain health in this population.
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http://dx.doi.org/10.1080/02699052.2020.1865569DOI Listing
January 2021

Imaging Acute Metabolic Changes in Patients with Mild Traumatic Brain Injury Using Hyperpolarized [1-C]Pyruvate.

iScience 2020 Dec 30;23(12):101885. Epub 2020 Nov 30.

Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

Traumatic brain injury (TBI) involves complex secondary injury processes following the primary injury. The secondary injury is often associated with rapid metabolic shifts and impaired brain function immediately after the initial tissue damage. Magnetic resonance spectroscopic imaging (MRSI) coupled with hyperpolarization of C-labeled substrates provides a unique opportunity to map the metabolic changes in the brain after traumatic injury in real-time without invasive procedures. In this report, we investigated two patients with acute mild TBI (Glasgow coma scale 15) but no anatomical brain injury or hemorrhage. Patients were imaged with hyperpolarized [1-C]pyruvate MRSI 1 or 6 days after head trauma. Both patients showed significantly reduced bicarbonate (HCO ) production, and one showed hyperintense lactate production at the injured sites. This study reports the feasibility of imaging altered metabolism using hyperpolarized pyruvate in patients with TBI, demonstrating the translatability and sensitivity of the technology to cerebral metabolic changes after mild TBI.
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http://dx.doi.org/10.1016/j.isci.2020.101885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736977PMC
December 2020

Leptin increases sympathetic nerve activity via induction of its own receptor in the paraventricular nucleus.

Elife 2020 06 15;9. Epub 2020 Jun 15.

Department of Physiology and Pharmacology, Portland, United States.

Whether leptin acts in the paraventricular nucleus (PVN) to increase sympathetic nerve activity (SNA) is unclear, since PVN leptin receptors (LepR) are sparse. We show in rats that PVN leptin slowly increases SNA to muscle and brown adipose tissue, because it induces the expression of its own receptor and synergizes with local glutamatergic neurons. PVN LepR are not expressed in astroglia and rarely in microglia; instead, glutamatergic neurons express LepR, some of which project to a key presympathetic hub, the rostral ventrolateral medulla (RVLM). In PVN slices from mice expressing GCaMP6, leptin excites glutamatergic neurons. LepR are expressed mainly in thyrotropin-releasing hormone (TRH) neurons, some of which project to the RVLM. Injections of TRH into the RVLM and dorsomedial hypothalamus increase SNA, highlighting these nuclei as likely targets. We suggest that this neuropathway becomes important in obesity, in which elevated leptin maintains the hypothalamic pituitary thyroid axis, despite leptin resistance.
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http://dx.doi.org/10.7554/eLife.55357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316512PMC
June 2020

Impaired cerebral blood flow regulation in chronic traumatic brain injury.

Brain Res 2020 09 4;1743:146924. Epub 2020 Jun 4.

Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, TX 75390, USA; Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, 8200 Walnut Hill Ln, Dallas, TX 75231, USA.

Baroreflex sensitivity (BRS) and cerebral autoregulation (CA) play an important role in maintaining constant cerebral blood flow (CBF) during systemic changes in blood pressure (BP). Impaired BRS and CA have been reported in acute traumatic brain injury (TBI) which may also contribute to secondary injury and poorer recovery after acute TBI; however, their status during chronic stages remains elusive. Thus, the goal of this study is to determine whether cardiac BRS and dynamic CA (dCA) were impaired during the chronic stage in patients with single TBI and persistent neurological symptoms. Twenty-two subjects with blunt head TBI ≥ 6 months prior to the study (13 mild and 9 moderate to severe TBI) and persistent symptoms on Rivermead Post-Concussion Symptoms Questionnaire at enrollment were compared to 22 age/sex/fitness level-matched healthy control subjects. Beat-to-beat changes in heart rate, BP, and CBF velocity were measured at rest and during a repeated sit-stand maneuver. Hemodynamic variability, dCA, and cardiac BRS were calculated using spectral and transfer function analyses. We found dCA phase in low frequency (LF) range of 0.07-0.20 Hz was lower in subjects with TBI than in control subjects (0.51 ± 0.19 vs. 0.63 ± 0.26, p = 0.043) during the resting condition. Among subjects with TBI, the lower dCA phase in LF was correlated with poorer performance on measures of cognitive function (all p < 0.05). These findings suggested that subjects with chronic TBI showed impaired dCA which may contribute to persistent cognitive impairment. Cerebrovascular measures may provide a physiological measure to evaluate interventions for chronic TBI and accompanying functional deficits.
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http://dx.doi.org/10.1016/j.brainres.2020.146924DOI Listing
September 2020

Glycine by MR spectroscopy is an imaging biomarker of glioma aggressiveness.

Neuro Oncol 2020 07;22(7):1018-1029

Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, Texas.

Background: High-grade gliomas likely remodel the metabolic machinery to meet the increased demands for amino acids and nucleotides during rapid cell proliferation. Glycine, a non-essential amino acid and intermediate of nucleotide biosynthesis, may increase with proliferation. Non-invasive measurement of glycine by magnetic resonance spectroscopy (MRS) was evaluated as an imaging biomarker for assessment of tumor aggressiveness.

Methods: We measured glycine, 2-hydroxyglutarate (2HG), and other tumor-related metabolites in 35 glioma patients using an MRS sequence tailored for co-detection of glycine and 2HG in gadolinium-enhancing and non-enhancing tumor regions on 3T MRI. Glycine and 2HG concentrations as measured by MRS were correlated with tumor cell proliferation (MIB-1 labeling index), expression of mitochondrial serine hydroxymethyltransferase (SHMT2), and glycine decarboxylase (GLDC) enzymes, and patient overall survival.

Results: Elevated glycine was strongly associated with presence of gadolinium enhancement, indicating more rapidly proliferative disease. Glycine concentration was positively correlated with MIB-1, and levels higher than 2.5 mM showed significant association with shorter patient survival, irrespective of isocitrate dehydrogenase status. Concentration of 2HG did not correlate with MIB-1 index. A high glycine/2HG concentration ratio, >2.5, was strongly associated with shorter survival (P < 0.0001). GLDC and SHMT2 expression were detectable in all tumors with glycine concentration, demonstrating an inverse correlation with GLDC.

Conclusions: The data suggest that aggressive gliomas reprogram glycine-mediated one-carbon metabolism to meet the biosynthetic demands for rapid cell proliferation. MRS evaluation of glycine provides a non-invasive metabolic imaging biomarker that is predictive of tumor progression and clinical outcome.

Key Points: 1. Glycine and 2-hydroxyglutarate in glioma patients are precisely co-detected using MRS at 3T.2. Tumors with elevated glycine proliferate and progress rapidly.3. A high glycine/2HG ratio is predictive of shortened patient survival.
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http://dx.doi.org/10.1093/neuonc/noaa034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339885PMC
July 2020

Reversible and Selective Interconversion of Hydrogen and Carbon Dioxide into Formate by a Semiartificial Formate Hydrogenlyase Mimic.

J Am Chem Soc 2019 11 28;141(44):17498-17502. Epub 2019 Oct 28.

Department of Chemistry , University of Cambridge , Lensfield Road , Cambridge CB2 1EW , U.K.

The biological formate hydrogenlyase (FHL) complex links a formate dehydrogenase (FDH) to a hydrogenase (Hase) and produces H and CO from formate via mixed-acid fermentation in . Here, we describe an electrochemical and a colloidal semiartificial FHL system that consists of an FDH and a Hase immobilized on conductive indium tin oxide (ITO) as an electron relay. These systems benefit from the efficient wiring of a highly active enzyme pair and allow for the reversible conversion of formate to H and CO under ambient temperature and pressure. The hybrid systems provide a template for the design of synthetic catalysts and surpass the FHL complex by storing and releasing H on demand by interconverting CO/H and formate with minimal bias in either direction.
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http://dx.doi.org/10.1021/jacs.9b09575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838786PMC
November 2019

Systemic serotonin inhibits brown adipose tissue sympathetic nerve activity via a GABA input to the dorsomedial hypothalamus, not via 5HT receptor activation in raphe pallidus.

Acta Physiol (Oxf) 2020 03 1;228(3):e13401. Epub 2019 Nov 1.

Department of Neurological Surgery, Oregon Health and Science University, Portland, OR, USA.

Aim: Serotonin (5-hydroxytryptamine, 5-HT), an important neurotransmitter and hormone, modulates many physiological functions including body temperature. We investigated neural mechanisms involved in the inhibition of brown adipose tissue (BAT) sympathetic nerve activity (SNA) and BAT thermogenesis evoked by 5-HT.

Methods: Electrophysiological recordings, intravenous (iv) injections and nanoinjections in the brains of anaesthetized rats.

Results: Cooling-evoked increases in BAT SNA were inhibited by the intra-rostral raphé pallidus (rRPa) and the iv administration of the 5-HT receptor agonist, 8-OH-DPAT or 5-HT. The intra-rRPa 5-HT, the intra-rRPa and the iv 8-OH-DPAT, but not the iv 5-HT-induced inhibition of BAT SNA were prevented by nanoinjection of a 5-HT receptor antagonist in the rRPa. The increase in BAT SNA evoked by nanoinjection of NMDA in the rRPa was not inhibited by iv 5-HT, indicating that iv 5-HT does not inhibit BAT SNA by acting in the rRPa or in the sympathetic pathway distal to the rRPa. In contrast, under a warm condition, blockade of 5HT receptors in the rRPa increased BAT SNA and BAT thermogenesis, suggesting that endogenous 5-HT in the rRPa contributes to the suppression of BAT SNA and BAT thermogenesis. The increases in BAT SNA and BAT thermogenesis evoked by nanoinjection of NMDA in the dorsomedial hypothalamus (DMH) were inhibited by iv 5-HT, but those following bicuculline nanoinjection in the DMH were not inhibited.

Conclusions: The systemic 5-HT-induced inhibition of BAT SNA requires a GABAergic inhibition of BAT sympathoexcitatory neurones in the DMH. In addition, during warming, 5-HT released endogenously in rRPa inhibits BAT SNA.
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http://dx.doi.org/10.1111/apha.13401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7035194PMC
March 2020

Recovery After Mild Traumatic Brain Injury in Patients Presenting to US Level I Trauma Centers: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study.

JAMA Neurol 2019 Sep;76(9):1049-1059

University of Southern California, Los Angeles.

Importance: Most traumatic brain injuries (TBIs) are classified as mild (mTBI) based on admission Glasgow Coma Scale (GCS) scores of 13 to 15. The prevalence of persistent functional limitations for these patients is unclear.

Objectives: To characterize the natural history of recovery of daily function following mTBI vs peripheral orthopedic traumatic injury in the first 12 months postinjury using data from the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study, and, using clinical computed tomographic (CT) scans, examine whether the presence (CT+) or absence (CT-) of acute intracranial findings in the mTBI group was associated with outcomes.

Design, Setting, And Participants: TRACK-TBI, a cohort study of patients with mTBI presenting to US level I trauma centers, enrolled patients from February 26, 2014, to August 8, 2018, and followed up for 12 months. A total of 1453 patients at 11 level I trauma center emergency departments or inpatient units met inclusion criteria (ie, mTBI [n = 1154] or peripheral orthopedic traumatic injury [n = 299]) and were enrolled within 24 hours of injury; mTBI participants had admission GCS scores of 13 to 15 and clinical head CT scans. Patients with peripheral orthopedic trauma injury served as the control (OTC) group.

Exposures: Participants with mTBI or OTC.

Main Outcomes And Measures: The Glasgow Outcome Scale Extended (GOSE) scale score, reflecting injury-related functional limitations across broad life domains at 2 weeks and 3, 6, and 12 months postinjury was the primary outcome. The possible score range of the GOSE score is 1 (dead) to 8 (upper good recovery), with a score less than 8 indicating some degree of functional impairment.

Results: Of the 1453 participants, 953 (65.6%) were men; mean (SD) age was 40.9 (17.1) years in the mTBI group and 40.9 (15.4) years in the OTC group. Most participants (mTBI, 87%; OTC, 93%) reported functional limitations (GOSE <8) at 2 weeks postinjury. At 12 months, the percentage of mTBI participants reporting functional limitations was 53% (95% CI, 49%-56%) vs 38% (95% CI, 30%-45%) for OTCs. A higher percentage of CT+ patients reported impairment (61%) compared with the mTBI CT- group (49%; relative risk [RR], 1.24; 95% CI, 1.08-1.43) and a higher percentage in the mTBI CT-group compared with the OTC group (RR, 1.28; 95% CI, 1.02-1.60).

Conclusions And Relevance: Most patients with mTBI presenting to US level I trauma centers report persistent, injury-related life difficulties at 1 year postinjury, suggesting the need for more systematic follow-up of patients with mTBI to provide treatments and reduce the risk of chronic problems after mTBI.
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http://dx.doi.org/10.1001/jamaneurol.2019.1313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547159PMC
September 2019

TMEM16B determines cholecystokinin sensitivity of intestinal vagal afferents of nodose neurons.

JCI Insight 2019 03 7;4(5). Epub 2019 Mar 7.

Department of Internal Medicine.

The satiety effects and metabolic actions of cholecystokinin (CCK) have been recognized as potential therapeutic targets in obesity for decades. We identified a potentially novel Ca2+-activated chloride (Cl-) current (CaCC) that is induced by CCK in intestinal vagal afferents of nodose neurons. The CaCC subunit Anoctamin 2 (Ano2/TMEM16B) is the dominant contributor to this current. Its expression is reduced, as is CCK current activity in obese mice on a high-fat diet (HFD). Reduced expression of TMEM16B in the heterozygote KO of the channel in sensory neurons results in an obese phenotype with a loss of CCK sensitivity in intestinal nodose neurons, a loss of CCK-induced satiety, and metabolic changes, including decreased energy expenditure. The effect on energy expenditure is further supported by evidence in rats showing that CCK enhances sympathetic nerve activity and thermogenesis in brown adipose tissue, and these effects are abrogated by a HFD and vagotomy. Our findings reveal that Ano2/TMEM16B is a Ca2+-activated chloride channel in vagal afferents of nodose neurons and a major determinant of CCK-induced satiety, body weight control, and energy expenditure, making it a potential therapeutic target in obesity.
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http://dx.doi.org/10.1172/jci.insight.122058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6483506PMC
March 2019

Risk of Posttraumatic Stress Disorder and Major Depression in Civilian Patients After Mild Traumatic Brain Injury: A TRACK-TBI Study.

JAMA Psychiatry 2019 03;76(3):249-258

Department of Rehabilitation Medicine, University of Washington, Seattle.

Importance: Traumatic brain injury (TBI) has been associated with adverse mental health outcomes, such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), but little is known about factors that modify risk for these psychiatric sequelae, particularly in the civilian sector.

Objective: To ascertain prevalence of and risk factors for PTSD and MDD among patients evaluated in the emergency department for mild TBI (mTBI).

Design, Setting, And Participants: Prospective longitudinal cohort study (February 2014 to May 2018). Posttraumatic stress disorder and MDD symptoms were assessed using the PTSD Checklist for DSM-5 and the Patient Health Questionnaire-9 Item. Risk factors evaluated included preinjury and injury characteristics. Propensity score weights-adjusted multivariable logistic regression models were performed to assess associations with PTSD and MDD. A total of 1155 patients with mTBI (Glasgow Coma Scale score, 13-15) and 230 patients with nonhead orthopedic trauma injuries 17 years and older seen in 11 US hospitals with level 1 trauma centers were included in this study.

Main Outcomes And Measures: Probable PTSD (PTSD Checklist for DSM-5 score, ≥33) and MDD (Patient Health Questionnaire-9 Item score, ≥15) at 3, 6, and 12 months postinjury.

Results: Participants were 1155 patients (752 men [65.1%]; mean [SD] age, 40.5 [17.2] years) with mTBI and 230 patients (155 men [67.4%]; mean [SD] age, 40.4 [15.6] years) with nonhead orthopedic trauma injuries. Weights-adjusted prevalence of PTSD and/or MDD in the mTBI vs orthopedic trauma comparison groups at 3 months was 20.0% (SE, 1.4%) vs 8.7% (SE, 2.2%) (P < .001) and at 6 months was 21.2% (SE, 1.5%) vs 12.1% (SE, 3.2%) (P = .03). Risk factors for probable PTSD at 6 months after mTBI included less education (adjusted odds ratio, 0.89; 95% CI, 0.82-0.97 per year), being black (adjusted odds ratio, 5.11; 95% CI, 2.89-9.05), self-reported psychiatric history (adjusted odds ratio, 3.57; 95% CI, 2.09-6.09), and injury resulting from assault or other violence (adjusted odds ratio, 3.43; 95% CI, 1.56-7.54). Risk factors for probable MDD after mTBI were similar with the exception that cause of injury was not associated with increased risk.

Conclusions And Relevance: After mTBI, some individuals, on the basis of education, race/ethnicity, history of mental health problems, and cause of injury were at substantially increased risk of PTSD and/or MDD. These findings should influence recognition of at-risk individuals and inform efforts at surveillance, follow-up, and intervention.
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http://dx.doi.org/10.1001/jamapsychiatry.2018.4288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6439818PMC
March 2019

Assessment of Follow-up Care After Emergency Department Presentation for Mild Traumatic Brain Injury and Concussion: Results From the TRACK-TBI Study.

JAMA Netw Open 2018 05 18;1(1):e180210. Epub 2018 May 18.

University of California, San Francisco.

Importance: Mild traumatic brain injury (mTBI) affects millions of Americans each year. Lack of consistent clinical practice raises concern that many patients with mTBI may not receive adequate follow-up care.

Objective: To characterize the provision of follow-up care to patients with mTBI during the first 3 months after injury.

Design, Setting, And Participants: This cohort study used data on patients with mTBI enrolled in the Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study between February 26, 2014, and August 25, 2016. We examined site-specific variations in follow-up care, the types of clinicians seen by patients receiving follow-up care, and patient and injury characteristics associated with a higher likelihood of receiving follow-up care. The TRACK-TBI study is a prospective, multicenter, longitudinal observational study of patients with TBI presenting to the emergency department of 1 of 11 level I US trauma centers. Study data included patients with head trauma who underwent a computed tomography (CT) scan within 24 hours of injury, had a Glasgow Coma Scale score of 13 to 15, were aged 17 years or older, and completed follow-up care surveys at 2 weeks and 3 months after injury (N = 831).

Main Outcomes And Measures: Follow-up care was defined as hospitals providing TBI educational material at discharge, hospitals calling patients to follow up, and patients seeing a physician or other medical practitioner within 3 months after the injury. Unfavorable outcomes were assessed with the Rivermead Post Concussion Symptoms Questionnaire.

Results: Of 831 patients (289 [35%] female; 483 [58%] non-Hispanic white; mean [SD] age, 40.3 [16.9] years), less than half self-reported receiving TBI educational material at discharge (353 patients [42%]) or seeing a physician or other health care practitioner within 3 months after injury (367 patients [44%]). Follow-up care varied by study site; adjusting for patient characteristics, the provision of educational material varied from 19% to 72% across sites. Of 236 patients with a positive finding on a CT scan, 92 (39%) had not seen a medical practitioner 3 months after the injury. Adjusting for injury severity and demographics, patient admission to the hospital ward or intensive care unit, patient income, and insurance status were not associated with the probability of seeing a medical practitioner. Among the patients with 3 or more moderate to severe postconcussive symptoms, only 145 of 279 (52%) reported having seen a medical practitioner by 3 months.

Conclusions And Relevance: There are gaps in follow-up care for patients with mTBI after hospital discharge, even those with a positive finding on CT or who continue to experience postconcussive symptoms.
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http://dx.doi.org/10.1001/jamanetworkopen.2018.0210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6324305PMC
May 2018

Central nervous system circuits that control body temperature.

Neurosci Lett 2019 03 23;696:225-232. Epub 2018 Dec 23.

Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, United States.

Maintenance of mammalian core body temperature within a narrow range is a fundamental homeostatic process to optimize cellular and tissue function, and to improve survival in adverse thermal environments. Body temperature is maintained during a broad range of environmental and physiological challenges by central nervous system circuits that process thermal afferent inputs from the skin and the body core to control the activity of thermoeffectors. These include thermoregulatory behaviors, cutaneous vasomotion (vasoconstriction and, in humans, active vasodilation), thermogenesis (shivering and brown adipose tissue), evaporative heat loss (salivary spreading in rodents, and human sweating). This review provides an overview of the central nervous system circuits for thermoregulatory reflex regulation of thermoeffectors.
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http://dx.doi.org/10.1016/j.neulet.2018.11.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397692PMC
March 2019

Salinity pulses interact with seasonal dry-down to increase ecosystem carbon loss in marshes of the Florida Everglades.

Ecol Appl 2018 12 30;28(8):2092-2108. Epub 2018 Oct 30.

Department of Biological Sciences and Southeast Environmental Research Center, Florida International University, Miami, Florida, 33199, USA.

Coastal wetlands are globally important sinks of organic carbon (C). However, to what extent wetland C cycling will be affected by accelerated sea-level rise (SLR) and saltwater intrusion is unknown, especially in coastal peat marshes where water flow is highly managed. Our objective was to determine how the ecosystem C balance in coastal peat marshes is influenced by elevated salinity. For two years, we made monthly in situ manipulations of elevated salinity in freshwater (FW) and brackish water (BW) sites within Everglades National Park, Florida, USA. Salinity pulses interacted with marsh-specific variability in seasonal hydroperiods whereby effects of elevated pulsed salinity on gross ecosystem productivity (GEP), ecosystem respiration (ER), and net ecosystem productivity (NEP) were dependent on marsh inundation level. We found little effect of elevated salinity on C cycling when both marsh sites were inundated, but when water levels receded below the soil surface, the BW marsh shifted from a C sink to a C source. During these exposed periods, we observed an approximately threefold increase in CO efflux from the marsh as a result of elevated salinity. Initially, elevated salinity pulses did not affect Cladium jamaicense biomass, but aboveground biomass began to be significantly decreased in the saltwater amended plots after two years of exposure at the BW site. We found a 65% (FW) and 72% (BW) reduction in live root biomass in the soil after two years of exposure to elevated salinity pulses. Regardless of salinity treatment, the FW site was C neutral while the BW site was a strong C source (-334 to -454 g C·m ·yr ), particularly during dry-down events. A loss of live roots coupled with annual net CO losses as marshes transition from FW to BW likely contributes to the collapse of peat soils observed in the coastal Everglades. As SLR increases the rate of saltwater intrusion into coastal wetlands globally, understanding how water management influences C gains and losses from these systems is crucial. Under current Everglades' water management, drought lengthens marsh dry-down periods, which, coupled with saltwater intrusion, accelerates CO loss from the marsh.
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http://dx.doi.org/10.1002/eap.1798DOI Listing
December 2018

Neurons in the rat ventral lateral preoptic area are essential for the warm-evoked inhibition of brown adipose tissue and shivering thermogenesis.

Acta Physiol (Oxf) 2019 04 14;225(4):e13213. Epub 2018 Dec 14.

Department of Neurological Surgery, Oregon Health & Science University, Portland, Oregon.

Aim: To determine the role of neurons in the ventral part of the lateral preoptic area (vLPO) in CNS thermoregulation.

Methods: In vivo electrophysiological and neuropharmacological were used to evaluate the contribution of neurons in the vLPO to the regulation of brown adipose tissue (BAT) thermogenesis and muscle shivering in urethane/chloralose-anaesthetized rats.

Results: Nanoinjections of NMDA targeting the medial preoptic area (MPA) and the vLPO suppressed the cold-evoked BAT sympathetic activity (SNA), reduced the BAT temperature (T ), expired CO , mean arterial pressure (MAP), and heart rate. Inhibition of vLPO neurons with muscimol or AP5/CNQX elicited increases in BAT SNA, T , tachycardia, and small elevations in MAP. The BAT thermogenesis evoked by AP5/CNQX in vLPO was inhibited by the activation of MPA neurons. The inhibition of BAT SNA by vLPO neurons does not require a GABAergic input to dorsomedial hypothalamus (DMH), but MPA provides a GABAergic input to DMH. The activation of vLPO neurons inhibits the BAT thermogenesis evoked by NMDA in the rostral raphe pallidus (rRPa), but not that after bicuculline in rRPa. The BAT thermogenesis elicited by vLPO inhibition is dependent on glutamatergic inputs to DMH and rRPa, but these excitatory inputs do not arise from MnPO neurons. The activation of neurons in the vLPO also inhibits cold- and prostaglandin-evoked muscle shivering, and vLPO inhibition is sufficient to evoke shivering.

Conclusion: The vLPO contains neurons that are required for the warm ambient-evoked inhibition of muscle shivering and of BAT thermogenesis, mediated through a direct or indirect GABAergic input to rRPa from vLPO.
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http://dx.doi.org/10.1111/apha.13213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686665PMC
April 2019

Preoptic area cooling increases the sympathetic outflow to brown adipose tissue and brown adipose tissue thermogenesis.

Am J Physiol Regul Integr Comp Physiol 2018 10 13;315(4):R609-R618. Epub 2018 Jun 13.

Department of Neurological Surgery, Oregon Health & Science University , Portland, Oregon.

Modest cold exposures are likely to activate autonomic thermogenic mechanisms due to activation of cutaneous thermal afferents, whereas central thermosensitive neurons set the background tone on which this afferent input is effective. In addition, more prolonged or severe cold exposures that overwhelm cold defense mechanisms would directly activate thermosensitive neurons within the central nervous system. Here, we examined the involvement of the canonical brown adipose tissue (BAT) sympathoexcitatory efferent pathway in the response to direct local cooling of the preoptic area (POA) in urethane-chloralose-anesthetized rats. With skin temperature and core body temperature maintained between 36 and 39°C, cooling POA temperature by ~1-4°C evoked increases in BAT sympathetic nerve activity (SNA), BAT temperature, expired CO, and heart rate. POA cooling-evoked responses were inhibited by nanoinjections of ionotropic glutamate receptor antagonists or the GABA receptor agonist muscimol into the median POA or by nanoinjections of ionotropic glutamate receptor antagonists into the dorsomedial hypothalamic nucleus (bilaterally) or into the raphe pallidus nucleus. These results demonstrate that direct cooling of the POA can increase BAT SNA and thermogenesis via the canonical BAT sympathoexcitatory efferent pathway, even in the face of warm thermal input from the skin and body core.
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http://dx.doi.org/10.1152/ajpregu.00113.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230895PMC
October 2018

Glucagon-like peptide-1 regulates brown adipose tissue thermogenesis via the gut-brain axis in rats.

Am J Physiol Regul Integr Comp Physiol 2018 10 30;315(4):R708-R720. Epub 2018 May 30.

Physiology and Behavior Laboratory, Eidgenössische Technische Hochschule Zürich, Schwerzenbach, Switzerland.

Endogenous intestinal glucagon-like peptide-1 (GLP-1) controls satiation and glucose metabolism via vagal afferent neurons (VANs). Recently, VANs have received increasing attention for their role in brown adipose tissue (BAT) thermogenesis. It is, however, unclear whether VAN GLP-1 receptor (GLP-1R) signaling affects BAT thermogenesis and energy expenditure (EE) and whether this VAN mechanism contributes to energy balance. First, we tested the effect of the GLP-1R agonist exendin-4 (Ex4, 0.3 μg/kg ip) on EE and BAT thermogenesis and whether these effects require VAN GLP-1R signaling using a rat model with a selective Glp1r knockdown (kd) in VANs. Second, we examined the role of VAN GLP-1R in energy balance during chronic high-fat diet (HFD) feeding in VAN Glp1r kd rats. Finally, we used viral transsynaptic tracers to identify the possible neuronal substrates of such a gut-BAT interaction. VAN Glp1r kd attenuated the acute suppressive effects of Ex4 on EE and BAT thermogenesis. Consistent with this finding, the VAN Glp1r kd increased EE and BAT activity, diminished body weight gain, and improved insulin sensitivity compared with HFD-fed controls. Anterograde transsynaptic viral tracing of VANs infected major hypothalamic and hindbrain areas involved in BAT sympathetic regulation. Moreover, retrograde tracing from BAT combined with laser capture microdissection revealed that a population of VANs expressing Glp1r is synaptically connected to the BAT. Our findings reveal a novel role of VAN GLP-1R signaling in the regulation of EE and BAT thermogenesis and imply that through this gut-brain-BAT connection, intestinal GLP-1 plays a role in HFD-induced metabolic syndrome.
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http://dx.doi.org/10.1152/ajpregu.00068.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6230883PMC
October 2018

Activation of TRPV1 in nucleus tractus solitarius reduces brown adipose tissue thermogenesis, arterial pressure, and heart rate.

Am J Physiol Regul Integr Comp Physiol 2018 07 28;315(1):R134-R143. Epub 2018 Mar 28.

Department of Neurological Surgery, Oregon Health & Science University , Portland, Oregon.

The sympathetic nerve activity (SNA) to brown adipose tissue (BAT) regulates BAT thermogenesis to defend body temperature in cold environments or to produce fever during immune responses. The vagus nerve contains afferents that inhibit the BAT SNA and BAT thermogenesis evoked by skin cooling. We sought to determine whether activation of transient receptor potential vanilloid 1 (TRPV1) channels in the nucleus tractus solitarius (NTS), which are prominently expressed in unmyelinated vagal afferents, would affect cold-evoked BAT thermogenesis, cardiovascular parameters, or their vagal afferent-evoked responses. In urethane-chloralose-anesthetized rats, during skin cooling, nanoinjection of the TRPV1-agonist resiniferatoxin in NTS decreased BAT SNA (from 695 ± 195% of baseline during cooling to 103 ± 8% of baseline after resiniferatoxin), BAT temperature (-0.8 ± 0.1°C), expired CO (-0.3 ± 0.04%), mean arterial pressure (MAP; -20 ± 5 mmHg), and heart rate (-44 ± 11 beats/min). Pretreatment of NTS with the TRPV1 antagonist capsazepine prevented these resiniferatoxin-mediated effects. Intravenous injection of the TRPV1 agonist dihydrocapsaicin also decreased all the measured variables (except MAP). Bilateral cervical or subdiaphragmatic vagotomy attenuated the decreases in BAT SNA and thermogenesis evoked by nanoinjection of resiniferatoxin in NTS but did not prevent the decreases in BAT SNA and BAT thermogenesis evoked by intravenous dihydrocapsaicin. We conclude that activation of TRPV1 channels in the NTS of vagus nerve intact rats inhibits BAT SNA and decreases BAT metabolism, blood pressure, and heart rate. In contrast, the inhibition of BAT thermogenesis following systemic administration of dihydrocapsaicin does not require vagal afferent activity, consistent with a nonvagal pathway through which systemic TRPV1 agonists can inhibit BAT thermogenesis.
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http://dx.doi.org/10.1152/ajpregu.00049.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087884PMC
July 2018

Reestablishment of Energy Balance in a Male Mouse Model With POMC Neuron Deletion of BMPR1A.

Endocrinology 2017 12;158(12):4233-4245

Integrative Physiology and Metabolism Section, Joslin Diabetes Center, Harvard Medical School.

The regulation of energy balance involves complex processes in the brain, including coordination by hypothalamic neurons that contain pro-opiomelanocortin (POMC). We previously demonstrated that central bone morphogenetic protein (BMP) 7 reduced appetite. Now we show that a type 1 BMP receptor, BMPR1A, is colocalized with POMC neurons and that POMC-BMPR1A-knockout (KO) mice are hyperphagic, revealing physiological involvement of BMP signaling in anorectic POMC neurons in the regulation of appetite. Surprisingly, the hyperphagic POMC-BMPR1A-KO mice exhibited a lack of obesity, even on a 45% high-fat diet. This is because the brown adipose tissue (BAT) of KO animals exhibited increased sympathetic activation and greater thermogenic capacity owing to a reestablishment of energy balance, most likely stemming from a compensatory increase of BMPR1A in the whole hypothalamus of KO mice. Indeed, control animals given central BMP7 displayed increased energy expenditure and a specific increase in sympathetic nerve activity (SNA) in BAT. In these animals, pharmacological blockade of BMPR1A-SMAD signaling blunted the ability of BMP7 to increase energy expenditure or BAT SNA. Together, we demonstrated an important role for hypothalamic BMP signaling in the regulation of energy balance, including BMPR1A-mediated appetite regulation in POMC neurons as well as hypothalamic BMP-SMAD regulation of the sympathetic drive to BAT for thermogenesis.
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http://dx.doi.org/10.1210/en.2017-00212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711385PMC
December 2017

Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase-II: A Phase II Randomized Trial.

Crit Care Med 2017 Nov;45(11):1907-1914

1University of Pittsburgh School of Medicine, Pittsburgh, PA. 2Uniformed Services University of the Health Sciences, Bethesda, MD. 3University of Washington, Seattle, WA. 4UT Southwestern Medical Center, Dallas, TX. 5University of Cincinnati College of Medicine, Cincinnati, OH. 6University of Miami, Miller School of Medicine, Miami, FL. 7Stanford University, Stanford, CA. 8Ohio State University College of Medicine, Columbus, OH. 9Temple University, Philadelphia, PA. 10Thomas Jefferson University, Philadelphia, PA. 11Lankenau Medical Center, Wynnewood, PA. 12Moberg Research, Ambler, PA. 13Baylor St. Luke's Medical Center, Houston, TX. 14Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

Objectives: A relationship between reduced brain tissue oxygenation and poor outcome following severe traumatic brain injury has been reported in observational studies. We designed a Phase II trial to assess whether a neurocritical care management protocol could improve brain tissue oxygenation levels in patients with severe traumatic brain injury and the feasibility of a Phase III efficacy study.

Design: Randomized prospective clinical trial.

Setting: Ten ICUs in the United States.

Patients: One hundred nineteen severe traumatic brain injury patients.

Interventions: Patients were randomized to treatment protocol based on intracranial pressure plus brain tissue oxygenation monitoring versus intracranial pressure monitoring alone. Brain tissue oxygenation data were recorded in the intracranial pressure -only group in blinded fashion. Tiered interventions in each arm were specified and impact on intracranial pressure and brain tissue oxygenation measured. Monitors were removed if values were normal for 48 hours consecutively, or after 5 days. Outcome was measured at 6 months using the Glasgow Outcome Scale-Extended.

Measurements And Main Results: A management protocol based on brain tissue oxygenation and intracranial pressure monitoring reduced the proportion of time with brain tissue hypoxia after severe traumatic brain injury (0.45 in intracranial pressure-only group and 0.16 in intracranial pressure plus brain tissue oxygenation group; p < 0.0001). Intracranial pressure control was similar in both groups. Safety and feasibility of the tiered treatment protocol were confirmed. There were no procedure-related complications. Treatment of secondary injury after severe traumatic brain injury based on brain tissue oxygenation and intracranial pressure values was consistent with reduced mortality and increased proportions of patients with good recovery compared with intracranial pressure-only management; however, the study was not powered for clinical efficacy.

Conclusions: Management of severe traumatic brain injury informed by multimodal intracranial pressure and brain tissue oxygenation monitoring reduced brain tissue hypoxia with a trend toward lower mortality and more favorable outcomes than intracranial pressure-only treatment. A Phase III randomized trial to assess impact on neurologic outcome of intracranial pressure plus brain tissue oxygenation-directed treatment of severe traumatic brain injury is warranted.
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http://dx.doi.org/10.1097/CCM.0000000000002619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679063PMC
November 2017

Tonic inhibition of brown adipose tissue sympathetic nerve activity via muscarinic acetylcholine receptors in the rostral raphe pallidus.

J Physiol 2017 12 21;595(24):7495-7508. Epub 2017 Nov 21.

Department of Neurological Surgery, Oregon Health & Science University, Portland, OR, 97239, USA.

Key Points: A tonically active, muscarinic cholinergic inhibition of rostral raphe pallidus (rRPa) neurons influences thermogenesis of brown adipose tissue (BAT) independent of ambient temperature conditions. The tonically active cholinergic input to rRPa originates caudal to the hypothalamus. Muscarinic acetylcholine receptor (mAChR) activation in rRPa contributes to the inhibition of BAT sympathetic nerve activity (SNA) evoked by activation of neurons in the rostral ventrolateral medulla (RVLM). The RVLM is not the sole source of the muscarinic cholinergic input to rRPa. Activation of GABA receptors in rRPa does not mediate the cholinergic inhibition of BAT SNA.

Abstract: We sought to determine if body temperature and energy expenditure are influenced by a cholinergic input to neurons in the rostral raphe pallidus (rRPa), the site of sympathetic premotor neurons controlling thermogenesis of brown adipose tissue (BAT). Nanoinjections of the muscarinic acetylcholine receptor (mAChR) agonist, oxotremorine, or the cholinesterase inhibitor, neostigmine (NEOS), in the rRPa of anaesthetized rats decreased cold-evoked BAT sympathetic nerve activity (SNA, nadirs: -72 and -95%), BAT temperature (Tbat, -0.5 and -0.6°C), expired CO (Exp. CO , -0.3 and -0.5%) and heart rate (HR, -22 and -41 bpm). NEOS into rRPa reversed the increase in BAT SNA evoked by blockade of GABA receptors in rRPa. Nanoinjections of the mAChR antagonist, scopolamine (SCOP), in the rRPa of warm rats increased BAT SNA (peak: +1087%), Tbat (+1.8°C), Exp. CO (+0.7%), core temperature (Tcore, +0.5°C) and HR (+54 bpm). SCOP nanoinjections in rRPa produced similar activations of BAT during cold exposure, following a brain transection caudal to the hypothalamus, and during the blockade of glutamate receptors in rRPa. We conclude that a tonically active cholinergic input to the rRPa inhibits BAT SNA via activation of local mAChR. The inhibition of BAT SNA mediated by mAChR in rRPa does not depend on activation of GABA receptors in rRPa. The increase in BAT SNA following mAChR blockade in rRPa does not depend on the activity of neurons in the hypothalamus or on glutamate receptor activation in rRPa.
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http://dx.doi.org/10.1113/JP275299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5730843PMC
December 2017
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